Effects of PKC isozyme inhibitors on constrictor responses in the feline pulmonary vascular bed

The effects of Gö-6976, a Ca2+-dependent protein kinase C (PKC) isozyme inhibitor, and rottlerin, a PKC-δ isozyme/calmodulin (CaM)-dependent kinase III inhibitor, on responses to vasopressor agents were investigated in the feline pulmonary vascular bed. Injections of angiotensin II, norepinephrine (NE), serotonin, BAY K 8644, and U-46619 into the lobar arterial constant blood flow perfusion circuit caused increases in pressure. Gö-6976 reduced responses to angiotensin II; however, it did not alter responses to serotonin, NE, or U-46619, whereas Gö-6976 enhanced BAY K 8644 responses. Rottlerin reduced responses to angiotensin II and NE, did not alter responses to serotonin or U-46619, and enhanced responses to BAY K 8644. Immunohistochemistry of feline pulmonary arterial smooth muscle cells demonstrated localization of PKC-α and -δ isozymes in response to phorbol 12-myristate 13-acetate and angiotensin II. Localization of PKC-α and -δ isozymes decreased with administration of Gö-6976 and rottlerin, respectively. These data suggest that activation of Ca2+-dependent PKC isozymes and Ca2+-independent PKC-δ isozyme/CaM-dependent kinase III mediate angiotensin II responses. These data further suggest that Ca2+-independent PKC-δ isozyme/CaM-dependent kinase III mediate responses to NE. A rottlerin- or Gö-6976-sensitive mechanism is not involved in mediating responses to serotonin and U-46619, but these PKC isozyme inhibitors enhanced BAY K 8644 responses in the feline pulmonary vascular bed.