A dihydropyridine calcium channel blocker with phosphodiesterase inhibitory activity: effects on cultured vascular smooth muscle and cultured heart cells.
To define the cellular mechanism of action of a dihydropyridine Ca channel antagonist in an experimental model system devoid of neural influences and reflex effects, we studied the actions of RS93522 on cultured vascular smooth muscle cells and on cultured chick embryo ventricular cells. 45Ca uptake by monolayer cultures of vascular smooth muscle cells was inhibited in a concentration-dependent manner. The IC50 for this effect was 10 nM, similar to that for nifedipine (7 nM) in the same system. 10(-6) M RS93522 inhibited 45Ca uptake more fully than 10(-6) M nifedipine (P less than 0.05). Using an optical-video system, the effect of RS93522 on amplitude of contraction of spontaneously beating cultured ventricular cells was studied. Amplitude of contraction was inhibited with IC50 = 7.9 x 10(-8)M. 45Ca uptake in myocytes was depressed by 15% at 5 min. RS93522 had the additional property of inhibiting phosphodiesterase activity in myocardial homogenates with IC50 = 1.6 x 10(-5)M; the potency and efficacy of phosphodiesterase inhibition was similar to that for milrinone in the same system. As expected of Ca channel antagonists, it has a negative inotropic effect on cultured myocardial cells. The compound also has phosphodiesterase inhibitory activity that possibly may potentiate vasodilatation and ameliorate, in part, negative inotropic effects. Thus, RS93522 has two distinct pharmacodynamic effects in myocytes and is a potent calcium channel blocker.
Marsh
J D
JD
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Dionne
M A
MA
Chiu
M
M
Smith
T W
TW
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D002642:Chick Embryo; D003864:Depression, Chemical; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology; D009543:Nifedipine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D010726:Phosphodiesterase Inhibitors; C059331:RS 93522-004; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D009543:Nifedipine; D002118:Calcium