Inhibition of furosemide-induced increases in plasma renin activity by amiloride.

Abstract

The effect of the potassium-sparing diuretic, amiloride, was studied in conscious rabbits bearing chronic indwelling cannulas to assess whether its reported in vitro kallikrein-inhibiting activity may produce a suppressive effect on furosemide-induced renin secretion similar to that previously demonstrated with another kallikrein inhibitor, aprotinin. Furosemide elicited a rapid and persistent rise in plasma renin activity (PRA), but pretreatment of the same rabbits with a 15-minute intravenous infusion of amiloride, which amounted to 1 mg/kg and commenced at 30 minutes before furosemide, completely prevented this rise. Amiloride also prevented furosemide-induced kaliuresis without an attenuation of the diuretic or natriuretic response and did not alter plasma potassium concentration in the absence of any change in external potassium balance, indicating that suppression of the PRA response is due neither to prevention of extracellular fluid volume contraction nor to the known suppressive effect of hyperkalemia. Mean arterial pressure tended to fall slightly but not significantly with or without amiloride pretreatment. On the basis of these findings and those of our antecedent study with aprotinin, we conclude that the striking similarity between the suppressive effects of two dissimilar inhibitors of kallikrein on pharmacologically evoked renin secretion is consistent with the hypothesis that renal kallikrein participates in the mechanism of renin secretion in vivo. (Hypertension 5: 706-711, 1983) KEY WORDS • renin secretion conscious rabbits kallikrein-kinin system • natriuresis • antikaliuresis U RINARY kallikrein of renal origin 1 has been reported to stimulate renin release in vitro directly by superfused rat renal cortical slices, 2 isolated rat glomeruli, 3 and isolated perfused hog kidneys. 4 In our earler attempt to investigate whether inhibition of kallikrein activity might suppress renin secretion in vivo, 5 we found that both the natriuresis and rise in plasma renin activity (PRA), used as an index of increased active renin secretion, in response to intravenous furosemide administration were markedly attenuated in conscious rabbits by a continuous infusion of aprotinin, a polyvalent bovine proteinase inhibitor that inhibits kallikrein. 6 Since prevention of urinary loss by continuous fluid replacement in our experiment 5 and ureterovenous anastomosis 7 did not prevent the stimu-latory effect of furosemide on PRA, we interpreted our results as indicating that the suppression of the furose-mide-induced rise in PRA by aprotinin was probably not secondary to suppression of natriuresis. However, because aprotinin also inhibits other serine proteases besides kallikrein, 1 6 our observations are only consistent with, but do not prove, the possibilities that renal kallikrein may mediate the release of active renin and participate in the natriuretic action of furosemide. As a logical sequel, we have therefore sought to obtain cor-roborative evidence under similar conditions by using amiloride, an N-amidino pyr...

Renin Release: Sites, Mechanisms, and Control

“…Conversely, infusion of catecholamines can raise renin release in vivo almost instantaneously (165). Similarly, administration of loop diuretics acutely increases renin release in vivo (166). The effect of loop diuretics is likely due to a direct effect on NKCC-1 in renin-producing cells, to a fall in blood pressure, and to interference with the salt-sensing transport process at the macula densa.…”