Adenylate cyclase activation promotes the recruitment of coronary vasodilator reserve and improves subendocardial contractility during coronary hypoperfusion.
This study was designed to examine the effects of an adenylate cyclase activator, NKH477, on epicardial and endocardial contraction and coronary blood flow (CoF) in the presence or absence of ischemia and to compare it to those of adenosine. We measured coronary pressures (CoP), coronary blood flow, epicardial and endocardial wall thickening (i.e., %EPWT and %ENWT, respectively, by sonomicrometry) in 18 anesthetized dogs. The left circumflex coronary artery was perfused with arterial blood using a pressure controlled servo pump. Propranolol (0.5 mg/kg) and atropine (0.25 mg) were used to minimize the neurogenic effects. CoP decreased from 100 mm Hg to 40 mm Hg with and without drugs. At CoP of 100 mm Hg, intracoronary infusion of NKH477 (10(-8) M/kg/min) produced a two-fold increase in CoF, but there were no changes in either the %EPWT or the %ENWT. During coronary hypofusion at coronary pressures equal to 40 mm Hg, NKH477 increased CoF from 16 +/- 2 to 28 +/- 4 mL/min (p < 0.05) and improved %ENWT significantly from 6 +/- 7 to 23 +/- 7% (p < 0.05). However %EPWT was not improved by NKH477. On the other hand, the intracoronary infusion of adenosine (10 micrograms/kg/min) increased CoF from 16 +/- 5 to 21 +/- 6 mL/min (p < 0.05) at CoP of 40 mm Hg. However, this dose of adenosine failed to improve %ENWT (16 +/- 10% vs. 14 +/- 10%, n.s.). Thus, the improvement of subendocardial function by NKH477 might be related to the improvement of subendocardial perfusion which could be induced by the potentiation of endogenously released adenosine as well as the direct vasodilator effect. This contrasts with the effects of exogenously administered adenosine, which failed to improve subendocardial contractility.
Second Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan.
Y
Y
Ikeda
T
T
Miura
N
N
Tanaka
S
S
Mikami
T
T
Oda
A
A
Takaki
T
T
Fujii
M
M
Kohno
K
K
Katayama
M
M
Matsuzaki
D000241:Adenosine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology; D014665:Vasodilator Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D014665:Vasodilator Agents; D005576:Colforsin; D000262:Adenylyl Cyclases; D000241:Adenosine