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 out for its prolonged hypotensive effect, and which is currently under investigation for the treatment of hypertension. The aim of the current series of studies was to investigate the effects of CS-905 on renal function in relation to its effects on arterial pressure. In anesthetized spontaneously hypertensive rats (SHR), intravenous bolus injection of CS-905 reduced mean arterial pressure (MAP) in a dose-dependent fashion. In parallel, there was a dose-related increase in urine flow (V), sodium excretion (UNaV), renal plasma flow (RPF), and glomerular filtration rate (GFR). In chronically cannulated unanesthetized SHR, single-dose CS-905 by gavage produced a sustained reduction in MAP, a significant increase in V and UNaV, no effect on RPF, and an increase in GFR. Continuous intrarenal infusion of CS-905 in anesthetized normotensive Munich Wistar rats at doses that did not affect MAP caused a marked 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 (Qvr) was studied by fluorescent videomicroscopy in anesthetized normotensive Munich Wistar rats during continuous intrarenal infusion. At low infusion rates, CS-905 was diuretic and natriuretic while increasing Qvr. With a high infusion rate, although the diuretic and natriuretic effects of CS-905 were maximal, Qvr decreased. 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 Qvr, and are most likely secondary to a direct action of CS-905 on renal tubule handling of sodium and water.
Yagil
Y
Y
University of Rochester School of Medicine and Dentistry, New York.
Miyamoto
M
M
Frasier
L
L
Oizumi
K
K
Koike
H
H
D000758:Anesthesia; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007267:Injections; D007668:Kidney; D007679:Kidney Medulla / Q000098:blood supply; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D001383:Azetidinecarboxylic Acid; C061679:azelnidipine