Differential Distribution of Electrophysiologically Distinct Myocytes in Conduit and Resistance Arteries Determines Their Response to Nitric Oxide and Hypoxia

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Abstract
The cellular mechanisms that determine differences in reactivity of arteries of varying size and origin are unknown. We evaluated the hypothesis that there is diversity in the distribution of K+ channels between vascular smooth muscle (VSM) cells within a single segment of the pulmonary arteries (PAs) and that there are differences in the prevalence of these cell types between conduit and resistance arteries, which contribute to segmental differences in the vascular response to NO and hypoxia. Three types of VSM cells can be identified in rat PAs on the basis of their whole-cell electrophysiological properties—current density and the pharmacological dissection of whole-cell K+ current (IK)—and morphology. Cells are referred to as “KCa, KDR, or mixed,” acknowledging the type of K+ channel that dominates the IK: the Ca2+-sensitive (KCa) channel, delayed rectifier (KDR) channel, or a mixture of both. The three cell types were identified by light and electron microscopy. KCa cells are large and elongated, and they have low current density and currents that are inhibited by tetraethylammonium (5 mmol/L) or charybdotoxin (100 nmol/L). KDR cells are smaller, with a perinuclear bulge, but have high current density and currents that are inhibited by 4-aminopyridine (5 mmol/L). Conduit arteries contain significant numbers of KCa cells, whereas resistance arteries have a majority of KDR cells and few KCa cells. NO rapidly and reversibly increases IK and hyperpolarizes KCa cells because of an increase in open probability of a 170-pS KCa channel. Hypoxia depolarizes KDR cells by rapidly and reversibly inhibiting one or more of the tonically active KDR channels (including a 37-pS channel) that control resting membrane potential. The effects of both hypoxia and NO on K+ channels are evident at negative membrane potentials, supporting their physiological relevance. The functional correlate of this electrophysiological diversity is that KDR-enriched resistance vessels constrict to hypoxia, whereas conduit arteries have a biphasic response predominated by relaxation. Although effective in both segments, NO relaxes conduit more than resistance rings, in both cases by a cGMP-dependent mechanism. We conclude that regional electrophysiological diversity among smooth muscle cells is a major determinant of segmental differences in vascular reactivity.