Responses to L-163,491, a nonpeptide angiotensin II mimic, in the pulmonary vascular bed of the cat

The effects of the non-peptide antagonist DuP 753 and its metabolite EXP3174 on responses to angiotensin II were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, injections of angiotensin II into the perfused lobar artery caused dose-related increases in lobar arterial pressure. Responses to angiotensin II were reproducible and were not changed by meclofenamate or prazosin, indicating that prostaglandin or norepinephrine release does not mediate or modulate pulmonary vascular responses to the peptide. DuP 753 (1–5 mg/kg iv) decreased responses to angiotensin II in a competitive manner, and the duration of the blockade was related to dose of the antagonist. DuP 753 had no significant effect on responses to U-46619, norepinephrine, serotonin, endothelin-1, vasopressin, or BAY K 8644. EXP3174 also decreased responses to angiotensin II without altering responses to agents that act by a variety of mechanisms. The inhibitory effect of EXP3174 (1 mg/kg iv) was not overcome by angiotensin II in the range of doses studied, and the shift to the right of the dose-response curve was nonparallel, suggesting that the blockade was noncompetitive. The blockade was long in duration, and, when the dose of EXP3174 was decreased to 0.1 mg/kg iv, the blockade was surmounted and the shift to the right of the dose-response relationship was parallel. DuP 753 and EXP3174 had little effect on mean baseline pressures in the cat.(ABSTRACT TRUNCATED AT 250 WORDS)

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.1.l50 ◽

2001 ◽

Vol 280 (1) ◽

pp. L50-L57 ◽

Cited By ~ 11

Author(s):

Bracken J. De Witt ◽

Alan D. Kaye ◽

Ikhlass N. Ibrahim ◽

Trinity J. Bivalacqua ◽

Fiona M. D'Souza ◽

...

Keyword(s):

Angiotensin Ii ◽

Bay K 8644 ◽

Kinase C ◽

Vascular Bed ◽

Flow Perfusion ◽

Dependent Protein ◽

Vasopressor Agents ◽

Pkc Isozymes ◽

Pulmonary Arterial ◽

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.

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