Reduction by (-)-cicletanine of the vascular reactivity to angiotensin II in rats.
Cicletanine [particularly the levorotatory (-)enantiomer] inhibits calcium/calmodulin cyclic GMP phosphodiesterase (PDE) in vascular smooth muscle (VSM) and potentiates the vasorelaxant actions of the guanylate cyclase activators sodium nitroprusside (SNP) and atriopeptin II, but the possible interference with vasopressor mechanisms remains to be determined. We tested racemic (+/-) cicletanine for its ability to modify the vascular responses to vasocontractant agents in pithed rats. The most significant results were obtained with angiotensin II (AII). Therefore, the dose of AII that increased the carotid artery blood pressure (BP) 50 mm Hg was twice as high in cicletanine-pretreated (50 mg/kg orally, p.o.) as that in vehicle-pretreated animals (ED50 = 0.48 +/- 0.012 vs. 0.25 +/- 0.007 microgram/kg, p < 0.05). The displacement by cicletanine represented 47.2% of that obtained with losartan (40 micrograms/kg, intravenously, i.v.). Similar results were obtained with (-)-cicletanine (p.o. or i.v.), but not with (+)-cicletanine. In isolated rat aorta, the contraction induced by AII was reduced by (-)-cicletanine in a noncompetitive manner (the percent reduction was independent of the AII concentration). (-)-Cicletanine reduces the vascular reactivity to AII, which plays a key role in several forms of hypertension. These findings are compatible with an action of (-)-cicletanine at any of the numerous steps that couple the occupation of AII receptors to the final contractile response, such as calcium/calmodulin cyclic GMP PDE.
INSERM U400, Faculté de Médecine, Créteil, France.
M
M
Alvarez-Guerra
O
O
Alda
E
E
Morin
M
M
Allard
R P
RP
Garay
D000284:Administration, Oral; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D019808:Losartan; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014667:Vasopressins / Q000494:pharmacology
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D000804:Angiotensin II; C038068:cicletanine; D019808:Losartan