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

The effects of Go-6976, a Ca2+-dependent protein kinase C (PKC) isozyme inh ibitor, and rottlerin, a PKC-delta isozyme/calmodulin (CaM)-dependent kinas e III inhibitor, on responses to vasopressor agents were investigated in th e feline pulmonary vascular bed. Injections of angiotensin II, norepinephri ne (NE), serotonin, BAY K 8644, and U-46619 into the lobar arterial constan t blood flow perfusion circuit caused increases in pressure. Go-6976 reduce d responses to angiotensin II; however, it did not alter responses to serot onin, NE, or U-46619, whereas Go-6976 enhanced BAY K 8644 responses. Rottle rin reduced responses to angiotensin II and NE, did not alter responses to serotonin or U-46619, and enhanced responses to BAY K 8644. Immunohistochem istry of feline pulmonary arterial smooth muscle cells demonstrated localiz ation of PKC-alpha and -delta isozymes in response to phorbol 12-myristate 13-acetate and angiotensin II. Localization of PKC-alpha and -delta isozyme s decreased with administration of Go-6976 and rottlerin, respectively. The se data suggest that activation of Ca2+-dependent PKC isozymes and Ca2+-ind ependent PKC-delta isozyme/ CaM-dependent kinase III mediate angiotensin II responses. These data further suggest that Ca2+-independent PKC-delta isoz yme/ CaM-dependent kinase III mediate responses to NE. A rottlerin- or Go-6 976-sensitive mechanism is not involved in mediating responses to serotonin and U-46619, but these PKC isozyme inhibitors enhanced BAY K 8644 response s in the feline pulmonary vascular bed.