PHORBOL ESTER POTENTIATION OF CANINE PULMONARY VASOREACTIVITY TO HISTAMINE

The effect of phorbol myristate acetate (PMA) on canine pulmonary vaso reactivity to histamine was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured by using vascular occlusion techniques. Histamine (10(-5) M) signific antly increased postcapillary resistance by venoconstriction and signi ficantly attenuated total vascular compliance by decreasing large-vess el compliance and middle-compartment compliance. Pretreatment with the phorbol ester PMA (10(-7) M) significantly potentiated the vasoactive response to histamine and elicited an edemagenic effect in the isolat ed dog lung through modulation of the histaminergic vasoconstrictor ef fect on precapillary resistance, postcapillary resistance, and pulmona ry vascular compliance. Pretreatment with the protein kinase C inhibit ors staurosporine (10(-7) M) and calphostin C (10(-6) M) and the dihyd ropyridine Ca2+ channel blocker nifedipine (10(-5) M) significantly at tenuated the effect of PMA on histaminergic-mediated vasoconstriction. The results of this study indicate that phorbol esters may exert thei r effect on canine pulmonary vasoreactivity predominantly through acti vation of protein kinase C and influx of Ca2+ through voltage-dependen t Ca2+ channels.