Isoproterenol sensitivity of isolated cardiac myocytes from rats with monocrotaline-induced right-sided hypertrophy and heart failure.
Rats treated with the alkaloid monocrotaline developed right ventricular hypertrophy with a left:right ventricle weight ratio of 1.35 +/- 0.10 (mean +/- s.e.m., n = 25) compared with 3.83 +/- 0.40 (n = 14) in diet-matched controls (P less than 0.001). Urine volume and sodium content were reduced and body water increased consistent with heart failure. In 10 out of 26 treated rats pleural, pericardial or peritoneal effusions were present. Urine norepinephrine content was significantly raised (P less than 0.02) but epinephrine was unchanged. Plasma norepinephrine levels were raised though not significantly. Myocytes isolated from the right ventricle had a reduced myosin Ca2+-activated ATPase (P less than 0.05) activity and a shift towards slower V2 and V3 myosin isoforms. There was no decrease in maximum contraction amplitude with calcium or isoproterenol in either left or right ventricular cells of treated rats. Right ventricular cells from treated rats showed a reduced rate of contraction in maximum isoproterenol (P less than 0.05) and a significant rightward shift in PD2 (P less than 0.05) representing a two-fold increase in EC50 for isoproterenol compared with right ventricular cells from control animals. There was no shift in EC50 for isoproterenol in left ventricle cells. In parallel experiments, myocytes isolated from both ventricles of rats treated with isoproterenol for one week showed a rightward shift of more than 50-fold in the isoproterenol concentration-response curve and a depressed response to maximum isoproterenol. In the rat monocrotaline model of right-sided cardiac hypertrophy and failure, changes in sensitivity to beta-adrenoceptor agonists are slight, and present only in the right ventricle. The lack of change in the left ventricle seems to suggest that this functional desensitisation is not a consequence of raised circulating catecholamines.
Vescovo
G
G
National Heart and Lung Institute, London, U.K.
Jones
S M
SM
Harding
S E
SE
Poole-Wilson
P A
PA
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D002395:Catecholamines / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004361:Drug Tolerance; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D016686:Monocrotaline; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology*; D009218:Myosins / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects
D002395:Catecholamines; D011763:Pyrrolizidine Alkaloids; D011943:Receptors, Adrenergic, beta; D016686:Monocrotaline; D009218:Myosins; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol