Relaxation Techniques

Staying Relaxed

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Relaxation Training Can Improve Glucose Tolerance And Reduce Longterm Hyperglycaemia

A variety of studies over the past two decades support the notion that improving stress management or coping skills can improve self-care, metabolic outcomes and quality of life. For example, several studies of people with type 2 diabetes generally report improved glucose tolerance and reduced long-term hyperglycaemia following biofeedback-assisted relaxation training (BART) - 0. Evidence for the effectiveness of BART in people with type 1 diabetes is less conclusive. While several studies11,12 reported positive effects of BART and related treatments for those with type 1 diabetes, others13-15 found no such benefits. Surwit and Feinglos15 suggest that sympathetic nervous system activity may be altered only in those with type 2 diabetes, making these individuals more sensitive than those with Marrero and colleagues19 found that adolescents who participated in a series of sessions designed to improve diabetes-related coping skills were less depressed, and also tended to have higher...

Assessment of Diastolic Function

Diastolic dysfunction is the hallmark of diabetic cardiomyopathy and echocardi-ography is invariably the most commonly employed test at the present time to reliably assess diastolic functional abnormalities. Left ventricular diastolic filling abnormalities in patients with diabetes do not correlate with the duration of diabetes nor with the presence of other complications such as retinopathy, nephropathy, or peripheral neuropathy. In diabetic cardiomyopathy, the initial abnormality of diastolic filling is characterized by a slowed or impaired myocardial relaxation as is the case for most other cardiac diseases. It should be noted that there is a gradual impairment of myocardial relaxation with normal aging, but in pathological states it is more pronounced than what is usually expected for the patient's age. With continued progression of the disease, LV compliance is reduced and elevation in left atrial pressure results in a restrictive LV filling pattern, which initially may be...

Possible mechanisms of impaired endotheliumdependent vasodilation

Although the data are conflicting, overwhelming evidence presently suggests that DM is associated with an impairment of endothelial vasodilation. The mechanism(s) for this impairment is even less well understood. The most likely initial insult is hyperglycemia. Tesfamarian and colleagues took normal rabbit aortic rings and exposed them to high concentrations of glucose (up to 800 mg dL for 3 hours), resulting in a decrease in endothelium-dependent relaxation, in response to acetylcholine and ADP (52,53). This effect appears to be both concentration and time dependent. As stated earlier, this effect does not appear to be a result of the hyperosmolar effects of glucose because mannitol did not cause any such endothelium-dependent vasodilation (53). Bohlen and Lash (73) demonstrated that hyperglycemia at 300 and 500 mg dL suppressed the vasodilatory response to acetylcholine but not to nitroprusside. Similarly, Williams and colleagues (68) found that acute hyperglycemia attenuated...

Human Studies of Endothelium Dependent Vasodilation

Human studies evaluating the effects of DM on endothelium-dependent vasodilation have yielded some conflicting results, although they generally corroborate those found in animal studies. Saenz de Tejada et al. (60) studied penile tissue excised from men with erectile dysfunction and found that endothelium-dependent relaxation is reduced in the corpus cavernosa of impotent men with diabetes relative to those who are nondiabetic. However, in vivo studies involving human subjects with insulin-dependent diabetes have demonstrated both blunted and normal vasodilatory responses to acetylcholine, methacholine, or carbachol (the latter two being acetylcholine analogs) in forearm resistance vessels in patients with DM (61-63). To evaluate in vivo endothelial function in these vessels, we and others have employed the venous occlusive plethysmography technique. Type 1 diabetic (61) individuals were shown to have impaired endothelium-dependent responses to methacholine in the forearm resistance...

Potential preventive and therapeutic options Oral Hypoglycemic Agents

The cornerstone of DM therapy is optimal glycemic control, because hyperglycemia is the basis of all the metabolic disturbances that occurs in the disease. As shown previously, both in vivo and in vitro elevated glucose levels have been shown to cause abnormal endothelium-dependent relaxation. Lower glucose levels also result in a decrease in insulin levels, which consequently may also improve endothelial function. Therefore, therapy should be directed toward lowering glucose levels and increasing insulin sensitivity. The effect of oral hypoglycemic agents on endothelial function is controversial and probably relates to the agent and model of diabetes being evaluated. Metformin has been shown to improve endothelium-dependent function in the mesenteric arteries of insulin-resistant rats in vitro (165), and the ATP-dependent potassium channel blocker gliclazide ameliorated endothelium-dependent relaxation of the aortas of (alloxan-induced) diabetic rabbits (166). However, clinical...

How can you cope with stress

Relaxation techniques and regular exercise can be helpful parts of stressmanagement programmes. Also, by thinking more appropriate and positive thoughts, you can go a long way towards reducing stress as well. But be realistic and remember that while stress can be managed and controlled, it cannot be eliminated. Your focus, then, should be on using the following 'Helpful tips' to help you to deal better with both the physical and the emotional effects of the stress response. Relaxation benefits you in many ways. First, it can give your body a chance to rest and recuperate. Also, a stronger body can help you to deal better with stress and life in general. Relaxation will help you sleep better, is pleasurable and will increase your feeling of emotional well-being. It can also give you a powerful sense of re-establishing control over your life, despite the presence of a chronic medical problem like diabetes. There are many different types of clinical relaxation techniques, including...

Pathophysiology Of Ed In Diabetes

The flaccid penis is restrained by the tonic contraction of the vascular smooth muscle in the cavernosal ar-terioles and sinusoids under the influence of nora-drenergic sympathetic neurons, allowing only a small amount of blood (1-4mL 100g tissue) to enter the penis. Penile erection is produced by the relaxation of these vessels combined with restriction of venous return, both of which result in engorgement of the sinusoids. It requires intact arterial blood flow via the iliac, femoral, pudendal, cavernosal and helicene arteries. The cavernosal smooth muscle surrounds a complex vascular network consisting of endothelial cell lined sinuses, or lacunae, and the helicene arteries. The corpora are enclosed by a dense non-distensible fibrous sheath, the tunica albuginea, and communicate with each other via a medial septum. Subtunical vessels pierce this sheath, coalescing to form the emissary veins, which provide the venous drainage of the corpora into the dorsal vein (Figure 7.2).

Effective Treatment For Anxiety Disorders In People With Diabetes

Anxiety disorders in some people with diabetes may be responsive to psychotherapy and related treatments. Studies10 of people with type 2 diabetes report improved glucose tolerance and reduced long-term hyper-glycaemia after biofeedback-assisted relaxation training (BART). The effectiveness of BART for those with type 1 diabetes is less clear-cut, although some studies68 have reported positive findings.

Increased Nitric Oxide Inactivation Decreased Bioavailability andor Breakdown of Nitric Oxide

High glucose levels lead to increased NOS activity, making it likely that decreased NO bioavailability through either increased breakdown or other mechanisms is central to the overall decrease in NO activity in the diabetic state. One possible candidate that may modulate NO bioavailability is oxygen-derived free radicals (58,102). These increased free radicals are derived from either increased production or a decrease in the free radical scavenger system. In some animal models of diabetes, a decrease has been seen in levels of endogenous antioxidants including superoxide dismutase (SOD), catalase, and glutathionine peroxidase (103,104). If the aortas of diabetic rats are exposed to free radicals via xanthine and xanthine oxidase, endothelium-dependent relaxation is attenuated further (105). Furthermore, the addition of the free radical scavengers including SOD prevents the impairment of endothelium-dependent relaxation seen in aortic rings of diabetic rats (106). Normal rabbit aortas...

Erectile Dysfunction In Diabetes

In recent years, there has been a seismic change in the recognition and management of diabetic patients with erectile dysfunction (ED). Fundamental to this is the recognition that ED represents a vascular complication of the disease. Cardiovascular disease increases the risk of ED, but ED itself is probably a risk factor for cardiovascular disease. The estimated prevalence of ED in diabetic populations is of the order of 38-55 making it one of the most common complications of diabetes in men. ED in diabetes is most likely to be as a result of a defect in nitric oxide-mediated smooth-muscle relaxation as a consequence of autonomic nerve damage and endothelial dysfunction. Large vessel disease and hypertension may also contribute.

The Kallikrein Kinin Pathway

Bradykinin is generated by kallikreins from their precursor kininogens and it is a potent vasodilator that increases vascular permeability and plays a primary role in inflammation. In noninjured vessels, bradykinin causes relaxation of the VSMC through the synthesis and release of NO from the endothelium (42). In contrast, when the integrity of the endothelium is compromised, bradykinin will act directly in VSMCs promoting their vasoconstriction (43) and fibrosis. The direct action of bradykinin in VSMCs is mediated by its binding to its B2 receptors and subsequent activation and nuclear translocation of p42 and p44 mitogen-activated protein kinase (MAPK) that induces c-fos and c-jun mRNA levels and generation of reactive oxygen species (44,45). Activation of the MAPK pathway leads to an increase in ECM proteins, such as collagen I and fibronectin (45,46). Douillet and associates (46) have shown that activation of transforming growth factor (TGF)-P together with MAPK activation,...

Endothelium Dependent Vasodilatation

Both ACE inhibition and AT1 receptor antagonism improves acetylcholine-induced vasorelaxation in NIDDM subjects (127,128). Treatment of normotensive type 1 diabetics with an ACE inhibitor has also been shown to increase acetylcholine-induced vasorelaxation in (129,130). In these studies, no difference in vasodilatation induced by NO donors (sodium nitroprusside) was observed in diabetic vs control subjects, suggesting that the endothelium dysfunction was related to impairment in the generation of NO rather than an impaired response potential. ACE inhibition may improve endothelium-dependent relaxation by suppressing Ang II effects on vascular NADH NADPH oxidase production of superoxide anions and or vascular insulin signaling (131-133). Although ACE inhibition improves endothelium-dependent vasorelaxation induced by acute aceylcholine infusion (127,130) it did not improve endothelial function in response to flow-mediated dilation (134,135). Therefore, ACE inhibition appears to...

Vascular Effects of Estrogens

Vasoregulation occurs as a balance between the release of relaxing and constricting factors. The predominant relaxing factor is nitric oxide (NO), which is synthesized from the amino acid L-arginine. NO release activates SMC guanylate cyclase, leading to increased cyclic guanosine monophosphate production and vascular relaxation (25). Other relaxing factors include prostacyclin and hyperpolarizing factor, which act through cyclic adenosine monophosphate and potassium channels respectively. The major constricting factors are endothelin-1, thromboxane, and prostaglandin H2 (24).

The prevalence of the metabolic syndrome of cardiovascular risk factors is increasing in many parts of the world

Atheromatous changes lead to impaired arterial relaxation due to reduced production of nitric oxide, a potent vasodilator insulin resistance per se may be associated with endothelial dysfunction. Diabetes mellitus is also associated with hypercoagulability, the procoagulant changes on the endothelial surface favouring thrombosis. Platelet-rich thrombus in the coronary arteries is unstable and likely to rupture, causing acute coronary occlusion. Plaque in patients with diabetes may be particularly vulnerable to rupture due to a high inflammatory cell content and other adverse components.

Increased Comorbidity

Survival is closely linked to residual left ventricular pump function following acute MI. The increased susceptibility to cardiac failure (a 4-fold increase for women in the Framingham Study) is an important factor in reducing survival in diabetics. Two factors may explain the increased incidence of heart failure post-MI. First, more severe and diffuse coronary disease limits the coronary reserve causing noninfarcted segments to be rendered more ischemic by an infarct of comparable size. Secondly, coexistent diabetic cardiomyopathy, which is independent of the coronary disease, impairs myocardial relaxation and contractility.

HMG CoA Reductase Inhibitors

Large clinical trials have determined that hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) significantly reduce cardiovascular morbidity and mortality. Furthermore, lipid-lowering therapy has been shown to improve endothelial function in several studies (204,205). Attempts to ameliorate the impaired endothelium-dependent vascular relaxation that occurs in diabetic patients with dyslipidemia are few and the results mixed. Impaired endothelium-dependent vasodilation in patients with type 2 DM with dyslipidemia has been reported to improve with fibrate therapy (206) (which lowers the serum triglyceride level) but not with simvastatin (206,207). 10. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980 288(5789) 373-376. 36. Bossaller C, et al. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery...

Vascular Contractility and Blood Flow

Changes in NO could also alter vascular contractility and blood flow. In the resistant vessels isolated from diabetic patients and animals, the relaxation phase after acetylcho-line stimulation appears to be delayed (134-137). These impaired vascular relaxation can be restored by PKC inhibitors and mimicked by phorbol ester in normal arteries (137). The inhibition of PKC increased mRNA expression of eNOS in aortic endothelial cells (138). We have observed reduced eNOS expression in microvasculature in Zucker fatty rats, which are the model of insulin resistance (33).

In Patients With Diabetes

Accordingly, when diabetic patients have CHF in association with coronary artery disease, they typically have conventional manifestations of myocardial ischemia (i.e., acute and chronic infarction, stunned and or hibernating myocardium) that result in both systolic failure, characterized by a reduced ejection fraction and ventricular chamber dilatation (when the process is chronic), and diastolic failure, characterized by upward displacement of the diastolic pressure-volume relationship due to slowed or incomplete relaxation and or decreased passive compliance (with or without a decrease in ejection fraction). In addition, remodeling of noninfarcted myocardium in patients with chronic infarction may also contribute to systolic failure. A depressed and even inverted FFR is a common manifestation of ischemic as well as nonischemic dilated cardiomyopathy. In view of the manifestations of and mechanisms underlying diabetic cardiomyopathy discussed above, it is not difficult to envision...

Endotheliumderived relaxing factor

In 1980, Furchgott discovered that the endothelium is responsible for the vasodilator action of acetylcholine (10). This finding has fostered a great number of investigations on the role of the endothelium on the initiation and development of vascular disease and its subsequent clinical sequelae. Further research indicated that acetylcholine released a soluble factor from the endothelium termed EDRF and that this substance was released by other agents including bradykinin, substance P, serotonin, and adenosine triphosphate (ATP), and shear stress (11). Ignarro used spectral analysis of hemoglobin to prove that EDRF was identical to NO (12). Shortly thereafter, Palmer and colleagues concluded that NO was derived from the terminal guanidino nitrogen of the amino acid L-arginine. The production of NO is catalyzed by the family of enzymes known as NO synthase (NOS) (13). Three isoforms of NOS have been identified endothelial NOS (eNOS), neuronal NOS (nNOS), and cytokine-inducible NOS...

Glomerular Cell Response To Mechanical Strain And High Glucose Cytoskeletal Changes

Cells respond to changes in the mechanical environment by directionally reorienting their cytoskeleton and modifying their shape, presumably to adapt to a more favorable conformation for structural stability and function. Repetitive mechanical changes of opposing sign (stretch relaxation) demand drastic cytoskeletal and ECM remodeling activity. In these circumstances, there is a change in cell orientation that seems to be universal to all adherent cells. Cyclic stretching of osteoblasts, fibroblasts, and vascular endothelial and smooth muscle cells, uniformly results in cell elongation with perpendicular alignment of the long cell axis to the direction of the stretching force 65-67 . In addition, actin filaments are reorganized, changing from a random network distribution to one of dense bundles of stress fibers arranged in the direction of the long cellular axis. Similarly, shear stress, a different form of mechanical strain, induces the realignment of endothelial cells and their...

Diabetic Cardiomyopathy Does It Exist

The occurrence of dilated cardiomyopathy in patients with diabetes who do not have coronary disease or hypertension is well documented. In an individual patient, it is impossible to know whether this represents a specific diabetic cardio-myopathy or simply the chance occurrence of two common diseases. Stronger evidence of a specific, underlying cardiomyopathic process comes from studies of patients with diabetes, typically younger, who do not have clinical signs or symptoms of heart disease. These subjects have normal contraction patterns but a high incidence (on the order of one-third to one-half) of abnormal mitral inflow patterns detected by Doppler echocardiography (e.g., increased E to A ratios) consistent with slowed myocardial relaxation and or decreased compliance. In addition, they have on average a larger myocardial mass than age-matched controls and frequently have increased myocardial ultrasonic backscatter. The latter is a nonspecific finding that can be caused by...

Genitourinary Autonomic Neuropathy

It has been reported that 50 of diabetic men and 30 of diabetic women have some degree of sexual dysfunction (106,107). Retrograde ejaculation reflects loss of coordinated internal sphincter closure with external vesicle sphincter relaxation during ejaculation and may become apparent as cloudy urine postcoitally, reflecting the presence of sperm. Diagnosis of retrograde ejaculation entails documentation of a low sperm count in the ejaculate. Impotence is commonly reported in DAN patients and usually occurs in the presence of other systemic manifestations of either somatic or autonomic neuropathy, but an attempt should be made to exclude other causes, including psychogenic, endocrine, vascular, iatrogenic (secondary to drugs, including antihypertensives, anti-cholinergics, antidepressants, and narcotics). Hormonal abnormalities should be screened by serum testosterone and prolactin levels. Nocturnal penile tumescence monitoring may be necessary to differentiate organic from psychogenic...

Role For Pkc Activation

The experimental evidence obtained with various PKC inhibitors as well as the dia-cylglycerol complexing agent cremophor by several groups (81,86-88) suggests the detrimental role of PKC activation in vasa nervorum. The PKC inhibitors, WAY151003, chelerythrine, and LY333531 as well as cremophor prevented or reversed NBF and conduction deficits (81,86,87), and the PKC inhibitor Ws-indolylmaleimide-1HCl corrected acetylcholine-mediated vascular relaxation in epineurial arterioles in the STZ-diabetic rat model (88). The role for neural PKC in the pathogenesis of PDN remains unclear. However, recent findings suggest that neuronal PKC might be related to diabetes-associated changes in expression, phosphorylation, and function of the vanilloid receptor 1, known to play an important role in diabetic neuropathic pain (89). The novel PKC-P isoform selective inhibitor JTT-010 was found to ameliorate nerve conduction deficits, hyperalgesia (formalin test in its first phase), and hypoalgesia...

Transurethral Alprostadil

Alprostadil was first licensed for the treatment of ED by intracavernous injection. Alprostadil, the synthetic preparation of the naturally occurring prostaglandin E1 acts by initiating the erection. In contrast to sildenafil it initiates the relaxation of cavernous smooth muscle to bring about erection. This drug has been incorporated into a pellet that can be given by intraurethral application Medical Urethral System for Erection (MUSE) . Patients need to be instructed in the use of MUSE which is introduced into the urethra with a disposable applicator. The patient first passes urine to act as a lubricant to facilitate the passage of the applicator and the absorption of the drug. Absorption of the drug is also facilitated by the patient rolling his penis between the palms of his hands. Some patients find that a constrictive ring around the base of the penis enhances the efficacy. The erection takes about 10 minutes to develop and the dose range varies between 125 and 1000 g although...

Inhibitors of AGE Production

As discussed earlier, one possible mechanism of endothelial dysfunction in both type 1 and type 2 DM is the inactivation of NO by oxygen-derived free radicals. There is also a decrease in levels of endogenous antioxidants including superoxide dismutase and catalase in animal models of diabetes (172). Furthermore, several clinical studies have reported a decrease in endogenous vitamin C (173,174) and E (173,175) levels in both type 2 and type 1 DM. Any means of decreasing the oxidative stress has the potential to improve endothelium-dependent vasodilation. Timimi et al. (176) and Ting and coworkers (177) (Fig. 6) found that intra-arterial infusion of vitamin C improved endothelium-depen-dent (but not endothelium-independent) relaxation in patients with type 1 and type 2 diabetes, respectively. Furthermore, the intra-artrial infusion of ascorbic acid restored the impaired endothelial vasodilation in healthy subjects exposed to hyperglycemic clamp (178).

Types of Stress Tests

Assessment of diastolic function by measuring the isovolumetric relaxation time, the deceleration time, the E A ratios, and the transmitral gradients can help determine the degree of diastolic impairment and serve as a baseline for therapeutic endeavors. These are defined as follows 1. The isovolumetric relaxation time is the time interval between closure of the aortic valve and the opening of the mitral valve.

Effects of HRT on Endothelial Function in Postmenopausal Women With Diabetes

Ation in a small cohort of postmenopausal women with diabetes before and 6 months after transdermal 17 -estradiol (80 mg twice weekly) in combination with oral nonethisterone (1 mg daily). The authors concluded that this particular HRT regimen had potentially beneficial effects on vascular relaxation. Data were consistent with improvements in endothelial function, vascular smooth muscle function, or both. Abnormal responses to endothelium-independent agonists have been reported in type 2 diabetes by other workers (165) but there have been no previous reports of augmented endothelium-independent responses after HRT in women with or without type 2 diabetes.

Mechanisms Of Renal Upregulation Of The Tgfp System In The Diabetic State In Relationship To Other Mediators

In addition to the metabolic factors listed above, hemodynamic and mechanical forces are operative in the diabetic state. The cyclical stretch relaxation of mesangial cells in culture, which closely mimics increased glomerular pressure in vivo 114, 196, 197 , has been associated with increased synthesis of TGF-P and extracellular matrix molecules. Fluid shear stress increases message expression and synthesis of the active form of TGF-P in cultured bovine aortic endothelial cells 198 .

Intrinsic Neural Control

Abnormalities of nNOS have been observed in animal models of diabetes. Stomachs of spontaneously diabetic rats and rats with streptozotocin-induced diabetes exhibit decreased NO-mediated relaxation of gastric muscle strips and decreased expression of nNOS. Watkins et al. (33) have subsequently demonstrated that nNOS protein and mRNA are depleted in the pyloric myenteric neurons of diabetic mice. Insulin treatment restores pyloric nNOS protein and reverses the delay in gastric emptying observed in such mice. Sildenafil, a cGMP phosphodiesterase inhibitor augments NO signaling and also reverses delayed gastric

Pathophysiology of coronary artery disease in type diabetes see also Chapter

It is generally accepted that the endothelium plays a central role in the initiation of early atherosclerosis (De Vriese etal., 2000). Particularly important is nitric oxide, which regulates vascular relaxation and structure. In addition, the endothelium synthesises other bioactive substances endothelin-1, angiotensin II, prostaglandins and other reactive oxygen species. In type 2 diabetes the production of nitric oxide is impaired because of insulin resistance, hyperglycaemia and elevated levels of free fatty acids (FFA) (Inoguchi etal., 2000). In contrast, the production of endothelin-1 is increased due to hyperglycaemia (Hattori etal., 1991) and hyperinsulinaemia (Ferri etal., 1995).

Practical description

Acetylcholine is the most commonly used vasodilator for assessing endothelium-dependent vasodilation. It is believed that the vasodilatory effect of acetylcholine is to bind to the muscarine receptor and activate endothelial NO-synthase, resulting in vascular relaxation. Although acetylcholine-induced vasodilation is mainly caused by endothelial cell NO release, potassium-ATP channels also play a role in acetylcholine induced vasodilation (Higashi & Yoshizumi 2003).

Genital Sexual Arousal Disorders Among Women with Diabetes

Data from epidemiological studies support the finding that sexual arousal disorder is the most commonly reported sexual problem among diabetic women (9, 19, 23, 25, 26). In physiological terms, genital sexual excitement is characterized by pelvic vasocongestion and swelling of the external genitalia, including clitoral and vaginal engorgement (106-109). Clitoral engorgement is a highly complex phenomenon, mainly characterized by hemodynamic modifications consequent to local smooth muscle relaxation. At least in an animal model, diabetes mellitus produces significant adverse effects on the hemodynamic mechanism of clitoral engorgement and leads to diffuse clitoral cavernous fibrosis (50). Indeed, diabetes is associated with atherosclerosis and microangiopathy, leading to an impairment of the clitoral hemodynamics. This might imply that decreased sexual arousal in diabetic women may result from hemodynamic-driven structural changes in the clitoris. Although controversial, vaginal...

Normal Endothelial Cell Function

The EC produces NO by way of eNOS activation resultant NO diffuses into the VSMC and activates guanylate cyclase, which in turn produces cGMP. cGMP reduces myosin light chain kinase activation, thus inducing muscle relaxation and thereby vasodilation. The continuous production of basal NO is responsible for the regulation of blood pressure. In addition to its vasodilating properties, NO contributes to the prevention of atherogenic process through cGMP-dependent inhibition of platelet aggregation and by regulation of VSMC proliferation (50). In addition to regulating vascular tone, NO is also involved in vascular homeostasis and neuronal and immunological functions.

Types of Neuropathy and Treatment

If these therapies aren't effective, ask for a referral to a pain clinic. There are also less conventional methods to treat the pain. Biofeedback training, hypnosis, relaxation exercises, acupressure, acupuncture, and use of a TENS (transcutaneous electrical nerve stimulation) unit have all been effective for some people.

Duration of Diabetes Diabetes Related Complications and Diabetes Control

A recent study by Kim et al. (48) supported these findings. Indeed, they observed that in strepto-zotocin-treated female rats, the vaginal blood flow response to pelvic nerve stimulation was significantly reduced as compared with healthy controls. Moreover, the histological examination of vaginal tissue from diabetic animals showed reduced epithelial thickness and atrophy of the muscular layer. Diabetic animals also had reduced vaginal levels of endothelial nitric oxide synthase and arginase I, but elevated levels of cyclic guanosine monophosphate-dependent protein kinase (three key enzymes that regulate smooth muscle relaxation). These alterations were accompanied by a reduction in both estrogen receptor alpha and androgen receptor expression in nuclear extracts of vaginal tissue from diabetic animals. The authors reported that similar changes were also found previously in ovariect-omized animals therefore, they hypothesized that diabetes may lead to multiple disruptions in sex...

Unique Characteristics Of Coronary Artery Disease In The Diabetic Population

In addition to a greater extent of epicardial coronary artery disease, there may be generalized endothelial dysfunction and abnormalities of small vessels in the diabetic patient. Dilatation of the coronary arteries in response to hypoxia is mainly dependent upon endothelium relaxing factor (2,35). Impaired endothelium-dependent relaxation is present in the vascular beds of diabetic patients, including coronary arteries (36-38). The auto-regulatory responses in the microcirculation also appear to be impaired (2).

Experimental Erectile Dysfunction

Experimental erectile dysfunction in experimental diabetes and aging has been studied in the rat (40-42). Rat studies typically consist a measurement of intracavernous pressure in response to electrical stimulation of the cavernous nerve in normal and diabetic rats (43). The pathophysiology of erectile dysfunction in DAN appears to mimic the human condition wherein it is vasculogenic resulting in engorgement of corpora cavernosa and is because of a deficiency of nitric oxide (40,44-46). In the penile corpora cavernosa, nitric oxide is produced mainly by the activation of the neuronal nitric oxide synthase (NOS) in the nerve terminals and, to a lesser extent, by endothelial NOS in the lacunar and vascular endothelium (40,46). Nitric oxide stimulates guanylate cyclase cGMP activation of phosphokinase G reduction of intracellular Ca2+ relaxation of the smooth muscle cells penile engorgement. Support for this concept in the rat derives from a number of observations. Nitric oxide...

Magnetic Resonance Imaging MRI and spectroscopy

Mri Spectroscopy Show Muscle

Of this macroscopic magnetisation, in a process called excitation. After switching off the RF waves, magnetisation returns to the thermal equilibrium in a time and direction dependent manner. This process is called relaxation and the changing macroscopic magnetisation induces an electrical signal in the receiver coil. Signal intensity in MRI is dependent not only on the proton density in the volume of interest, but also on the interaction between tissue protons and externally applied RF waves during the excitation, and on the interaction between nuclei within the tissue during the relaxation. The different physical properties of protons within water and fatty acid molecules result in strong differences in the time and phase dependent behaviours of these nuclei during the relaxation, producing a relaxation and phase dependent contrast for magnetic resonance imaging. T -relaxation based contrast can be used for volumetric measurements of subcutaneous and intra-abdominal fat...

Extrapancreatic Effects Of Sulfonylureas And Meglitinides

Some studies, such as the University Group Diabetes Program (UGDP) (23) in 1976, suggested that sulfonylureas are associated with a poor outcome after a myocardial infarction, but these studies have been heavily criticized (24), and do not correspond with current standards. Theoretically, sulfonylureas might close ATP-dependent potassium channels possessing a SUR2a b subunit, which are present on cardiomyocytes and coronary and arterial vessel smooth muscle cells, thereby preventing adaptive changes and relaxation of cardiomyocytes and vascular smooth muscle cells in response to hypoxia. This would occur by preventing smooth muscle cell hyperpolarization caused by potassium efflux, due to the closure of KATP-channels by the sulfonylurea, which might enlarge the infarct area. Although sulfonylureas bind the SURl on beta cells with much higher affinity than SUR2a b, some activation appears possible. Glimepiride and nateglinide show much lower affinity for the cardiac SUR2b sulfonylurea...

Endothelium Dependent Vasodilation in Animal Models

Similarly, in an animal model of type 2 diabetes, the Zucker rat, which is characterized by hyperglycemia because of insulin resistance, abnormal endothelium-dependent va-sodilation is also seen (46). The early vascular dysfunction that occurs in type 1 diabetic animal models can be prevented by insulin therapy (50,51). The abnormal endothelial cell function that develops appears to be as a result of hyperglycemia rather than any other metabolic disturbance. This has been demonstrated by in vitro incubation experiments in which isolated arteries exposed to elevated glucose concentrations have similar decreases in endothelium-dependent vasodilation (52,53). This effect does not seem to be as a result of the hyperosmolarity because similar concentrations of mannitol have no effect on endothelium-dependent relaxation (52). The decreased endothelium-dependent vasodilation that occurs may be as a result of decreased synthesis or release of NO, decreased Early in the course of experimental...

Physiology and Pathophysiology

Guanil Cyclase

Penile erection is a neurovascular event modulated by psychological factors and hormonal status depending on appropriate trabecular smooth muscle and arterial relaxation in the corpus cavernosum (Fig. 1). On sexual stimulation, nerve impulses cause the release of cholinergic and non-adrenergic non-cholinergic (NANC) neurotransmitters that mediate erectile function by relaxing the smooth muscle of the corpus cavernosum. A principal neural mediator of erection is NO which activates guanil cyclase to form intracellular cyclic guanosine monophosphate (GMP), a potent second messenger for smooth muscle relaxation. Cyclic GMP in turn activates a specific protein kinase, which phosphorylates certain proteins and ion channels, resulting in a drop of cytosolic calcium concentrations and relaxation of the smooth muscle. During the return to the flaccid state, cyclic GMP is hydrolyzed GMP by phosphodiesterase (PDE) type 5. In the corpus cavernosum four PDE isoforms have been FIGURE 1 Mechanisms...

Etiology Of The Afferent Arteriolar Dilation Underlying Diabetic Hyperfiltration

H2o2 Redutcion

The best-documented vascular consequence of oxidative stress in T1D is a decreased half-life of NO (accelerated degradation as a result of ONOO- formation). The resulting impairment of agonist-induced NO-dependent relaxation in aorta and other vascular beds is normalized by antioxidant maneuvers (22-24). Agonist-induced endothelium-dependent relaxation is impaired in small intrarenal arteries from STZ rats, apparently as a result of O2'-, OH , and prostaglandin endoperoxide opposition of the effects of NO (25). O2'--dependent processes are also implicated in impaired endothelium-dependent relaxation of afferent arterioles isolated from diabetic rabbits (26). As illustrated in Fig. 3, renal arteriolar constrictor responses to NOS inhibition are attenuated in kidneys from STZ rats, but restored by acute exposure to SOD (27). This observation indicates that O2- production diminishes the tonic dilator influence of endogenous NO on the renal microvasculature. The O2--dependent decrease in...

Stress And Blood Glucose Control

Evidence from animal models also suggests a role for stress in the onset of type 2 diabetes (45). Ineffective coping (e.g., avoidance, denial, detachment, anger) has been shown to be associated with poorer metabolic control in diabetes and adaptive coping (e.g., active problem solving and ability to obtain social support) with a stress-buffering role (46), highlighting the role of patient perceptions of stressful events. It is unclear whether relaxation training (e.g., biofeedback) produces glycemic benefits in type 2 diabetes (47). Generally, there is a paucity of studies on stress in type 2 diabetes.

Effects of Estrogen on Endothelial Function

ERT also provides insights into NO regulation by estrogen. Thus, endothelium-depen-dent vasodilation of the branchial and coronary arteries is enhanced after ERT in postmenopausal women and levels of plasma NO and NO metabolites are increased (36,37). It is of interest that inclusion of progesterone in postmenopausal HRT may blunt the effects of estrogen on endothelial NO production (38). Similar effects of enhanced endot-helial function have been observed after ERT in young women with premature ovarian failure or following ovariectomy and in young women receiving oral contraception (33,39). Furthermore, a case has been reported of a young man with nonfunctional ERa as a result of mutation of the ER gene (40). The man was found to have impaired branchial endothelium-dependent relaxation and early coronary calcification supporting the view that ERa is important for endothelial NO release. environment, ultimately leading to eNOS stimulation (43-45). Additional mechanisms for nongenomic...

Insulin Resistance and Nitric Oxide

Insulin mediates NO production through specific pathway, which includes insulin receptor tyrosine, phosphatidyl inositol 3-kinase and its downstream effector, akt (118,119). This increase in NO release, in turn, results in vasodilation (120). This endot-helial-dependent relaxation is accompanied by an increase in glucose transport and metabolism (121,122) and may also potentially result in the removal of postprandial glucose. Therefore, endothelial dysfunction may lead to insulin resistance. This argument is further strengthened by the findings of Petrie and coworkers (123), which showed a correlation between basal endothelial function and insulin sensitivity in healthy controls. This relationship was not seen with either nitroprusside or acetylcholine, suggest

Depression Treatment Considerations For Diabetic Patients

Interventions into the management of diabetes has been demonstrated to improve metabolic control as well as quality of life. To date, however, there has been little empirical support for the successful use of non-pharmacological therapies (psychotherapies, relaxation) for the management of depression specifically in persons with diabetes. Non-pharmacologic interventions are particularly useful in the initial management of patients who may have mild depressive symptoms and are concerned about taking medications or in older adults who may take multiple medications for co-occurring illnesses.

Erectile Dysfunction in Diabetes and Its Treatment

The penile nerve system is both autonomic and somatic and the relaxation of the smooth muscle tissue of the corpus cavernosum results from the interaction of three systems adrenergic, cholinergic and VIPergic. Other factors like nitric oxide (NO) initially called endothelium-derived relaxing factor (EDRF) and produced by constitutive nitric oxide synthetase (cNOS) which increases the concentration of intracellular cyclic guanosine monophosphate (cGMP) may well be involved in the relaxation of the smooth muscle in the corpus cavernosum. As we know, the earliest studies into NO production by cNOS were carried out on bioptic samples taken from the corpus cavernosum tissue of impotent diabetics who presented reduced acetylcholine vasodilation. The reduced NO production and consequent reduction in intracellular cGMP probably leads to an increase in intracytosolic calcium that is responsible for the contraction in smooth muscle cells. In diabetics there may well also be a reduction in the...

Stress management

Teaching people with diabetes methods for reducing stress and tension, including diaphragmatic breathing, muscle relaxation or meditation (see page 47 above). In addition, stress inoculation involves having people visualise stressful situations while practising their relaxation skills, therefore allowing them to practise managing stressors in a safe environment and improving their confidence in coping with stressful situations. These techniques are designed to reduce tension and associated changes that occur in your body in response to stressors and have been found to be very effective for numerous health-related problems, including diabetes.


Reduce their salt intake and consider other non-pharmacological measures such as stress reduction and relaxation. However, most patients will still need medication. Angiotensin converting enzyme (ACE) inhibitors are the first-line treatment, followed by beta blockers and thiazides, then calcium channel antagonists. Once-daily preparations are more likely to be remembered than multiple-dosage regimens. Obviously, all blood pressure lowering agents are capable of causing hypotension particularly postural hypotension which may be worse in patients with autonomic neuropathy. This should be sought by asking about postural dizziness or light-headedness, and by measuring lying and standing blood pressures. ACE inhibitors, beta blockers, and diuretics can all cause fluid or electrolyte imbalance. Many hypotensive agents interact with other drugs and this should be checked before prescribing. They can cause erectile dysfunction.


The hemodynamic glomerular injury of diabetes is closely related to the loss of afferent arteriole autoregulation of pressure, the presence of glomerular hypertrophy and the occurrence of large moment-to-moment oscillations in capillary wall tension. This mechanical injury is possible due to the elasticity of the glomerular structure permitting the repeated stretch relaxation of the cellular component. The cellular response to this mechanical stimulus is one leading to the enhanced activity of signaling cascades and overexpression of growth factors and the accumulation of extracellular matrix. These processes are further aggravated by an environment of high glucose concentration which, in turn, also induces the disassembly of the F-actin cytoskeleton, weakening of the structure-stabilizing forces and further amplification of mechanical strain (Fig. 2).


Numerous animal and clinical studies have demonstrated that hypertension reduces endothelium-dependent relaxation (149-153). Two studies have shown that basal production or release of NO is decreased in hypertensive patients (63,154). The possible mechanisms underlying the endothelial vasodilator dysfunction associated with hypertension include L-arginine deficiency (155), decreased muscarinic receptor function (156,157) abnormalities in signal transduction (158), or NO inactivation by oxygen-derived free radicals (159-162).

In Vitro Studies

In vitro studies have shown that AGEs have complex properties that promote vascular disease including an ability to form chemically irreversible intra- and intermolecular crosslinks with matrix proteins in the vascular wall increasing arterial rigidity (5,138). Also, the interaction of AGEs with endothelial cell receptors induces increased vascular permeability, increases procoagulant activity, migration of macrophages and T-lympho-cytes into the intima (initiating a subtle inflammatory response), and impairment of endothelium-dependent relaxation (139). Impaired endothelial relaxation and endothe-lial migration of monocytes are generally considered to be among the first steps in atherogenesis. At the same time, AGE-induced activation of monocyte macrophages leads to the release of a variety of inflammatory cytokines and growth factors, which induce over production of extracellular vascular wall matrix (5,140).

Nitric Oxide

Impairment of NO-mediated vasodilation has been shown in both type 1 and type 2 diabetes (17,18) and it may contribute to the accelerated development of macrovascular disease in diabetes. Recent studies using an inducible NO synthase (iNOS)-deficient mice shows that there is decreased response to acetylcholine in wild-type diabetic animals when compared to nondiabetic animals. No difference in response was, however, observed in the diabetic iNOS-deficient mice thus giving the first direct evidence that impairment of endothelium-dependent relaxation during diabetes is dependent on iNOS expression (19). Oxidized lipoproteins, which are present in increased levels in diabetes, may be behind the reduced NO activity in diabetes, as shown by several studies (20-22). Interestingly, NO may also influence lipoprotein oxidation. If cells are stimulated to express active NOS, their oxidative capability is lost (23). On the other hand, if conditions in the vessel wall favor the release of...

In Renal Disease

Patients with diabetes have an increased risk of cardiovascular events (Table 2) and heart failure (Table 3). Early in the course of diabetes, cardiac fibrosis and hypertrophy occur, leading to diastolic dysfunction, characterized by impaired relaxation and a stiff ventricle (47,48). Anemia has the potential to exacerbate cardiac dysfunction in diabetes. In normal subjects, a fall in Hb from 140 to 40 g L evokes an adaptive response in the heart. In the short term, oxygen extraction increases from 24 to 31 and cardiac output increases from 3 to 5.5 L min m2 (49). In the long term, these adaptive changes may lead to left ventricular hypertrophy (LVH), a known risk factor for adverse clinical outcomes. Several observational studies have demonstrated that anemia in combination with severe renal insufficiency (50,51) or cardiac failure (52) is an independent risk factor for worse cardiovascular outcomes (Table 2). For example, in a Canadian study of patients with ESRD, a decrease in Hb...

Diet and exercise

Behavioural interventions have also been examined. A variety of techniques have been employed and have been shown to be effective compared to conventional treatment, usually dietary advice and medical follow up. Cognitive behavioural therapy, relaxation therapy and family therapy all appear to be effective (Warschburger et al., 2001 Duffy and Spence, 1993 Epstein et al., 1985c Senediak and Spence, 1985). There is also the suggestion that therapies involving the parents as the main motivators of change are more effective than treatments which are predominantly child focused. However, it is important to note that the great majority of these studies have involved younger children and it is uncertain whether these results could be extrapolated to emotionally challenging adolescents with weight problems.

With Fetal Growth

So far there are no published studies that investigate if protocols incorporating fetal AC or another growth parameter could lower the frequency of growth disturbances in pregnancies with preexisting diabetes. The need for insulin therapy is obvious in women with type 1 or type 2 diabetes but the need to individualize glycemic targets can be debated. Analogous to GDM, in preexisting diabetes, if there are identical glucose targets in every women, then we are faced with the same problem that the same degree of hyperglycemia may have different effects on the fetus. In the absence of vascular diabetes-related complications or pregnancy-induced hypertension that might cause growth retardation by reduced placental flow, a fetal AC < 10th percentile could be a sign of undernutrition of the fetus due to strict glucose control. In this case moderate relaxation of glucose control should be considered to prevent further impairment of growth and delivery of a SGA newborn. However, in another...

Fecal Incontinence

Anorectal function can be evaluated by anorectal manometry and tests of continence for solids and liquids. Anorectal manometry gives information about the maximum basal sphincter pressure, the maximum squeeze sphincter pressure, and the rectoanal inhibitory reflex (inflation of a balloon in the rectum causes a reflex relaxation of the internal anal sphincter). Continence for solids and liquids can be directly assessed simulating the stress of stools with a solid sphere or with rectally infused saline. Unfortunately, these tests do not appear to be very helpful in making therapeutic decisions. Appropriate treatment of incontinence in diabetics includes optimizing blood sugar control and biofeedback therapy. Surgical intervention should be reserved for cases refractory to medical treatment or for those patients with rectocele or obstetrical injury (95). The clinical outcome of surgical treatment of incontinence is far from uniform and caution is advisable before recommending it.

Ciq Kidney Disease

Becker B, Yasuda T, Kondo S, Vaikunth S, Homma T, Harris RC. 1998. Mechanical stretch relaxation stimulates a cellular renin-angiotensin system in cultured rat mesangial cells. Exp Nephrol 6 57-126. Harris RC, Haralson MA, Badr KF. 1992. Continuous stretch-relaxation in culture alters rat mesangial cell morphology, growth characteristics, and metabolic activity. Lab Invest, 66 548-554. 129. Homma T, Akai Y, Burns KD, Harris RC. 1992. Activation of S6 kinase by repeated cycles of stretching and relaxation in rat glomerular mesangial cells. J Biol Chem, 267 23129-23135.

Erectile Dysfunction

Neuroendocrine Control Penile Erection

Penile erection is a neurovascular event modulated by psychological factors and hormonal status depending on appropriate trabecular smooth muscle and arterial relaxation in the corpus cavernosum. On sexual stimulation, nerve impulses cause the release of cholinergic and NANC neurotransmitters that mediate erectile function by relaxing the smooth muscle of the corpus cavernosum. A principal neural mediator of erection is nitric oxide (NO), which activates guanil cyclase to form intracellular cyclic guanosine monophosphate (GMP), a potent second messenger for smooth muscle relaxation (Fig. 1). Cyclic GMP in turn activates a specific protein kinase, which phosphorylates certain proteins and ion channels, resulting in a drop of cytosolic calcium concentrations and relaxation of the smooth muscle. During the return to the flaccid state, cyclic GMP is hydrolyzed GMP by phosphodiesterase (PDE) type 5 (2,9). In the corpus cavernosum four PDE isoforms have been identified (types 2-5), but PDE...

Low Back Pain

If muscle relaxation is the clue, we must ask why these muscles spasm so easily. Any muscle spasms if you irritate or injure it suddenly. In fact, your whole body spasms and flinches if a sliver or bit of broken glass is in your shoe. If you remove these objects, the leg can walk normally.