EFFECTS OF INTRACELLULAR AND EXTRACELLULAR CALCIUM BLOCKERS ON THE PULMONARY VASCULAR-RESPONSES TO PGF2-ALPHA AND U46619

In this study, TMB-8, an intracellular calcium antagonist, and verapamil, an extracellular calcium antagonist, were used simultaneously to elucidate the role of calcium in the pulmonary vasopressor response induced by PGF2.alpha. and U46619. The pulmonary vasoconstrictor action of these two agonists was evaluated in the canine isolated lung lobe preparation. Lobar arterial pressure was constantly monitored and changes in arterial pressure were recorded as a percentage from baseline. Control responses to PGF2.alpha. (42.0 .+-. 8.2%) and U46619 (47.2 .+-. 7.0%) were obtained prior to the administration of TMB-8 and verapamil. After administration of TMB-8 and verapamil, the PGF2.alpha. (7.4 .+-. 3.1%) and U46619 (28.8 .+-. 6.2%) responses were significantly attenuated. We conclude that the PGF2.alpha. pressor response is dependent on a TMB-8-sensitive intracellular calcium pool and a verapamil-sensitive slow-channel calcium influx. In contrast, the degree of attenuation of the U46619 response was similar to the vasopressor response in the presence of verapamil alone, as described previously. This indicates a direct dependence on extracellular calcium. An additional source of calcium insensitive to verapamil and TMB-8 may also be activated and contribute to the pulmonary vasoconstrictor action. These results suggest that each agonist possesses a mechanism of action distinctly different from the other.