Influence of bisindolylmalemide I on vasoconstrictor responses in the pulmonary vascular bed of the cat

Objective: Protein kinase C s known to contain at least three regions; the catalytic, the regulatory, and the ATP-domains. It has pre viously been shown that the alkaloid staurosporine, an inhibitor of the protein kinase C catalytic domain, reduced pressor responses to norepinephrine and angiotensin II in the pulmonary circulation. However, vasopressor responses following blockade of the protein kinase C ATP-dependent domain have not been investigated in the pulmonary vascular bed. Material and Methods: The effects of bisin dolylmaleimide 1 (GF 109203X), an ATP-dependent domain protein kinase Cinhibitor, or pressor responses to angiotensin II, the throm boxane A2 mimic, U46619, norepinephrine, serotonin, and the calcium channel agonist, Bay K 8644, were studied in the pulmonary vascular bed of the intact-chest anesthetized cat. Under conditions of constant lobar blood flow, injections of the angiotensin II, U46619, into the lobar arterial perfusion circuit caused dose related increases in lobar arterial pressure and responses were reproducible with respect to time. Results: Infusion of bisindolylmaleimide I into the perfused lobar artery at 5 μg/kg/min for 10 minutes reduced the pressor response to the angiotensin II, however, bisindelyl-maleimide I did not after responses to U46619, norepinephrine or serotonin, while responses to Bay K B644 were enhanced. Conclusions: These data support the hypothesis that responses to angiotensin II are mediated in part through activation of protein kinase Cand that blockade of the protein kinase C ATP-domain will significantly decrease angiotensin II responses. Also, these data suggest that inhibition of the protein kinase CATP domain does not significantly alter norepinephrine-mediated pressor responses in the pulmonary vascular bed of the cat.