Identification of endothelial H1, vascular H2 and cardiac presynaptic H3 receptors in the pithed rat

Abstract

In pithed and vagotomized rats the effects of the H₃ receptor agonist R-(−)-α-methylhistamine, the H₁ receptor agonist 2-(2-thiazolyl)ethylamine and the H₂ receptor agonist dimaprit on basal diastolic blood pressure, basal heart rate and the electrically induced rise in heart rate were examined. Basal diastolic blood pressure was not altered by low, but increased by high doses of R-(−)-α-methylhistamine; the latter effect was not affected by selective H₁, H₂ or H₃ receptor antagonists and by prazosin, but was attenuated by rauwolscine. Rauwolscine also unmasked a vasodepressor response to R-(−)-α-methylhistamine not affected by the H₃ receptor antagonist thioperamide, but counteracted by the H₁ receptor antagonist dimetindene or the H₂ receptor antagonist ranitidine. The vasodepressor responses to 2-(2-thiazolyl)ethylamine and dimaprit were antagonized by dimetindene and ranitidine, respectively. The vasodepressor response to 2-(2-thiazolyl)ethylamine was not altered by indomethacin, but reduced by an inhibitor of endothelial nitric oxide synthase, N^ω-nitro-L-arginine methyl ester (which, by itself, markedly increased blood pressure). Both drug tools did not alter the effect of dimaprit. Basal heart rate was not affected by 2-(2-thiazolyl)ethylamine (examined after administration of propranolol), dimaprit and R-(−)-α-methylhistamine. The electrically induced increase in heart rate (studied in animals which had received rauwolscine) was decreased by R-(−)-α-methylhistamine but not affected by 2-(2-thiazolyl)ethylamine and dimaprit. The effect of R-(−)-α-methylhistamine was abolished by thioperamide. R-(−)-α-methylhistamine did not influence the increase in heart rate produced by isoprenaline. In conclusion, the pithed rat offers the opportunity to study cardiac presynaptic H₃ receptors, endothelial H₁ receptors and vascular H₂ receptors in the same experimental model. Cardiac presynaptic H₁ and H₂ receptors as well as postsynaptic H₃ receptors in the heart and in the resistance vessels were not found. R-(−)-α-methylhistamine is a weak agonist at α₂, H₁ and H₂ receptors.