Mechanism Of Hypoxic Pulmonary Vasoconstriction Research Articles

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

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 X 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 less than 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 less than 0.01). BAY (1.2 X 10(-7) mol/kg) given during normoxia in seven dogs increased pulmonary vascular resistance 2.5 +/- 0.3 to 5.0 +/- 1.2 Torr X 1(-1) X min (P less than 0.05), and systemic vascular resistance 55 +/- 4.9 to 126 +/- 20.7 Torr X 1(-1) X min (P less than 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 less than 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, suggests that increased Ca2+ channel activity may be important in the mechanism of hypoxic pulmonary vasoconstriction.

BAY K 8644 potentiates and A23187 inhibits hypoxic vasoconstriction in rat lungs

The susceptibility of hypoxic pulmonary vasoconstriction to inhibition by Ca2+ channel antagonists suggests that membrane depolarization and Ca2+ influx are components of the hypoxic mechanism. Recent characterization of BAY K 8644 as a 1,4-dihydropyridine that facilitates Ca2+ influx through partially activated voltage-dependent Ca2+ channels provides a new pharmacological tool to further test this idea. Effects of BAY K 8644 on normoxic vascular tone and on hypoxic and angiotensin II-induced vasoconstriction were examined in isolated rat lungs perfused with either blood or physiological salt solution (PSS) containing meclofenamate. Parallel experiments were performed with the Ca2+ ionophore A23187 for comparison with a Ca2+-active agent that does not act selectively on the voltage-dependent Ca2+ channel. Addition of BAY K 8644 (10(-7) to 10(-5) M) to the perfusate did not alter base-line vascular tone of the normoxic lung, but it potentiated hypoxic and angiotensin II pressor responses. For example, addition of 10(-7) M BAY K 8644 to five PSS-perfused lungs increased the hypoxic (5% O2) pressor response from 8.7 +/- 2.1 to 19.5 +/- 4.2 Torr and the angiotensin II (0.1 micrograms) response from 2.1 +/- 0.4 to 6.5 +/- 2.0 Torr. In contrast, addition of A23187 (10(-7) to 10(-6) M) to the perfusate increased normoxic perfusion pressure and inhibited hypoxic vasoconstriction. The respective effects of BAY K 8644 and A23187 were essentially the same in both blood- and PSS-perfused lungs. These results indicate that a Ca2+ channel facilitator and a Ca2+ ionophore have diametric effects on pulmonary vasoreactivity. The marked potentiation of hypoxic vasoconstriction by BAY K 8644 supports the idea that activation of voltage-dependent Ca2+ channels is an important component of the mechanism of hypoxic pulmonary vasoconstriction.