Forskolin potentiates myocardial reactive hyperaemia in the open chest dog: the contribution of adenylate cyclase.
Forskolin, a diterpene, directly stimulates adenylate cyclase and also potentiates receptor mediated stimulation of this enzyme by many stimulatory agonists. We exploited the potentiating effect of forskolin to test the hypothesis that activation of adenylate cyclase contributes to myocardial reactive hyperaemia, especially by release of adenosine at the time of brief coronary occlusions. In 10 open chest dogs, intracoronary forskolin infusions which produced plasma concentrations between 0.22 and 0.34 mumol.litre-1 slightly increased coronary blood flow and had no effect on haemodynamics or myocardial metabolism. Under these conditions, though peak reactive hyperaemic flow rates were not affected, forskolin infusions reversibly potentiated repayments of flow debt by 28, 25 and 27% following coronary occlusions of 15 s, 20 s and 30 s, respectively (p less than 0.05). In another seven dogs, after observations of the effects of forskolin (0.16-0.26 mumol), 10 mumol of 8-phenyltheophylline, a potent adenosine antagonist, was infused simultaneously with forskolin into the coronary arteries. Forskolin increased debt repayments by about 23-27% following 15 s, 20 s and 30 s occlusions, but with simultaneous 8-phenyltheophylline, forskolin induced increments in the debt repayments were reduced significantly (p less than 0.05). These results indicate that adenylate cyclase contributes to myocardial reactive hyperaemia, and adenosine has a significant role as metabolic regulator of reactive hyperaemia through activation of adenylate cyclase.
First Department of Internal Medicine, Okayama University Medical School, Japan.
K
K
Hina
H
H
Watanabe
M
M
Ueeda
N
N
Yamada
D
D
Saito
S
S
Haraoka
T
T
Tsuji
S
S
Kusachi
D000241:Adenosine / Q000037:antagonists & inhibitors; D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000150:complications; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D006940:Hyperemia / Q000209:etiology*; D009206:Myocardium / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D005576:Colforsin; D013806:Theophylline; C028322:8-phenyltheophylline; D000262:Adenylyl Cyclases; D000241:Adenosine