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

Abstract

1 Reactive hyperaemia is a transient vasodilatation following a brief ischaemic period. ATPdependent 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¯ow debt repayment) were assessed after global zero-¯ow ischaemia (5 ± 120 s) in the presence of nitro-L-arginine methyl ester (L-NAME, 10 75 M, n=9), 8-phenyltheophylline (8-PT, 10 76 M, n=12) and indomethacin (10). Glibenclamide (10 76 M, n=12) a non-selective K ATP channel inhibitor and 5-hydroxydecanoic acid (5-HD, 10 74 M, n=10) a selective mitochondrial K ATP channel inhibitor were also used. The speci®city of the eects of glibenclamide and 5-HD (n=6 each) were con®rmed using pinacidil (38 nmol ± 10 mmol) and diazoxide (42 nmol ± 2 mmol). 4 Glibenclamide was most eective in blocking the hyperaemic response (by 87%, P50.001) although 5-HD and 8-PT also had a marked eect (40% inhibition, P50.001 and 32%, P50.001, respectively). L-NAME and indomethacin had little eect. 5 Perfusion with L-NAME and glibenclamide signi®cantly reduced baseline coronary¯ow (22%, P50.01 and 33%, P50.01) while 8-PT, indomethacin and 5-HD had no eect. 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.

Preclinical evaluation of coronary vascular function after cardioplegia with HTK and different antioxidant additives

“…1-3 the use of a traditional cardioplegic solution, Bretschneider HTK, also did not offer good endothelial preservation in the whole heart as indicated by three independent indices of coronary regulatory functions (vasodilations toward bradykinin and ATP, reactive hyperaemic response). Reactive hyperaemia is largely mediated by activation of K + ATP channels, most likely present on vascular smooth muscle cells, and involvement of the myocardial metabolite adenosine [15]. Bradykinin has been shown to act via stimulation of endothelial NO release [16].…”

Spontaneous Coronary Vasospasm in K ATP Mutant Mice Arises From a Smooth Muscle–Extrinsic Process

“…Vascular K ATP channels have also been implicated in the coronary vasodilatory response to exercise 15 and hypoxia. 16 K ATP channels may also play a role in endotoxic vasodilation. 17 Independent gene targeting studies in mice of either the gene encoding SUR2 (ABCC9) or Kir6.1 (KCNJ8) produced an identical phenotype of coronary artery spasm seen as transient ST segment elevation accompanied by atrioventricular heart block, bradycardia, and sudden death.…”

Metabolic hyperemia requires ATP-sensitive K+ channels and H2O2 but not adenosine in isolated mouse hearts

“…The K ATP channel has been reported to be involved in coronary ischemic vasodilation (24,41,42,57), although its role in metabolic vasodilation remains controversial (13,15,23,35,47,55). In isolated mouse hearts, the present study showed that glibenclamide (5 M) significantly reduced CF (by ϳ45%; Fig.…”