Cardiovascular Effects of FR34235, a New Dihydropyridine Slow Channel Blocker, in Isolated Rabbit Myocardium and Aorta

The effects of FR34235 (FR) on isolated rabbit cardiac muscle, sinus node, and aortic strips were evaluated and compared with those of nifedipine. FR decreased the developed tension and shortened the action potential duration of ventricular and atrial muscle without affecting the upstroke velocity (Vmax). Nifedipine induced similar but more pronounced electromechanical changes. The ED50 values for FR and nifedipine for producing their negative inotropic effects on ventricular muscle were 1.0 +/- 0.4 X 10(-6) and 2.0 +/- 0.6 X 10(-7), respectively. The slow response and its associated contraction of ventricular muscle were inhibited by FR (5 X 10(-6) M). Both effects of FR were antagonized by increasing [Ca]0. FR, at concentrations higher than 10(-7) M, reduced the amplitude and Vmax of the sinus node action potential. However, these effects were less than those of nifedipine. Spontaneous firing rate was not affected by either drug. The high K+-induced contractile response in rabbit aortic strips was inhibited by both FR and nifedipine at lower concentrations than in cardiac tissue, whereas the potency of FR was greater than nifedipine. The ED50 values for FR and nifedipine were 1.0 +/- 0.3 X 10(-9) and 4.0 +/- 0.4 X 10(-9) M, respectively. The inhibitory action of FR on the contractile response to excess Ca2+ was also greater than that of nifedipine. The inhibitory actions of both FR and nifedipine on the norepinephrine response were less than those on the K+ response. These results indicate that FR has characteristics of slow channel blockade similar to those of nifedipine. However, inhibitory action of FR was more potent in vascular smooth muscle of rabbit aorta and less potent in cardiac tissue than that of nifedipine.