Identification and functional role of beta-adrenergic receptor subtypes in primate and rodent: in vivo versus isolated myocytes.
We determined the relationship between the beta 1- and beta 2-adrenergic receptor subtypes in isolated myocytes and their physiological responsiveness in chronically instrumented conscious baboons and rats. In conscious baboons, isoproterenol (ISO) (0.02 microgram/kg) increased left ventricular (LV) dP/dt by 89 +/- 6.7% from 2898 +/- 370 mmHg/s and only by 13 +/- 3.3% from 2491 +/- 146 mmHg/s after beta 1-adrenergic receptor blockade, indicating that the predominant physiological response was mediated by beta 1-adrenergic receptors. Decreases in mean arterial pressure (-11 +/- 0.5 mmHg v -16 +/- 4.6 mmHg) and coronary vascular resistance (-3.1 +/- 0.4 v -3.6 +/- 0.4 mmHg/ml/min) induced by ISO were not different before and after beta 1-blockade, indicating that beta 2-adrenergic receptors were not blocked. In conscious rats, ISO (0.4 microgram/kg) increased LV dP/dt by 50 +/- 4.9% from 13252 +/- 2002 mmHg/s and only by 10 +/- 3.9% from 10793 +/- 1364 mmHg/s after beta 1-adrenergic receptor blockade: whereas decreases in mean arterial pressure induced by ISO were not different before and after beta 1-blockade (-19 +/- 2.4 mmHg v -16 +/- 2.2 mmHg), i.e. very consistent with the physiological responses in baboons. In vitro studies of isolated myocytes, using radioligand binding with 125I-cyanopindolol (125I-cyp) and the subtype beta 1-selective antagonist betaxolol and the beta 2-selective antagonist ICI 118551 indicated that the beta 1/beta 2 ratio of rat myocytes was 92/8: whereas baboon myocytes were more equally distributed (59/41). Thus, in both species the preponderance of effects of ISO on ventricular function was beta 1-adrenergic receptor mediated, which is consistent with the beta 1/beta 2 ratio in rat myocytes but not in baboon myocytes, where a significant fraction of beta 2-adrenergic receptors does not appear to exert an effect on conctractility in vivo.
Cui
Y
Y
Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Massachusetts General Hospital, Boston 02114, USA.
Shen
Y T
YT
Kalthof
B
B
Iwase
M
M
Sato
N
N
Uechi
M
M
Vatner
S F
SF
Vatner
D E
DE
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015784:Betaxolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010215:Papio; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; C047975:cyanopindolol; D010869:Pindolol; D007545:Isoproterenol; D015784:Betaxolol