The best known manifestation of early dysautonomia in human diabetic neuropathy is a loss of cardiovagal function (7). Similar abnormalities have been described after several months of diabetes in experimental diabetic neuropathy (EDN). In a study of Yucatan miniature pigs, blood pressure (BP) and heart rate where recorded telemetrically (8). After 3 months of diabetes induced with streptozotocin (STZ), there was a marked reduction in respiratory sinus arrhythmia. Beyond 3 months, the impairment of cardiovagal function became more pronounced and was associated with increased resting heart rate. Similar observations were reported in spontaneous diabetes in the WBN/Kob rat (9). Florid hyperglycemia was present by 8-9 months, at which time there was a loss of the circadian rhythm of the heart rate and BP with a loss of the nocturnal fall in BP. Sympathetic failure is typically preceded by evidence of sympathetic overactivity, and much of the resting tachycardia is sympathetic in origin.
Baroreflex sensitivity is typically studied in human subjects as heart period change in response to induced reduction followed by an increase in BP. The agents used are usually intravenous boluses of phenylephrine followed by nitroprusside. This has been studied in experimental diabetes using this paradigm and was found to be significantly reduced (10). These workers studied baroreflex gain in alloxan diabetic rabbits after 12 and 24 weeks of diabetes (10). Baroreflex control of heart rate was evaluated in conscious rabbits by measuring changes in heart rate during phenylephrine-induced increases and nitroglycerin-induced decreases in arterial pressure. In diabetic rabbits, the gain of the baroreflex-mediated bradycardia in response to transient hypertension was significantly reduced after 12 and 24 weeks of diabetes. The gain of the barore-flex-mediated tachycardia in response to induced hypotension was not altered. Baroreflex function in anesthetized STZ rat was reported to be unchanged (11). These workers measured heart rate and renal sympathetic nerve activity. The effect of anesthesia in blunting baroreflex function needs to be considered because there were other changes in these rats including hypertension and resting tachycardia, suggesting that dysautonomia was present.
The neuropathological correlate to these changes in cardiovagal function has been explored (12,13). STZ-induced diabetic (STZ-D) and euglycemic control rats were studied at 8- and 16-week time-points after initiation of the diabetic state. Activation of the afferent limb of the baroreceptor reflex was assessed by measuring the numbers of c-Fos-immunoreactive neurons in the brainstem site of termination of the barore-ceptor afferent neurons, the nucleus of the solitary tract. Initial experiments established that baseline cardiovascular parameters and nucleus of tractus solitarius expression of c-Fos-immunoreactive neurons were not different between diabetic and control rats at either time-point. Phenylephrine-induced activation of baroreceptors resulted in a significant increase in immunoreactive neurons in this nucleus of control rats. Although diabetic rats showed similar pressor responses to phenylephrine (PE), the activation of c-Fos-positive neurons in the solitary nucleus of diabetic rats was significantly attenuated. At both 8 and 16 weeks, STZ-D rats had significantly fewer positive neurons in the commissural nucleus of solitary tract and in the caudal subpostremal region of this nucleus when in comparison with the nondiabetic control animals receiving phenylephrine. These data suggest that diabetes results in reduced activity in the afferent baroreceptor input to the nucleus of solitary tract and are consistent with diabetes-induced damage to baroreceptor afferent nerves. Oxidative injury may be involved as these authors described attenuation of these changes with a-lipoic acid treatment given during the last 4 weeks before the final experiment (13).
Changes in cardiac adrenergic innervation has been described in experimental human diabetic autonomic neuropathy (DAN) (14,15). Schmid et al. (14) evaluated myocardial sympathetic innervation scintigraphically using the sympathetic neuro-transmitter analog C-11 hydroxyephedrine ([11C]HED) and compared with regional changes in myocardial nerve growth factor protein abundance and norepinephrine content after 6 and 9 months in nondiabetic and STZ-D rats. In nondiabetic rats, no difference in [11C]HED retention or norepinephrine content was detected in the proximal versus distal myocardium. After 6 months, compared with nondiabetic rats, myocardial [11C]HED retention had declined in the proximal segments of diabetic rats by only 9% (NS) compared with a 33% decrease in the distal myocardium (p < 0.05). Myocardial norepinephrine content was similar in both groups of rats. At 6 months, left venticular myocardial nerve growth factor protein content in diabetic rats decreased by 52% in the proximal myocardial segments (p < 0.01 vs nondiabetic rats) and by 82% distally (p < 0.01 vs nondiabetic rats, p < 0.05 vs proximal segments). By 9 months, [11C]HED retention had declined in both the proximal and distal myocardial segments of the diabetic rats by 42% (p < 0.01 vs nondiabetic rats), and left ventricular norepinephrine content and nerve growth factor protein were decreased in parallel. Therefore, 6 months of diabetes results in heterogeneous cardiac sympathetic denervation in the rat, with maximal denervation occurring distally, and is associated with a proximal-to-distal gradient of left ventricular nerve growth factor protein depletion, suggestive of heterogeneous cardiac sympathetic denervation complicating diabetes.
In a different preliminary study, cardiac adrenergic innervation was evaluated using 123I-metaiodobenzylguanidine imaging in spontaneous Otsuka Long-Evans Tokushima
Fatty rats, an animal model of spontaneous noninsulin-dependent diabetes mellitus (15). Male rats that were 31-week-old were maintained for 8 weeks with or without 30% sucrose solution as drinking water. Long-Evans Tokushima Otsuka rats served as controls. Plasma and cardiac tissue cathecolamine levels were also determined. Plasma glucose levels of diabetic rats with and without sucrose loading (554 ± 106 and 141 ± 1.5 mg/dL, respectively) were significantly higher than those of control rats (116 ± 3.7 mg/dL). Norepinephrine concentrations in heart and plasma tended to be lower in diabetic rats. Cardiac uptake of 123I-MIBG, calculated as % dose/g of tissue, was significantly lower in diabetic rats than in control rats, indicative of reduced adrenergic innervation.
Peripheral vasoregulation has been studied in the nerves of limbs and the splanchnic-mesenteric bed. Mesenteric arterial function was assessed in constantly perfused preparations isolated from rats 12 weeks after treatment with STZ to induce diabetes (16). Frequency-dependent vasoconstrictor responses to electrical field stimulation of sympathetic nerves were severely attenuated in preparations from STZ-diabetic rats. These results suggest 12 weeks after induction of STZ-diabetes in rats, there is prejunctional impairment of sympathetic neurotransmission and impaired endothelial function of the mesenteric arteries.
A major problem in DAN is excessive splanchnic mesenteric venous pooling, which reduces venous return and contributes to the development of orthostatic hypotension (17). Mesenteric venous pooling may also occur in experimental diabetic neuropathy (18). Veins from rats with STZ-induced diabetes were markedly dilated in vivo compared with veins from control animals. Dilation appeared to be the result of loss of smooth muscle tone. Using quantification by image analysis and double-labeling immunohistochemistry on mesenteric veins, significant reductions in the density of nerve plexuses staining for 5-hydroxytryptamine and tyrosine hydroxylase were shown in vessels from diabetic rats compared with controls. These deficits may contribute to an increase in venous pooling of blood in the splanchnic vasculature of diabetic rats and thus, to inadequate venous return to the heart (18). Adrenergic innervation of vessels is reduced. For instance, 6 weeks of alloxan-induced diabetes mellitus was found to result in a neuropathy of arteries characterized by a 38% reduction in the arterial content of norepinephrine. Norepinephrine release from the nerves measured from electrically stimulated superfused arterial segments was decreased. The cocaine-sensitive accumulation of [3H]-norepinephrine was also reduced, reflecting decreased neuronal uptake (19).
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