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.
McMurtry
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IF
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D008168:Lung / Q000098:blood supply*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010100:Oxygen / Q000502:physiology; D010477:Perfusion; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects*
D007473:Ion Channels; D000001:Calcimycin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D010100:Oxygen; D002118:Calcium