Investigation of mechanisms that mediate reactive hyperaemia in guinea‐pig hearts: role of K ATP channels, adenosine, nitric oxide and prostaglandins

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. 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. 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). 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 μmol) and diazoxide (42 nmol – 2 μmol). 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. 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. 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.British Journal of Pharmacology (2001) 132 , 1209–1216; doi: 10.1038/sj.bjp.0703929