EFFECTS OF CS-905, A NOVEL DIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKER, ON ARTERIAL-PRESSURE, RENAL EXCRETORY FUNCTION, AND INNER MEDULLARY BLOOD-FLOW IN THE RAT

CS-905 is a dihydropyridine calcium channel antagonist which stands ou t for its prolonged hypotensive effect, and which is currently under i nvestigation for the treatment of hypertension. The aim of the current series of studies was to investigate the effects of CS-905 on renal f unction in relation to its effects on arterial pressure. In anesthetiz ed spontaneously hypertensive rats (SHR), intravenous bolus injection of CS-905 reduced mean arterial pressure (MAP) in a dose-dependent fas hion. In parallel, there was a dose-related increase in urine flow (V) , sodium excretion (UNaV), renal plasma flow (RPF), and glomerular fil tration rate (GFR). In chronically cannulated unanesthetized SHR, sing le-dose CS-905 by gavage produced a sustained reduction in MAP, a sign ificant increase in V and UNaV, no effect on RPF, and an increase in G FR. Continuous intrarenal infusion of CS-905 in anesthetized normotens ive Munich Wistar rats at doses that did not affect MAP caused a marke d diuresis and natriuresis, without affecting RPF or GFR. To determine whether the diuretic and natriuretic effects of CS-905 were mediated by changes in inner medullary blood flow, the effect of CS-905 on vasa recta blood flow (Q(vr)) was studied by fluorescent videomicroscopy i n anesthetized normotensive Munich Wistar rats during continuous intra renal infusion. At low infusion rates, CS-905 was diuretic and natriur etic while increasing Q(vr). With a high infusion rate, although the d iuretic and natriuretic effects of CS-905 were maximal, Q(vr) decrease d. These findings suggest that the diuretic and natriuretic effects of CS-905 are dissociated from and cannot be accounted for by changes in RPF, GRF, or Q(vr), and are most likely secondary to a direct action of CS-905 on renal tubule handling of sodium and water.