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Production by R-alpha-methylhistamine of a histamine H3 receptor-mediated decrease in basal vascular resistance in
R L McLeod1, S B Gertner, J A Hey
1Department of Pharmacology and Toxicology, New Jersey Medical School-UMDNJ, Newark.
British Journal of Pharmacology
|October 1, 1993
Summary
The selective histamine H3 receptor agonist, R-alpha-methylhistamine, lowers blood pressure and total peripheral resistance in guinea pigs. This effect is mediated by peripheral H3 receptors, likely through reduced noradrenaline release from sympathetic nerves.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Neuroscience
Background:
- Histamine receptors play a role in regulating cardiovascular function.
- The specific role of peripheral histamine H3 receptors in blood pressure regulation is not fully understood.
- Investigating novel targets for cardiovascular drug development is crucial.
Purpose of the Study:
- To investigate the cardiovascular effects of the selective histamine H3 receptor agonist, R-alpha-methylhistamine.
- To determine the mechanism of action underlying these cardiovascular effects.
- To explore the potential of peripheral H3 receptors as a therapeutic target for hypertension.
Main Methods:
- Administration of R-alpha-methylhistamine intravenously to bilaterally vagotomized, anesthetized guinea pigs.
- Measurement of cardiovascular parameters including total peripheral resistance (TPR), heart rate (HR), blood pressure (BP), cardiac output (CO), and stroke volume (SV).
- Pharmacological blockade of histamine H1 and H2 receptors, and selective H3 receptor antagonism with thioperamide.
- Assessment of interactions with vasodilators (hydralazine) and vasopressors (adrenaline).
- Studies in adrenalectomized guinea pigs.
Main Results:
- R-alpha-methylhistamine induced a dose-dependent hypotension and decreased TPR.
- A decrease in HR and rate pressure product (RPP) was observed, without affecting CO or SV.
- The effects were completely blocked by the H3 antagonist thioperamide, but not by H1/H2 blockade.
- R-alpha-methylhistamine did not directly affect vascular smooth muscle or the pressor response to adrenaline.
- Adrenalectomy did not alter the hypotensive effects of R-alpha-methylhistamine.
Conclusions:
- Activation of peripheral H3 receptors by R-alpha-methylhistamine lowers basal blood pressure, heart rate, and total peripheral resistance.
- The mechanism is likely peripheral and prejunctional, involving a reduction in noradrenaline release from sympathetic nerves innervating resistance blood vessels.
- Peripheral H3 receptors represent a potential target for managing cardiovascular conditions characterized by elevated blood pressure.