Tone-dependent responses of histamine in feline pulmonary vascular bed

Under conditions of controlled pulmonary blood flow and constant left atrial pressure, histamine produced tone-dependent responses in the pulmonary vascular (PV) bed of intact-chest, spontaneously breathing cats. At low, baseline PV tone, histamine produced dose-dependent increases in mean lobar arterial pressure that were antagonized by the selective histamine H₁- receptor antagonist, diphenhydramine. The cyclooxygenase inhibitor, meclofenamate, and the thromboxane A₂ (TxA₂) receptor antagonist, SQ- 29548, had no effect on these vasoconstrictor responses of histamine. After an increase in PV tone with an intralobar arterial infusion of a TxA₂ mimic, U-46619, histamine produced vasodilator responses at low doses, biphasic vasodilator/vasoconstrictor responses at midrange doses, and vasoconstrictor responses at high doses. Diphenhydramine antagonized vasoconstrictor responses and the vasodilator responses of low to midrange doses and enhanced vasodilator responses of high doses of histamine at elevated PV tone. Selective H₂-receptor antagonists, ranitidine and meclofenamate, and selective H₃-receptor antagonist, thioperamide, did not antagonize vasodilator responses of histamine. H₁- and H₂-receptor antagonism was more effective in reducing the vasodilator responses of histamine at elevated PV tone than H₁-receptor antagonism alone. These data support that histamine produces vasoconstrictor responses at low baseline and elevated PV tone by acting on H₁ receptors that do not induce the release of vasoconstrictor prostanoids. At elevated PV tone, histamine produces vasodilation by acting on H₁ receptors that are not coupled to the release of vasodilator prostaglandins and also, in part, by acting on H₂ receptors.