THE EFFECT OF ISCHEMIA ON ENDOTHELIUM-DEPENDENT VASODILATATION AND ADRENOCEPTOR-MEDIATED VASOCONSTRICTION IN RAT ISOLATED HEARTS

1 The aim of this study was to investigate whether global ischaemia an d reperfusion in rat isolated hearts affects endothelium-dependent vas odilatation and adrenoceptor-mediated vasoconstriction. In addition, i t was first determined whether inhibition of the actions of nitric oxi de (NO) influenced the responses to a-adrenoceptor agonists in the rat coronary vasculature. 2 In rat isolated, Langendorff perfused hearts, inhibition of NO with haemoglobin (Hb, 6 mu M) significantly inhibite d the vasodilator responses to the endothelium-dependent vasodilators, acetylcholine (ACh, 3-100 pmol), carbachol (CCh, 10-300 pmol), bradyk inin (Bk, 1-30 pmol) and histamine (0.3-10 nmol) but did not affect re sponses to the endothelium-independent vasodilator, sodium nitroprussi de (SNP, 0.01-1 nmol). 3 Inhibition of the action of NO by Hb signific antly enhanced the vasoconstrictor response to the nonselective a-adre noceptor agonist, noradrenaline (NA, 0.1-10 nmol) and the alpha(2)-adr enoceptor agonist, B-HT 920 (0.001-1 mu mol) but had no effect on the vascular response to the alpha(1)-adrenoceptor agonist, methoxamine (M TX, 10-300 nmol). 4 In the perfused hearts ischaemia, induced by 30 mi n perfusion at 5% of the normal rate of flow, followed by 15 min of re perfusion (ischaemia/reperfusion) selectively impaired the vasodilator responses to ACh and CCh which act by muscarinic receptor stimulation but did not affect responses to the other endothelium-dependent vasod ilators Bk and histamine or to the endothelium-independent dilator SNP . 5 After ischaemia/reperfusion the coronary vasoconstrictor responses to B-HT 920 were slightly but significantly enhanced whereas the resp onses to NA and MTX were unaffected. 6 Thus, in the rat isolated heart , low flow induced-ischaemia and reperfusion causes a selective impair ment of muscarinic receptor-mediated vasodilatation but does not impai r responses to all endothelium-dependent vasodilators. Enhanced constr ictor responses to noradrenaline and B-HT 920 in the presence of Hb in dicates that endogenous NO modulates the constriction of coronary resi stance vessels in response to stimulation of alpha(2)-adrenoceptors. I schaemia and reperfusion in this isolated vascular bed caused only a s mall increase in the coronary vasoconstrictor response to alpha(2)-adr enoceptor stimulation. It appears that in the rat isolated heart the d egree of endothelial dysfunction caused by ischaemia/reperfusion is in sufficient to cause a functionally significant change in alpha-adrenoc eptor-mediated constriction.