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Am J Physiol Lung Cell Mol Physiol 280: L50-L57, 2001;
1040-0605/01 $5.00
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Vol. 280, Issue 1, L50-L57, January 2001

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

Bracken J. De Witt, Alan D. Kaye, Ikhlass N. Ibrahim, Trinity J. Bivalacqua, Fiona M. D'Souza, Ronald E. Banister, A. Salam Arif, and Bobby D. Nossaman

Departments of Anesthesiology and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430; and Departments of Anesthesiology and Pharmacology, Tulane University Medical Center, New Orleans, Louisiana 70112

The effects of Gö-6976, a Ca2+-dependent protein kinase C (PKC) isozyme inhibitor, and rottlerin, a PKC-delta 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-alpha and -delta isozymes in response to phorbol 12-myristate 13-acetate and angiotensin II. Localization of PKC-alpha and -delta isozymes decreased with administration of Gö-6976 and rottlerin, respectively. These data suggest that activation of Ca2+-dependent PKC isozymes and Ca2+-independent PKC-delta isozyme/CaM-dependent kinase III mediate angiotensin II responses. These data further suggest that Ca2+-independent PKC-delta 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.

angiotensin; norepinephrine; calmodulin-dependent kinase III; calcium; BAY K 8644


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