Vasomodulator Mechanisms in Rat Carotid Artery and in Vessels from an Experimental Model of Heart Failure

The purpose of the work presented here was to investigate: i) in the rat isolated common carotid artery the population of postjunctional alpha-adrenoceptors, subtypes of alpha1-adrenoceptors and their interaction with nitric oxide, ii) in the rabbit isolated saphenous vein the subtypes of alpha1-adrenoceptors, iii) in the rabbit coronary ligation model of heart failure endothelium-dependent and -independent relaxations, contraction to NA and effect of cocaine treatment on large blood vessels. The major findings are briefly summarised below: Rat carotid artery 1 The dominance of alpha1-adrenoceptors is shown by the high sensitivity of NA or PE to prazosin and the ineffectiveness of rauwolscine except in non-selective concentrations. UK-14304 produced contraction and it is theoretically possible that UK-14304 exerts its actions through combined alpha1 and alpha2 activation, but the effectiveness of prazosin and the ineffectiveness of rauwolscine except in non-selective concentrations, shows that even this effect is mediated through alpha1-adrenoceptors. Thus we suggest that the population of postjunctional alpha-adrenoceptors mediating contraction of smooth muscle in the rat carotid artery is predominantly alpha1. 2 Rat carotid artery showed moderate sensitivity to alpha1A-selective antagonists and low sensitivity to CEC. The pA2 values correlated best with the published affinities of these compounds for the expressed alpha1d-adrenoceptor clone and poorly with those at either the expressed alpha1b- or alpha1a-adrenoceptor clones. This suggests negative evidence that contractions of the rat common carotid artery are mediated by non-alpha1A non-alpha1B-adrenoceptors. The data is consistent with a functional alpha1-adrenoceptor such as was reported in rat aorta. 3 In the rat isolated carotid artery, UK-14304 induced relaxation of NA-induced tone (but not thromboxane-induced tone) which was independent of alpha2-adrenoceptors, functional endothelium, production of NO and cyclo-oxygenase products. There was no specific evidence from our study that alpha2-adrenoceptors can mediate the release of EDRF in rat carotid artery. We suggest that UK-14304 acted as a partial agonist at alpha1-adrenoceptors in this artery. 4 Inhibition of NO synthesis by L-NAME results in significant vasoconstriction. Also, L-NAME prevented the relaxation of rat carotid artery by acetylcholine. Thus we suggest that both basal and stimulated release of nitric oxide can regulate vascular tone in this artery. 5 Mechanical disruption of the vascular endothelium (to an extent which prevented vasodilation by acetylcholine) reduced, but did not abolish the ability of L-NAME to produce contraction. This suggests an extra-endothelial site for nitric oxide synthesis in rat common carotid artery. 6 The effect of UK-14304 was significantly enhanced in the presence of L-NAME. Inhibition of nitric oxide synthase with L-NAME potentiates responses to PE and UK-14304 but not to NA. Mechanical disruption of the vascular endothelium mimicked the effect of L-NAME on contractile responses to UK-14304 and PE consistent with L-NAME inhibiting endothelium-derived nitric oxide synthase. There was one unexplained difference between L-NAME and denuding endothelium. Although L-NAME did not increase sensitivity to NA, mechanical disruption increases potency of NA. Overall the results suggest that constitutive NO activity has substantial inhibitory influence on vasoconstrictor responses to PE and UK-14304 but not to NA. 7 Since L-NAME greatly potentiates responses to UK-14304, a series of experiments were conducted to see whether other stimuli that produces submaximal contraction would have a similar synergistic effect. Submaximal contraction with KCl increased responses significantly, but inducing tone with PE, U-46619 and 5HT had no effect on responses to UK-14304. The presence of All increased responses though less than KCl. Overall the greatest influence found was blockade of nitric oxide synthase. (Abstract shortened by ProQuest.)