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Endothelin‐1 activates voltage‐gated Ca2+ channels via protein kinase C (PKC) and rho kinase in pulmonary arterial smooth muscle cells (PASMCs) isolated from chronically hypoxic rats

Chronic hypoxia (CH), as occurs with many lung diseases, is a major cause of pulmonary hypertension. The vasoconstrictor, ET‐1 plays a role in the development of hypoxic pulmonary hypertension. In PASMCs from chronically hypoxic rats, ET‐1 signaling is altered, with the change in intracellular Ca2+ concentration (Δ[Ca2+]i) occurring via activation of voltage‐gated Ca2+ channels (VGCCs) independent of depolarization. We previously demonstrated that ET‐1‐induced activation of VGCCs in PASMCs from rats exposed to CH could be attenuated by inhibitors of PKC or rho kinase. In the current study, we tested whether activators of PKC and rho kinase stimulate Ca2+ entry through VGCCs, and whether the two kinases are acting through the same or additive pathways in response to ET‐1. [Ca2+]i was measured using the Ca2+‐sensitive dye, Fura‐2, and fluorescent microscopy in PASMCs from rats exposed to CH (10% O2, 3 wks). Similar attenuation of the response to ET‐1 was observed using Y‐27632 (rho kinase inhibitor), staurosporine (PKC inhibitor), and genistein (tyrosine kinase inhibitor), either individually or in combination. Guanosine 5′‐[γ‐thio]triphosphate tetralithium salt (GTP‐γ‐S) and phorbol 12‐myristate 13‐acetate (PMA), rho kinase and PKC activators, respectively, caused an increase [Ca2+]i that was inhibited by pretreatment with nifedipine, a VGCC antagonist. Our data suggest that following exposure to CH, the ET‐1‐induced [Ca2+]i in PASMCs is due to activation of Ca2+ influx through VGCCs, via a pathway that includes PKC, rho kinase, and tyrosine kinase.