Exacerbation of reperfusion arrhythmias by alpha 1 adrenergic stimulation: a potential role for receptor mediated activation of sarcolemmal sodium-hydrogen exchange.
OBJECTIVE
Stimulation of myocardial alpha 1 adrenoceptors causes (1) exacerbation of reperfusion induced arrhythmias, and (2) stimulation of sarcolemmal Na+/H+ exchange. The aims of this study were to identify the alpha 1 adrenoceptor subtype involved in the former effect and to determine whether stimulation of the Na+/H+ exchanger may play a role in this phenomenon.


METHODS
Isolated rat hearts were subjected to independent perfusion of the left and right coronary beds. After 15 min of aerobic perfusion of both beds, the alpha 1 adrenoceptor agonist phenylephrine (0.1, 1, or 10 microM) was infused selectively into the left coronary bed for 2 min. The left coronary bed was then subjected to 7 min of zero flow ischaemia and 5 min of reperfusion.


RESULTS
The incidence of reperfusion induced ventricular fibrillation was increased from 0% in controls to 8%, 42%*, and 75%* with 0.1, 1, and 10 microM phenylephrine (*P < 0.05); this dose dependent effect occurred in the absence of significant intergroup differences in vascular resistance or heart rate. Similar infusion of methoxamine at 10 microM also increased the incidence of reperfusion induced ventricular fibrillation from 13% to 88%*. Infusion of 10 microM phenylephrine during reperfusion alone did not affect the incidence of reperfusion induced ventricular fibrillation. Infusion of the selective alpha 1A adrenoceptor antagonist WB4101 at 0.1, 1, or 10 microM for 2 min immediately before ischaemia (concomitantly with 10 microM phenylephrine) reduced the incidence of reperfusion induced ventricular fibrillation from 83% to 75%, 25%*, and 0%*. Similar infusion of the selective alpha 1B adrenoceptor antagonist chloroethylclonidine (0.1 or 1 microM) or the selective beta 1 adrenoceptor antagonist atenolol (0.1 or 1 microM) did not reduce the incidence of reperfusion induced ventricular fibrillation. The novel NHE-1 selective Na+/H+ exchange inhibitor HOE694 (10 microM), when infused into the left coronary bed before ischaemia (concomitantly with 10 microM phenylephrine) and throughout reperfusion, reduced the incidence of reperfusion induced ventricular fibrillation from 83% to 25%*. In hearts that received 10 microM phenylephrine before ischaemia. HOE694 (10 microM) was partially effective when infused during reperfusion alone (ventricular fibrillation incidence reduced from 83% to 42%).


CONCLUSIONS
(1) the exacerbation of reperfusion induced arrhythmias by alpha 1 adrenergic stimulation during ischaemia is mediated by the alpha 1A adrenoceptor subtype, and (2) increased Na+/H+ exchanger activity during ischaemia and reperfusion may play a causal role in this phenomenon.
Yasutake
M
M
Rayne Institute, St Thomas' Hospital, London, United Kingdom.
Avkiran
M
M
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D012508:Sarcolemma / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013268:Stimulation, Chemical
D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D017923:Sodium-Hydrogen Exchangers; D010656:Phenylephrine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D008729:Methoxamine