Karoon, Parastoo; (1998) Local control of vascular tone: Changes in hibernation, hypertension, hyperlipidemia and after sensory denervation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis examines aspects of local regulation of vascular tone during a number of physiological and pathophysiological conditions. There is particular emphasis on changes in the adrenergic and purinergic components of sympathetic neurotransmission and vascular responses mediated by endothelin receptors. Pharmacological studies and biochemical assays were performed on isolated ring preparations of rat tail and femoral arteries, hamster renal artery, postmortem human cerebral artery and the isolated mesenteric arterial bed of the rat. In the renal artery of the euthermic golden hamster, the responses to stimulation of sympathetic nerves were remarkably enhanced during hibernation and to a lesser extent with exposure to cold. This enhancement occurred at both pre- and post-junctional levels and mostly involved the noradrenergic component of sympathetic cotransmission through α1-adrenoceptors. Chronic treatment of Donryu rats with a cholestrol- supplemented diet led to altered levels of circulating lipid fractions, accompanied by reduced sympathetic neurotransmission and reduced noradrenaline content of the tail artery. This alteration was predominantly prejunctional and mostly involved the noradrenergic component of perivascular sympathetic co-transmission. Chronic inhibition of the actions of endogenous adenosine by 1,3-dipropyl-8-sulfophenylxanthine (DPSPX) resulted in hypertension accompanied by enhanced sympathetic cotransmission and enhanced noradrenaline content of the rat tail artery. This alteration was predominantly prejunctional, both noradrenergic and purinergic components of perivascular sympathetic neurotransmission being enhanced during DPSPX- induced hypertension. Long-term sensory-motor denervation by neonatal capsaicin treatment resulted in augmentation of sympathetic neurotransmission in the isolated mesentric arterial bed, accompanied by enhanced noradrenaline content of the proximal mesentric artery of the rat. This augmentation occurred at both pre- and post-junctional levels. Endothelins were shown to produce both contraction and relaxation of blood vessels, mediated by their actions on vascular smooth muscle and endothelial cells via ETA and ETB receptor subtypes, respectively. In rat femoral artery, agonist profile and selective antagonist inhibition of contractile responses to endothelin-1, suggested predominance of ETA receptors. In addition to direct vasoconstrictor actions on smooth muscle, endothelin-1 inhibits endothelium-dependent relaxation. The existance of P2X purinoceptors in postmortem human cerebral artery, was demonstrated functionally and by localization of specific binding sites to P2X purinoceptors radioligand and antibody on vascular smooth muscle. It is concluded that autonomic innervation of blood vessels shows remarkable plasticity in both physiological and pathophysiological conditions.

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