Studies on the glomerular microcirculatory actions of manidipine and its modulation of the systemic and renal effects of endothelin.
We examined the actions of intravenously administered manidipine on systemic and renal microcirculatory hemodynamics and its efficacy in antagonizing endothelin-1 (ET-1)-evoked responses. Manidipine was a potent vasodilator with preferential activity in the renal vasculature. Its administration in optimal doses resulted in decreases in systemic arterial pressures accompanied by increases in renal perfusion and filtration rates. Its primary sites of action in the kidney were at both pre- and postglomerular arteriolar sites. Manidipine was capable of near-total reversal of the sustained elevations in arterial pressure and the progressive reductions in renal blood flow and glomerular filtration rates induced by intravenously administered ET-1. In the presence of prolonged calcium channel blockade, subsequent administration of ET-1 led to paradoxic hypotensive responses, which could be profound and blocked by an inhibitor of nitric oxide synthesis. These unexpected vasorelaxant actions of ET-1 in the presence of manidipine were likely caused by the dual effects of antagonism of its own intrinsic vasoconstrictor action (through calcium channel blockade), as well as ET-1-evoked release of the endothelium-derived relaxing factor, nitric oxide.
Takahashi
K
K
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2372.
Katoh
T
T
Fukunaga
M
M
Badr
K F
KF
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004347:Drug Interactions; D016232:Endothelins / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide; D009578:Nitrobenzenes; D010879:Piperazines; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology; D019323:omega-N-Methylarginine
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016232:Endothelins; D009578:Nitrobenzenes; D010879:Piperazines; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C054218:manidipine; D001120:Arginine; D014700:Verapamil