Antihypertensive Treatment And Renal Autoregulation

Changes in cytosolic Ca2+ is recognized as a pivotal step in mediating smooth muscle contraction. Myogenic control of renal autoregulation is primarily regulated by afferent arteriolar smooth muscle permeability to Ca2+ [86,87]. In accordance, data have revealed that the major vasoconstrictive effect of raised extracellular ionised Ca2+ is a pressure dependent alteration in membrane Ca2+ permeability [88]. The efferent arteriole seems to be less responsive to changes in membrane Ca2+ permeability [87,89], and respond to angiotensin II with a major component of intracellular calcium release. The different signalling mechanisms in afferent and efferent arterioles indicate that the overall autoregulatory response to pressure changes is characterized by a combination of calcium entry and mobilization pathways [90].

Since calcium channel blockers (CCBs) interfere with the influx of Ca2+ they may affect normal renal autoregulation. Studies of dogs [91,92], isolated perfused rat kidneys [88,93], normal rat kidneys [94], hydronephrotic rat kidneys [50,95], remnant rat models [96], models of spontaneously hypertensive rats

[30,97-99] and rat models of diabetes [66] have all shown that CCB's impair renal autoregulation. The effect of CCB's on autoregulation seems to be a dose-dependent inhibition of the vasoconstriction [50,100], which at high doses make the system pressure-passive (abolish autoregulation) [91] and not influenced by renin secretion [93].

In a placebo controlled cross-over study of hypertensive Type 2 diabetic patients without overt nephropathy, therapy with dihydropyridine CCB induced a variable response ranging from no impact to impaired or abolished GFR autoregulation [101]. In fact 38% of these patients showed complete pressure passive vasculature during CCB treatment. The patients with abolished autoregulation of GFR had an increase in GFR during CCB treatment. The enhanced GFR probably reflects a more pronounced vasodilatation of the afferent arteriole during isradipine treatment as compared to patients without this response. The CCB therapy induced vasodilatation enhances the transmission of the systemic BP into the glomerular capillary network resulting in increased glomerular capillary hydraulic pressure (PGC) and GFR.

Animal studies have revealed that angiotensin II receptor antagonists (AIIA) do not change whole kidney autoregulation. In hypertensive Type 2 diabetic patients without overt nephropathy treatment with candesartan cilexetil16 mg o.d does not interfere with normal GFR autoregulation [102].

In animal studies the effect of Alpha 1-receptor blockade on renal autoregulation have been investigated, and no impact on whole kidney autoregulation has been demonstrated [103,104].

Only one study has investigated the effect of beta-adrenergic blockade on renal autoreguation. The results suggested that autoregulation of both GFR and RBF are maintained during propranolol-treatment[105].

Thiazide diuretics decrease systemic vascular resistance, whereas the opposite effect has been demonstrated in the renal vasculature [106]. This results in a decrease in RBF and GFR [106,107]. However there are disagreements on the effect of thiazide diuretics on TGF [108].

Whereas amilorid have no effect on TGF, the acute effects of loop diuretics have been shown to be a dose dependent impairment of both TGF [109] and the myogenic response to changes in renal perfusion pressure [46,110]. However, if loop diuretic is given as a continuous infusion both autoregulation of RBF and GFR are maintained [111,112].

CONSEQUENCES OF DEFECTIVE AUTOREGULATION

The interplay between impaired renal autoregulation on one hand, and systemic BP [20,78,113-116], glomerular mechanical strain [75,76,117-120], different growth hormones [121-124], glomerular permselective properties [125,126], diabetes [69,127,128], albuminuria [81,82,85] on the other hand, and the development/progression of renal histological changes has been studied [84,113,129]. Although the pathogenesis in the different models differs in several aspects, impairment of renal autoregulation might induce the following pathological events: Enhanced transmission of systemic BP into the capillary network, induces wide swings and increased glomerular volume [119,130]. These alterations are further magnified by hypertension [119]. The pressure induced wide swings induces capillary distension and mesangial stretch [131]. Capillary distension induces glomerular epithelial cell hypertrophy with epithelial cell protein droplets, increase in lysosomes, vacuolisation [132], focal and segmental detachment of endothelial and epithelial cells from the basement membrane [85,126], segmental capillary collapse with adhesion to Bowman's capsule [132] and fusion of foot processes [129,130]. These changes combined with increased in PGC [85,125] lead to changes in size- and charge-selective properties of the glomerular capillaries, and results in increase urinary albumin excretion rate [85,126].

Cultured mesangial cells undergoing cyclic stretching demonstrates increased synthesis of extracellular matrix components (collagen, laminin, fibronectin) [75], this synthesis is further increased in the presence of high glucose concentration [117]. Furthermore mechanical stretching increases the synthesis and activation of the prosclerotic molecule transforming growth factor-B [118]. Transforming growth factor-B is found to be a critical mediator in the net accumulation of extracellular matrix especially in cell culture exposed to high glucose [120,124]. The above-mentioned changes are ultimately leading to albuminuria and glomerulosclerosis with hyalinosis [81,116,128].

The importance of glomerular capillary hypertension in the development/ progression of renal disease is supported by the fact that normotension [82,84, 113,114] and reduction of glomerular capillary pressure with antihypertensive treatment [132,134,135] or low protein diet [79,116,126,129,136] protects against the development and progression in renal disease in animals.

The clinical significance of impaired autoregulation of GFR in hypertensive diabetic patients with nephropathy is lack or diminished protection against hyper- or hypoperfusion induced by alteration in blood pressure. In other words, there is increased vulnerability to hypertension or ischemic injuries of glomerular capillaries in diabetic patients with nephropathy.

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