LY249933: a cardioselective 1,4-dihydropyridine with positive inotropic activity.
Compound LY249933 and its component diastereomers, (RR) and (SR), were studied for their vascular and cardiac effects in vitro and in vivo. In guinea pig cardiac ventricular membranes, LY249933, (RR), and (SR) potently displaced bound [3H]nitrendipine (Kd values = 2-6 nM). In isolated guinea pig right ventricular strips, LY249933 produced a small but significant increase in contraction, whereas (RR) substantially increased (-log EC50 (M) = 4.6 +/- 0.8) and (SR) decreased contraction (-log EC50 (M) = 4.1 +/- 0.8). In isolated canine cephalic vein, contracted with 80 mM KCl, an increase in contraction was produced by (RR), whereas relaxation was produced by LY249933 (-log EC50 (M) = 5.9 +/- 0.9) and (SR) (-log EC50 (M) = 6.0 +/- 0.7). At 20 mM KCl, (RR) increased, (SR) decreased, but LY249933 did not alter contraction. In anesthetized dogs, LY249933 (200 micrograms/kg/min, i.v.) increased dP/dt60, decreased heart rate, but did not change vascular resistance or rate pressure product. At the same dose, (RR) and (SR) both tended to increase dP/dt60 nonsignificantly, whereas (RR) increased and (SR) decreased vascular resistance. Both (RR) and (SR) tended to decrease heart rate nonsignificantly, whereas (RR) did not change and (SR) decreased rate pressure product. Thus, LY249933 produced potentially beneficial cardiovascular changes resulting from the combined actions of its (RR) and (SR) diastereomers that are postulated to be calcium agonist and antagonist, respectively.
Holland
D R
DR
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Wikel
J H
JH
Kauffman
R F
RF
Smallwood
J K
JK
Zimmerman
K M
KM
Utterback
B G
BG
Turk
J A
JA
Steinberg
M I
MI
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009568:Nitrendipine / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D013237:Stereoisomerism; D013268:Stimulation, Chemical
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C061198:LY 249933; D011189:Potassium Chloride; D009568:Nitrendipine