Myocardial anti-ischemic characteristics of a novel class of beta-adrenoceptor blockers.
The effect of different beta-adrenoceptor blockers on free radical-mediated cardiac membrane lipid peroxidation (CMLP) was compared to their beta-blocking potency (pA2). CMLP was determined by the measurement of malondialdehyde (MDA) formation in rat cardiac membrane homogenates exposed to a free radical generating system (FeCL3/ADP/DHF) in the presence or absence of the beta-adrenoceptor blockers (1-1,000 microM). beta-adrenoceptor blocking potency (pA2) was determined using guinea pig right atria stimulated with isoproterenol. The catechol containing beta-blocker (DCC-10255) was shown to be a potent inhibitor of CMLP via an iron-dependent mechanism. On the other hand, the non-catechol beta-adrenoceptor blocker, timolol, was shown to be a weak inhibitor of CMLP. Furthermore, dl- and d-propranolol were active and equipotent though less potent than DCC-10255 in inhibiting CMLP. The myocardial cytoprotective efficacy for catechol and non-catechol beta-adrenoceptor blockers was evaluated in an isolated rat myocyte model. It was demonstrated that catechol-containing agents with either strong or weak beta-adrenoceptor blockade possess a relatively potent in vitro antioxidant and myocardial cytoprotective efficacy against free radical mediated CMLP and myocyte injury, respectively. It is concluded that the inhibition of CMLP by beta-adrenoceptor blockers is independent of their beta-adrenoceptor blockade.
Du Pont Merck Pharmaceutical Company, Cardiovascular Diseases Research, Wilmington, Delaware 19880.
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D000319:Adrenergic beta-Antagonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D003327:Coronary Disease / Q000517:prevention & control*; D005609:Free Radicals / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D000319:Adrenergic beta-Antagonists; D005609:Free Radicals; D008563:Membrane Lipids