Is there a prostaglandin involvement in the positive inotropic action of histamine in isolated pregnant rat uterus, apparently mediated via H1-receptors activation?

Abstract

Cumulative dose-response curves for histamine induced responses in mesometrial (ME) and antimesometrial (AME) regions of uterine horns isolated from rats at 7th, 16th and 22nd days of pregnancy, were constructed. Histamine inhibited, in dose-related fashion, the isometric developed tension in ME and AME strips obtained at the 7th day of pregnancy, an action antagonized by cimetidine (10⁻⁴–10⁻⁵M). On the contrary, at the 16th and 22nd days, histamine (10⁻⁵–10⁻³M), stimulated spontaneous contractions in the ME region but had no effect in the AME segment. Although histamine and SKF-71481-A₂,aH₁-receptor agonist, both at 10⁻⁴M, enhanced similarly ME inotropism at the 16th and at 22nd days of pregnancy, the positive contractile action of histamine was greater at the 16th than at the 22nd day. Moreover, cumulative dose-response curves for histamine and SKF-71481-A₂ in the ME region of uteri isolated at the 16th day of gestation, showed that both agonists have approximately the same inotropic potency and efficacy. On the other hand, pyrilamine (at 10⁻⁴M, but not at 10⁻⁵M),aH₁-receptor antagonist, shifted to the right the dose-response curve for histamine in ME strips from uteri at the 16th day of pregnancy and attenuated significantly, the magnitude of the positiue inotropism evoked by the amine. Similar findings were observed in the presence of chlorpheniramine (at 10⁻⁶M) another H₁-receptor blacker. In addition, the positive uterine inotropism evoked by histamine in the ME region of preparations isolated at the 16th day of pregnancy, was significantly reduced by an antagonist of phospholipase A₂ (mepacrine, 10⁻⁴M) as well as by acetylsalicylic acid (ASA at 10⁻⁴M), an inhibitor of cyclooxygenase. Results also indicate that the excitatory uterine inotrpism elicited by the agonistic amine in ME strips isolated from rats at the 16 th day of pregnancy, was coincident with an enhanced release of prostaglandins (PGs) E₂ and F₂ α, but not of PGE₁ and that both augmenting actions of histamine were antagonized by histamine H₁ receptor-blockers, namely pyrilamine (mepyramine or chlorpheniramine. Results suggest that histamine at early pregnancy diminished myometrial inotropism via its interaction with H₂-receptors, whereas from mid pregnancy up to the moment of parturition it evokes contractile stimulation, most likely due to the activation of H₁-receptor located at the mesometrial region of rat uterine horns. Altogether the present data suggest that after mid pregnancy, histamine acts at the ME region of the uterus through a cascade of influences: (a) activation of H₁ receptors, (b) stimulation of phospholipase A₂ (via an increased permeability of calcium ions?), which catalyzes the release of a PG fatty acid precursor (most likely arachidonic acid rather than dihomo-gamma-linolenic acid) providing a substrate for cyclo-oxygenase and further enzymes involved in the synthesis of bioactive lipid metabolites of the 2 series (PGE₂ and PGF₂ α), and as a consequence,(c) induction of positive myometrial inotropism.