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Central administration of PD 123319 or EXP-3174 inhibits effects of angiotensin II
R E Widdop1, S M Gardiner, P A Kemp
1Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, United Kingdom.
Insights
Intracerebroventricular angiotensin II (ANG II) triggers cardiovascular changes in rats. Both AT1 and AT2 receptor antagonists block these effects, suggesting receptor interdependence or unique drug metabolism.
Area of Science:
- Cardiovascular Physiology
- Neuroendocrinology
- Pharmacology
Background:
- Angiotensin II (ANG II) plays a crucial role in regulating cardiovascular function.
- The central nervous system, particularly the brain, is a key site for ANG II's actions.
- Understanding the specific receptor subtypes involved in ANG II's central effects is vital for therapeutic development.
Purpose of the Study:
- To investigate the cardiovascular responses to intracerebroventricular ANG II in conscious rats.
- To determine the roles of AT1 and AT2 receptors in mediating these central ANG II effects.
- To compare the inhibitory profiles of AT2 receptor antagonist PD 123319 and AT1 receptor antagonist EXP-3174.
Main Methods:
- Conscious rats were chronically instrumented for hemodynamic measurements.
- Cardiovascular responses to intracerebroventricular ANG II were assessed over four days.
- Rats were treated with either the AT2 antagonist PD 123319 or the AT1 antagonist EXP-3174.
Main Results:
- Intracerebroventricular ANG II induced pressor and bradycardic effects, accompanied by vasoconstriction in mesenteric, hindquarters, and renal beds.
- Both PD 123319 and EXP-3174 abolished the cardiovascular responses to intracerebroventricular ANG II.
- PD 123319 produced a prolonged inhibition (1-2 days), while EXP-3174 caused immediate but transient inhibition.
Conclusions:
- The findings suggest concurrent and interdependent activation of AT1 and AT2 receptors mediate ANG II's central hemodynamic effects.
- Alternatively, PD 123319 might be biotransformed in the brain to yield AT1 receptor antagonist activity.
- These results highlight the complex central regulation of cardiovascular function by ANG II.
Abstract:
Cardiovascular responses to intracerebroventricular angiotensin II (ANG II) were measured in conscious rats, chronically instrumented for the measurement of regional hemodynamics, over 4 consecutive days in the absence and presence of either the AT2 receptor antagonist, PD 123319 (experiment 1), or the AT1 receptor antagonist, EXP-3174 (experiment 2). Intracerebroventricular ANG II had pressor and bradycardic effects, which were associated with marked mesenteric and hindquarters vasoconstriction, and a small transient renal vasoconstriction. Both PD 123319 and EXP-3174, given intracerebroventricularly, abolished the cardiovascular response to intracerebroventricular ANG II, although the profiles of activity of the compounds were different. PD 123319 caused a slowly developing, but remarkably prolonged (1-2 days) inhibition of the effects of ANG II, whereas EXP-3174 caused an immediate inhibition of the effects of ANG II, although responses to ANG II had returned to control levels by the following day. These data suggest that the hemodynamic effects of ANG II may involve concurrent, and interdependent, activation of AT1 and AT2 receptors or that PD 123319 undergoes a unique biotransformation in the brain to some product(s) with AT1 receptor antagonist activity.