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

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(I(K))-and morphology. Cells are referred to as "K(Ca), K(Dr), or mixed," acknowledging the type of K+ channel that dominates the IK: the Ca2+-sensitive (K(Ca)) channel, delayed rectifier (K(Dr)) channel, or a mixture of both. The three cell types were identified by light and electron microscopy. K(Ca) 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). K(Dr) 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 K(Ca) cells, whereas resistance arteries have a majority of K(Dr) cells and few K(Ca) cells. NO rapidly and reversibly increases I(K) and hyperpolarizes K(Ca) cells because of an increase in open probability of a 170-pS K(Ca) channel. Hypoxia depolarizes K(Dr) cells by rapidly and reversibly inhibiting one or more of the tonically active K(Dr) 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 K(Dr)-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.

Role of NO pathway, calcium and potassium channels in the peripheral pulmonary vascular tone in dogs

“…The present experiments operated on a peripheral portion of the pulmonary vascular bed where the arteries are mainly resistance arteries. As we did not ®nd any activity of K ATP channel openers, these results are consistent with those of Archer et al [26].…”

“…In conduit arteries, the calcium activated K + channels (K Ca channels) are predominant. No K ATP cell was identi®ed in resistance arteries which have a majority of voltage-gated potassium (K v ) channels [26]. Nine families of K v channels are recognized from cloning studies (K v1 ±K v9 ), each with subtypes.…”

Preferential Vasodilator Effects of Levosimendan in Resistance Pulmonary Arteries in a Rodent Pulmonary Embolism Model

“…The pulmonary vasculature consists of large, elastic, extraparenchymal conduit pulmonary arteries (CPA, order 1 to 2) that arise from the sixth aortic arch and small, muscular resistance intrapulmonary arteries (RPA, ≥ 4th order), that originate from the mesenchymal lung bud by capillary plexus expansion [1]. This subdivision is associated with different response to several stimuli.…”

“…While CPA dilates or fails to constrict to hypoxia, RPA is responsible for hypoxic pulmonary vasoconstriction, control the regional distribution of blood flow and largely determine pulmonary vascular resistance. This functional difference mainly depends on the distribution of electrophysiologically distinct myocytes in CPAs and RPAs arteries [1,2].Levosimendan is a positive inotropic agent (by increasing the sensitivity of troponin C to calcium) with vasodilating properties (by lowering of intracellular free Ca++, opening of different potassium channels and the inhibition of phosphodiesterase type III), also termed inodilator [3,4]. There are several animals studies in different acute pulmonary hypertension (PH) models secondary to thromboxane A2 infusion [5], endotoxemia [6], acute pulmonary embolism (PE) [7,8], and hypoxia [9] and some clinical studies that demonstrated the vasodilator effect of levosimendan on the pulmonary circulation, restoring right ventricular-arterial coupling as it increased right ventricular contractility concomitantly [10,11].…”

Pre–B-cell Colony-Enhancing Factor Regulates Vascular Smooth Muscle Maturation Through a NAD + -Dependent Mechanism

“…1 Moreover, many vibrant "vascular villages" display rich diversity within a single vascular segment, with heterogeneity in SMCs that exist side by side. 2,3 The article by Pickering's group addresses the molecular mechanism underlying a form of SMC diversity that has morphological and functional aspects; namely the existence of synthetic versus contractile SMCs. 4 It is an important contribution because, in addressing their own hypothesis, they reveal a mechanism that has relevance to several unresolved questions in vascular biology.…”