Myocardial protection by the novel vasodilating beta-blocker, carvedilol: potential relevance of anti-oxidant activity.
OBJECTIVE
Carvedilol is a multiple action antihypertensive drug with potential use in angina and congestive heart failure. The pharmacological profile of carvedilol includes both beta-adrenoceptor blockade and vasodilation, the latter primarily a result of alpha 1-adrenoceptor blockade. Since many beta-blockers have cardioprotective properties, the present study was designed to determine whether carvedilol is also cardioprotective. Because oxygen radicals are believed to influence ischemic tissue injuries, a secondary study was designed to determine whether carvedilol has anti-oxidant actions which could contribute to cardioprotective properties of carvedilol.


METHODS
Four different models of acute myocardial infarction in were examined in three animal species, and the effects of carvedilol were compared to those of propranolol. First, in rats subjected to 30 min of cardiac ischemia followed by 24 h of reperfusion, carvedilol was administered both pre- and post-ischemia (1 mg/kg, intravenously). Second, minipigs were subjected to 45 min of cardiac ischemia followed by 4 h of reperfusion, with carvedilol pretreatment (0.3 or 1 mg/kg intravenously). Third, dogs were subjected to 1 h of cardiac ischemia followed by 24 h of reperfusion with carvedilol pretreatment (1 mg/kg, intravenously) or to permanent coronary occlusion (6 h) with carvedilol pretreatment (0.3 or 1 mg/kg, intravenously). Finally, to examine the anti-oxidant activity of carvedilol, pig myocardial membranes were exposed to oxidizing systems that elicit lipid peroxide products assessed as thiobarbituric acid-reactive substances (TBARS).


RESULTS
In the rats, carvedilol reduced the infarct size by 47% (P < 0.01), in contrast to propranolol, which is inactive in this model. In the minipigs the infarct size was reduced by 46 and 89% (P < 0.01) with carvedilol at 0.3 and 1 mg/kg, respectively; at comparable beta-adrenoceptor blocking doses, carvedilol produced a significantly greater reduction in the infarct size than propranolol (89 versus 48%). In dogs, carvedilol reduced the infarct size by 78% (P < 0.05) compared to the 64% reduction produced by propranolol. In dogs with permanent coronary occlusion, carvedilol produced dose-dependent reductions in the infarct size of 46 and 63% for 0.3 and 1 mg/kg, respectively (P < 0.05), compared to propranolol which did not reduce the infarct size in this model. Carvedilol inhibited lipid peroxidation in a dose-dependent manner with a 50% inhibitory concentration (IC50) of 5 mumol/l. Moreover, superoxide generation by activated human neutrophils in vitro was also inhibited by carvedilol with an IC50 of 28 mumol/l. Finally, carvedilol was shown to scavenge oxygen free radicals in a cell-free system with an IC50 of 25 mumol/l.


CONCLUSIONS
Taken together, these data indicate that carvedilol is a potent cardioprotective drug, which presumably acts by multiple mechanisms, possibly including a novel anti-oxidant effect that is not shared by other beta-blockers.
Feuerstein
G Z
GZ
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0930.
Yue
T L
TL
Cheng
H Y
HY
Ruffolo
R R
RR
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004285:Dogs; D016166:Free Radical Scavengers; D006321:Heart / Q000187:drug effects*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013556:Swine, Miniature; D014665:Vasodilator Agents / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D016166:Free Radical Scavengers; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol