Stimulation of both the systemic and local renin-angiotensin systems participates in the pathogenesis of tissue injury observed in experimental renal disease. However, substantial information demonstrating excessive activation of the renin-angiotensin system in patients with chronic renal disease is not available in spite of the well-established role of this system in the progression of renal damage. This investigation examined the plasma renin activity (PRA) and the ratio of this parameter to the simultaneously measured glomerular filtration rate (PRA/GFR) in normal volunteers (mean values 3.2 ng/ml/h and 3.0 ng/ml/h/100 ml GFR, respectively) and in patients with chronic renal disease (1.6 ng/ml/h and 28.5 ng/ml/h/100 ml GFR, respectively). A mean tenfold increase in the PRA/GFR ratio was observed in patients with chronic renal disease as compared to normal volunteers. The observed augmentation in PRA was not caused by physiologic mechanisms aimed at conserving urinary sodium since a positive correlation was found between PRA/GFR and the fractional excretion of sodium (y = 2.75+ 2.23x; r = 0.781, p < 0.01), as opposed to that of normal controls (y = 5.3- 1.46x; r = -0.640, p < 0.01). Consequently, our results support the existence of inappropriate activation of the renin-angiotensin system in humans with chronic renal disease. Such stimulation might play a critical role in the pathophysiology of advanced renal injury.
The reduction in renal blood flow (RBF) and glomerular filtration rate (GFR) observed after the administration of the carbonic anhydrase inhibitors acetazolamide and benzolamide had been explained as due to activation of the tubuloglomerular feedback mechanism. If correct, pharmacologic blockade of this pathway should prevent the development of renal vasoconstriction with the carbonic anhydrase inhibitors. Thus, the current study evaluates in the dog whole kidney the effect of acetazolamide (20 mg/ kg body weight) in the presence or absence of furosemide (5 mg/kg body weight), a drug which blocks the tubuloglomerular feedback. Acetazolamide resulted in a large increase in urinary bicarbonate excretion accompanied by a significant reduction in GFR (16%) and RBF (18%). By contrast with the effects of acetazolamide, furosemide did not alter GFR and increased RBF. In addition, the loop diuretic induced a large chloruresis without changes in urinary bicarbonate excretion. The infusion of acetazolamide in furosemide-treated dogs resulted in a significant increment in renal bicarbonate excretion and in a significant reduction in the levels of both GFR (28%) and RBF (13%). Therefore, furosemide pretreatment did not block the effects of acetazolamide on renal hemodynamic parameters. Consequently, the acetazolamide-induced reduction in both GFR and RBF cannot ba accounted for by changes in chloride levels in the juxtaglomerular region due to enhanced salt transport in the macula densa/distal nephron. The increased renal vascular resistance observed with acetazolamide might occur by either a direct effect of this agent on the renal circulation or as a result of changes in intrarenal pressure secondary to the inhibition of proximal fluid reabsorption.
To assess whether an intact mechanism of sodium transport in the distal nephron is a prerequisite for the development of a kaliuresis in response to an acute potassium load (0.4 M KCl, l ml/min), the effects of a simultaneous infusion of KCl and amiloride (1 mg/kg/h) were evaluated in anesthetized dogs. A major reduction in potassium excretion mainly due to a sharp decrease in urine + concentration to one tenth of control levels was found after amiloride. The simultaneous infusion of KCl and amiloride resulted in a rapid and major increase in kaliuresis that was accounted for mostly by the rise in urine K+ concentration. The increased kaliuresis after the acute potassium infusion was of similar magnitude when expressed as percent value of control to that previously reported in dogs not receiving amiloride; the absolute rates of K+ excretion, however, were only 2.7 and 7.3% (before and after KCl infusion, respectively) of the values in dogs not receiving amiloride. Our observations suggest that potassium infusion in the intact dog increases kaliuresis primarily as a result of a more favorable chemical gradient of this cation between blood and/or distal tubular cells and urine. Yet, when a chemical gradient is the only driving force of potassium secretion, as was the case in our amiloride-treated dogs, the absolute rate of kaliuresis is very modest. The presence of an unimpaired electrical profile and sodium transport mechanisms in the distal nephron, although not critical for the development of kaliuresis in response to a K+ load, accounts for a severalfold rise in renal potassium excretion above basal levels.
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