Ca2 Sparks Elicit Membrane Depolarization in Pulmonary Artery Smooth Muscle Cells

A major difference in the physiological function between Ca2+ sparks of pulmonary and systemic myocytes is their role in £m regulation. Em of adult rat intralobar PASMCs, when measured using perforated-patch to avoid disturbing subcellular Ca2+ dynamics, is usually less quiescent than those recorded under conventional whole-cell configuration. Small sporadic depolarizations are frequently observed. Activation of Ca2+sparks with a subthreshold concentration (0.5 mM) (Fig. 1 A) ofcaffeine elicits immediate membrane depolarizations from an averaged Em of-45 to -37 mV that can be completely blocked by ryanodine (Fig. IB) (39). This is in sharp contrast to the hyperpolarization elicited by Ca2+ sparks in systemic myocytes and raises the possibility that Ca2+ sparks may contribute to vasoconstriction, rather than vasorelaxation.

The disparity from systemic myocytes is likely due to i) diminished influence of KCa channels, ii) prominent expression of ClCa channels, and Hi) activation of other Ca2+ dependent membrane transporters in rat PASMCs. Developmental studies showed that Ca2+ sparks and STOCs are very active in fetal rabbit PASMCs (38). However, the occurrence of STOCs, the expression of KCa protein and mRNA and the responses of [Ca2+]| to KCa channel blockers in distal PASMCs diminished with maturation (38, 40). The lower expression of KCa channels in adult PASMCs, and/or less effective coupling between RyRs and KCa channels may compromised the ability of Ca2+ spark to induce hyperpolarization. On the other hand, prominent ClCo channels and STICs are found in PASMCs of several species. A recent study shows that metabolic inhibition with a low concentration of cyanide (1 mM) which has no effect on global [Ca2+]; activates Ca2+ sparks and elicits STICs in rat PASMCs (50), suggesting a close association between Ca2+ sparks and ClCa channels. Moreover, ion channels are differentially expressed in PASMCs, such that ClCa and voltage-gated K+ (Kv) channels are more abundant and KCa channels are much reduced in PASMCs of distal arteries (1, 46). The specific distributions of ion channels, hence, allow Ca2+ sparks to preferentially exert its depolarizing influence in distal resistant arteries. In addition, Ca2+ sparks may cause further depolarization by inhibiting Kv channels (15) and by activating the electrogenic Na+/Ca2+ exchange.

In contrast to adult rat distal PASMCs, Ca2+ sparks primarily activate KCa channels to generate STOCs, causing membrane hyperpolarization and relaxation in fetal PASMCs (38, 40), similar to systemic arterial myocytes. Normoxia or high 02 tension activates this Ca2+ spark/KCa channel mechanism to elicit 02-pulmonary vasodilation, which is critical for the transition to air breathing. Malfunction of this mechanism is found to be associated with an experimental model of pulmonary hypertension of the newborn. Moreover, STOCs have been recorded in small pulmonary arteries of adult rabbit (3). Therefore, the net effect of sparks on may depend on developmental state, species, and location, all of which have significant bearings on the relative activities of the counteracting Ca2+-activated channels in PASMCs.

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