Pulmonary vascular tone is increased by a voltage-dependent calcium channel potentiator

Abstract

The mechanism of hypoxia-induced pulmonary vasoconstriction remains unknown. To explore the possible dependence of the hypoxic response on voltage-activated calcium (Ca2+) channels, the effects of BAY K 8644 (BAY), a voltage-dependent Ca2+ channel potentiator, were observed on the pulmonary vascular response to hypoxia of both the intact anesthetized dog and the perfused isolated rat lung. In six rat lungs given BAY (1 .times. 10-6 M), hypoxia increased mean pulmonary arterial pressure (Ppa) to 30.5 .+-. 1.7 (SEM) Torr compared with 14.8 .+-. 1.2 Torr for six untreated rat lungs (P < 0.01). After nifedipine, the maximum Ppa during hypoxia fell 14.1 .+-. 2.4 Torr from the previous hypoxic challenge in the BAY-stimulated rats (P < 0.01). BAY (1.2 .times. 10-7 mol/kg) given during normoxia in seven dogs increased pulmonary vascular resistance 2.5 .+-. 0.3 to 5.0 .+-. 1.2 Torr .cntdot. l-1 .cntdot. min (P < 0.05), and systemic vascular resistance 55 .+-. 4.9 to 126 .+-. 20.7 Torr .cntdot. l-1 .cntdot. min (P < 0.05). Systemic mean arterial pressure rose 68 Torr, whereas Ppa remained unchanged. Administration of BAY during hypoxia produced an increase in Ppa: 28 .+-. 1.5 to 33 .+-. 1.9 Torr (P < 0.05). Thus BAY, a Ca2+ channel potentiator, enhances the hypoxic pulmonary response in vitro and in vivo. This, together with the effect of nifedipine on BAY potentiation, suggest that increased Ca2+ channel activity may be important in the mechanism of hypoxic pulmonary vasoconstriction.