Effects of (-)-desmethoxyverapamil on heart and vascular smooth muscle.
(-)-Desmethoxyverapamil [also known as (-)-devapamil or (-)-D888] has been developed as a verapamil type radioligand for the study of calcium channels. In the present investigation, the effects of (-)-desmethoxyverapamil on action potential (AP) and force of contraction in heart muscle preparations and on tension and 45Ca influx in vascular smooth muscle are described. In part, the effects were compared with the (+)-isomer of desmethoxyverapamil and the isomers of both verapamil and methoxyverapamil. In atrial and/or ventricular heart muscle preparations from guinea pigs, cats and man, (-)-desmethoxyverapamil decreased the force of contraction and shortened the AP duration. Slow response APs were depressed, whereas dV/dtmax of phase 0 of the AP remained unchanged. The rank order of potency of the (-)-isomers was as follows: desmethoxyverapamil greater than methoxyverapamil greater than verapamil. Potassium-induced contractures and 45Ca influx were depressed by the (-)-isomers of desmethoxyverapamil, methoxyverapamil and verapamil in the same potency rank order as observed in heart muscle. The (+)-isomers exerted qualitatively similar effects at about 10 to 200 times higher concentrations. Correspondingly, the increase in potency of the racemic mixtures of the drugs was accompanied by increases in stereoselectivity. It is concluded that (-)-desmethoxyverapamil is the most potent stereoselective calcium antagonist of the verapamil type with respect to its effects on heart and vascular smooth muscle.
Nawrath
H
H
Department of Pharmacology, University of Mainz, Federal Republic of Germany.
Raschack
M
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002415:Cats; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014316:Tritium; D014700:Verapamil / Q000031:analogs & derivatives* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D014316:Tritium; C043184:4-desmethoxyverapamil; D014700:Verapamil; D002118:Calcium