Comparison of pharmacodynamics between carvedilol and metoprolol in rats with isoproterenol-induced cardiac hypertrophy: effects of carvedilol enantiomers.
A recent clinical study has shown that carvedilol has a significantly more favorable effect than metoprolol on survival rate in patients with heart failure. This may be due to actions of carvedilol such as beta(2)-adrenoceptor blockade, alpha-adrenergic receptor blockade and other properties such as anti-oxidant effects that are not yet fully understood. We compared the effects of racemic carvedilol, metoprolol and carvedilol enantiomers on cardiac hypertrophy at similar heart rate in rats with isoproterenol-induced cardiac hypertrophy. Continuous administration of isoproterenol for 2 weeks produced heart failure, which is characterized by an increased heart rate, cardiac hypertrophy and downregulation of beta-adrenoceptors. The doses of racemic carvedilol and metoprolol were adjusted to obtain a similar heart rate in rats with isoproterenol-induced cardiac hypertrophy. The reduction of left ventricular weight and improvement of cAMP production induced by carvedilol were superior to those induced by metoprolol. Although heart rate, blood pressure and cAMP production were not affected by R-carvedilol, left ventricular weight was significantly reduced as a result of alpha-adrenoceptor blockade. The improvement of cAMP production by S-carvedilol was significantly higher than that induced by coadministration of R-carvedilol and metoprolol, suggesting that beta(2)-adrenoceptor blockade partly contributed to the improvement of signal transduction in rats with isoproterenol-induced cardiac hypertrophy. This study has demonstrated that the effects of carvedilol on cAMP production and cardiac hypertrophy in rats with isoproterenol-induced cardiac hypertrophy are superior to those induced by metoprolol at a similar heart rate.
Hanada
Kazuhiko
K
Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan. hanada@my-pharm.ac.jp <hanada@my-pharm.ac.jp>
Asari
Kazuhiko
K
Saito
Masako
M
Kawana
Jun-Ichi
J
Mita
Mitsuo
M
Ogata
Hiroyasu
H
D000262:Adenylyl Cyclases / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077261:Carvedilol; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D008790:Metoprolol; D007545:Isoproterenol