Investigation of the Mechanisms of Excitation and Contraction in Rat Pulmonary and Systemic Resistance Arteries

Abstract

In the pulmonary circulation voltage-gated K+ (KV) channels control resting membrane potential. Their direct contribution to the development of hypoxic pulmonary vasoconstriction (HPV), the unique response of the pulmonary artery (PA) to hypoxia, however remains controversial. KCNQ channels are thought to contribute to the control of PA excitability but their relative contribution compared to the KV channels and the role in HPV is unknown. Recent electrophysiological evidence suggests tight coupling between KV channels and mitochondria, a putative oxygen sensor in PA. No focussed studies to examine these questions in intact arteries were performed. Therefore, the main aims were to investigate: i) a relative role of KV and KCNQ channels in the regulation of PA excitability and contractility, ii) relative sensitivity of these channels to hypoxia, iii) a relationship between KV channels and mitochondria and cellular metabolism, in the intact PA. Rat mesenteric artery (MA) was used as a representative of systemic circulations. Small vessel myography, microelectrode technique, confocal imaging and western blot together with selective pharmacological agents were employed to address these questions. The main findings are: i) the presence of mutual physiological interaction between KV and KCNQ channels in the regulation of PA excitability, ii) KV, but not KCNQ, channels are inhibited by hypoxia in PA, iii) the existence of specific interactions between mitochondria and KV channels which are potentiated and altered in hypoxia in PA, not in MA, iv) these interactions may contribute to contractions caused by the KV inhibition 2+ 2+ additionally to the voltage-dependent Caentry and Rho-kinase dependent Casensitisation, v) contractions are less metabolic dependent in PA than in MA, vi) the effects are not species dependent as some were observed in the mouse. These findings suggest the presence of specific mitochondrial-dependent mechanisms in PA which play role in physiological conditions and in HPV.

Date of Award	1 Aug 2010
Original language	English
Awarding Institution	University of Bath
Supervisor	Sergey Smirnov (Supervisor)