Cardiovascular properties of LF 2.0254, a new potent vasoselective calcium channel blocker with a slow onset of action.
The effects of LF 2.0254, a new 1,4-dihydropyridine derivative, were studied in rabbit aorta stimulated by various contractile agents and in isolated guinea pig atria. LF 2.0254 inhibited in a time-dependent fashion K(+)- and CA2(+)-induced contractions of rabbit aorta with respective IC50 of 2.7 nM and 1.7 nM. An action of LF 2.0254 at the voltage operated calcium channel was consistent with the finding that LF 2.0254 antagonized 45Ca2(+)-uptake induced by depolarisation of smooth muscle, and since contractile responses evoked by (-) norepinephrine and the calcium ionophore A23187 were insensitive to the drug. In isolated paced left atria and spontaneously beating right atria of guinea pig, LF 2.0254 added for 60 min at 1 microM only slightly decreased the contractile force and beating rate. In anesthetized open-thorax dogs, LF 2.0254 (1 to 100 micrograms/kg, iv) dose-dependently lowered systemic blood pressure and increased cardiac output with a slower onset of action than nifedipine. LF 2.0254 and nifedipine decreased total peripheral, coronary, femoral and vertebral resistance. In marked contrast to nifedipine, LF 2.0254 induced only a slight decrease in left ventricular dP/dt. In conscious hypertensive dogs LF 2.0254 (0.1 and 0.3 mg/kg per os) decreased blood pressure and concomitantly increased heart rate and plasma renin activity. It is concluded that LF 2.0254 differ markedly from nifedipine in its more gradual onset of action and greater selectivity for the vasculature with respect to the myocardium.
Pruneau
D
D
Laboratoires Fournier SA, Centre de Recherche, Fontaine-lès-Dijon, France.
Roy
F
F
Brown
N L
NL
D000758:Anesthesia; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002122:Calcium Chloride / Q000494:pharmacology; D002132:Calcium Radioisotopes; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D051381:Rats
D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D004095:Dihydropyridines; C059213:LF 2-0254; D000001:Calcimycin; D009543:Nifedipine; D002122:Calcium Chloride; D011188:Potassium; D009638:Norepinephrine