Investigation of mechanisms that mediate reactive hyperaemia in guinea-pig hearts: role of K(ATP) channels, adenosine, nitric oxide and prostaglandins.
1. Reactive hyperaemia is a transient vasodilatation following a brief ischaemic period. ATP-dependent K(+) (K(ATP)) channels may be important in mediating this response, however it is unclear whether mitochondrial K(ATP) channels contribute to this in the heart. 2. We examined the involvement of K(ATP) channels and the relative role of mitochondrial channels as mediators of coronary reactive hyperaemia and compared them to mechanisms involving NO, prostaglandins and adenosine in the guinea-pig isolated heart. 3. Reactive hyperaemic vasodilatation (peak vasodilator response and flow debt repayment) were assessed after global zero-flow ischaemia (5 -- 120 s) in the presence of nitro-L-arginine methyl ester (L-NAME, 10(-5) M, n=9), 8-phenyltheophylline (8-PT, 10(-6) M, n=12) and indomethacin (10(-5) M, n=12). 4. Glibenclamide (10(-6) M, n=12) a non-selective K(ATP) channel inhibitor and 5-hydroxy-decanoic acid (5-HD, 10(-4) M, n=10) a selective mitochondrial K(ATP) channel inhibitor were also used. The specificity of the effects of glibenclamide and 5-HD (n=6 each) were confirmed using pinacidil (38 nmol -- 10 micromol) and diazoxide (42 nmol -- 2 micromol). Glibenclamide was most effective in blocking the hyperaemic response (by 87%, P<0.001) although 5-HD and 8-PT also had a marked effect (40% inhibition, P<0.001 and 32%, P<0.001, respectively). L-NAME and indomethacin had little effect. 5. Perfusion with L-NAME and glibenclamide significantly reduced baseline coronary flow (22%, P<0.01 and 33%, P<0.01) while 8-PT, indomethacin and 5-HD had no effect. 6. K(ATP) channels are the major mediators of the coronary reactive hyperaemic response in the guinea-pig. Although mitochondrial K(ATP) channels contribute, they appear less important than sarcolemmal channels.
Kingsbury
M P
MP
Academic Cardiology Unit, National Heart and Lung Institute, Imperial College School of Medicine St Mary's Campus, London W2 1NY.
Robinson
H
H
Flores
N A
NA
Sheridan
D J
DJ
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006331:Heart Diseases / Q000378:metabolism*; D006940:Hyperemia / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D015221:Potassium Channels; D011453:Prostaglandins / Q000378:metabolism
D008565:Membrane Proteins; D015221:Potassium Channels; D011453:Prostaglandins; C117780:mitochondrial K(ATP) channel; D009569:Nitric Oxide; D000241:Adenosine