Effects of a new dihydropyridine derivative, S12968 (pranedipine), and its stereoisomer, S12967, on renal effects of endothelin-1.
The purpose of the present study was to assess in rats the prevention by two enantiomers of a new dihydropyridine derivative (pranedipine) (called S12967 for the dextrogyre (+) and S12968 for the levogyre (-) molecules) of the renal and cardiovascular effects induced by endothelin-1. The injection of endothelin-1 (1 nmol/kg body weight) induced a sharp and transient decrease in urine flow, sodium and potassium excretion, glomerular filtration rate, renal plasma flow, and renal blood flow, a significant increase in renal vascular resistance, and a small but significant increase in arterial pressure. Treatment with S12968 alone (0.3 mg/kg) induced a 2.5-fold increase in urine flow and potassium excretion and a 4.5-fold increase in sodium excretion. Pretreatment with S12968 completely blocked the endothelin-1 induced increase in arterial pressure, did not affect the acute effect of endothelin-1 on urine flow, sodium and potassium excretion, filtration rate, and renal blood flow, but blunted the effect on renal vascular resistance. Administration of S12967 alone (1 mg/kg) did not induce changes in either renal function or arterial pressure. In S12967-treated animals, endothelin-1 also induced a transient increase in arterial pressure nad renal vascular resistance but failed to change renal function in a significant manner. In summary, the above reported experiments show that at the higher, nonhypotensive doses, the levogyre enantiomer (S12968) of a new dihydropyridine derivative (pranedipine) completely prevented the hypertensive effect of endothelin 1, and partially prevented the effect of endothelin-1 on renal vascular resistance. The dextrogyre enantiomer (S12967) had almost no effect on either mean arterial pressure or renal vascular resistance but completely blocked the endothelin-1-induced decrease in urine flow and urinary sodium excretion.
Montañés
I
I
Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Salamanca, Spain.
Flores
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O
Eleno
N
N
López-Novoa
J M
JM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D013237:Stereoisomerism; D014563:Urodynamics / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016232:Endothelins; C067838:S 11568; D012964:Sodium