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Production by R‐α‐methylhistamine of a histamine H 3 receptor‐mediated decrease in basal vascular resistance in guinea‐pigs

1993; Wiley; Volume: 110; Issue: 2 Linguagem: Inglês

10.1111/j.1476-5381.1993.tb13846.x

1476-5381

Robbie L. McLeod, Sheldon B. Gertner, John A. Hey,

Food Allergy and Anaphylaxis Research

The effect of the selective histamine H 3 receptor agonist, R ‐α‐methylhistamine given intravenously (10–100 μg kg −1 ) was examined on baseline total peripheral resistance (TPR), and cardiovascular haemodynamics in bilaterally vagotomized, anaesthetized guinea‐pigs. R ‐α‐methylhistamine produced a dose‐dependent hypotension and fall in TPR at 30 and 100 μg kg −1 . A decrease in heart rate (HR) was observed at a dose of 100 μg kg −1 . R ‐α‐methylhistamine (10–100 μg kg −1 ) also produced a dose‐dependent fall in rate pressure product (RPP). There was no effect on cardiac output (CO) or stroke volume (SV) at these doses. Histamine H 1 and H 2 blockade in animals pretreated with a combination of chlorpheniramine (0.3 mg kg −1 ) and cimetidine (3.0 mg kg −1 ) did not alter the haemodynamic actions of R ‐α‐methylhistamine (100 μg kg −1 , i.v.). Pretreatment with the selective H 3 antagonist, thioperamide (1 mg kg −1 ), completely blocked the action of R ‐α‐methylhistamine on haemodynamic parameters. To study the mechanism of action of R ‐α‐methylhistamine, the vasodilator hydralazine (1 mg kg −1 , i.v.) was used. Hydralazine lowered BP, TRP and RPP in guinea‐pigs pretreated with ipratropium (50 μg kg −1 , i.v.). Hydralazine had no effect on HR, SV or CO. R ‐α‐methylhistamine (100 μg kg −1 ) did not affect the vasopressor action and increases in TPR produced by adrenaline (1 and 3 μg kg −1 ). On the other hand, the vasodilator hydralazine (1 mg kg −1 , i.v.) inhibited the effects of adrenaline (3 μg kg −1 ) on TPR and RPP. The effect of both doses of adrenaline on BP were attenuated by hydralazine. Therefore, the inhibitory effects of R ‐α‐methylhistamine are not mediated through a direct action on vascular smooth muscle. In adrenalectomized guinea‐pigs, R ‐α‐methylhistamine (100 μg kg −1 ) produced a drop in BP and HR. There was no difference between the effects of R ‐α‐methylhistamine on blood pressure and heart rate in adrenalectomized and non‐adrenalectomized guinea‐pigs. These results show that activation of peripheral H 3 receptors lowers basal BP, HR and TPR, most likely by a peripheral prejunctional mechanism. The fall in BP and TPR is probably due to a decrease in noradrenaline release from sympathetic effector nerves innervating the resistance blood vessels.