Endothelin is a potent vasoconstrictor, whereas endothelium-derived relaxing factor (EDRF) is a potent vasodilator. Both are produced by the endothelium. Although they have been studied extensively in large vessels, little is known about their actions in renal microvessels. Using microdissected rabbit afferent arterioles, we studied the vascular response to synthetic endothelin and its interaction with EDRF and the effect of endothelin on renin release. Afferent arterioles were either microperfused in vitro at 60 mm Hg to measure luminal diameter or incubated without microperfusion to assess renin release. When added to the bath, 10~1 0 or 10"' M endothelin decreased the diameter by 32±8% (n=7, /><0.01) or 76±7% (p<0.0001), respectively. Pretreatment with jV-nitro L-arginine, which inhibits synthesis of EDRF, decreased basal diameter by 15±1% (/><0.001) and augmented endothelin-induced constriction; decrease in diameter with 10"'° M endothelin was 78±10% (n=4, p<0.01 versus nontreated). T he endothelium produces vasodilators, collectively called endothelium-derived relaxing factors (EDRFs), 1 as well as vasoconstrictors, one of which has recently been identified and named endothelin.2 Although both endothelin and EDRF have been studied extensively in large vessels, little is known about their actions on the glomerular afferent arterioles or about possible interactions between them.In addition to its potent vasoconstrictor action, endothelin has been demonstrated to decrease renin release from rat renal cortical slices, 3 isolated glomeruli, 4 and dispersed rat renal cortical cells. 5 Because endothelin causes the increase in intracellular calcium that is proposed to mediate both vasocon-
To examine whether a hypotensive effect of converting enzyme inhibitor captopril was mediated partly by a potentiation of endogenous bradykinin, a newly synthesized competitive antagonist of bradykinin (B 4147) was used in anesthetized rats. The injection of B 4147 alone (50 and 100 micrograms) elicited significant increases in blood pressure. Although the administration of captopril (1 mg/kg, i.v.) caused a decrease in mean arterial pressure (MAP), the injection of the kinin antagonist (50 and 100 micrograms) after the captopril produced an increase in MAP by an average of 42 and 47% of the initial fall induced by captopril, respectively. The hypertensive effect of B 4147 was enhanced in magnitude and duration after the captopril. These results suggest that an accumulation of endogenous kinins by captopril contributes partly to the acute hypotensive effect of converting enzyme inhibitors in anesthetized rats.
SUMMARY We examined a possible interaction between the calcium entry blocker nifedipine and atrial natriuretic peptide on blood pressure and natriuresis in anesthetized rabbits. The administration of atrial natriuretic peptide (0.05 /xg/kg/min) produced a significant decrease in mean arterial pressure. Similar reductions in blood pressure were obtained during the administration of nifedipine (1.0 //.g/kg/min). Atrial natriuretic peptide produced a consistent increase in glomerular filtration rate that was higher than the increase in renal blood flow; hence, the filtration fraction was significantly elevated. Atrial natriuretic peptide also elicited a significant increment in urine volume and urinary sodium excretion, while nifedipine was devoid of any significant effects on renal hemodynamics and renal excretory function during the experimental period. The administration of atrial natriuretic peptide superimposed on an ongoing infusion of nifedipine resulted in a greater fall of blood pressure than that seen during the administration of atrial natriuretic peptide or nifedipine alone. Sodium excretion was also potentiated, but there were no changes in renal hemodynamics or in the filtration fraction. These results suggest that calcium entry blockers potentiate the vasodepressor and the natriuretic effects of atrial natriuretic peptide but prevent its renal hemodynamic effects. M AMMALIAN atria contain peptides with potent diuretic, natriuretic, and vasorelaxant properties, 1 ' 2 and rat 3 " 6 and human 7 atrial natriuretic peptides (ANPs) have been purified and synthesized. However, it remains unclear whether the natriuretic effect of these peptides is due to their direct action on renal tubules 8 " 10 or to indirect actions through renal hemodynamic changes,"" 15 or to both. The administration of ANP induces a reduction in arterial pressure. Although the mechanism for this action is not clear, it has been reported that the reduction in arterial pressure results from a decrease in either cardiac output 16 " 18 or systemic vascular resistance. 19 -20 On the other hand, it has been proposed that one of the mechanisms in the actions of ANP is an interference with calcium ion movements through the cell membrane. 13 Renal hemodynamic, diuretic, and natriuretic effects of atrial extracts have been reported to be blunted by pretreatment with verapamil or perfusion with low concentrations of Ca 2+ in the isolated, perfused rat kidney. ANP also inhibits vascular contraction induced by angiotensin, norepinephrine, and potassium. 21 Thus, ANPs could influence Ca 2+ influx across the membrane.In the present study, we examined a possible interaction between the Ca 2+ entry blocker nifedipine and a-human ANP on blood pressure, renal hemodynamics, and natriuresis in anesthetized rabbits. Materials and MethodsExperiments were performed on 22 female albino rabbits (weight, 3.0-3.5 kg; age, 6-7 months) supplied by Oriental Kohbo (Tokyo, Japan). The rabbits fasted overnight but were allowed free access to water. Animals were anes...
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