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U-54,669F: a novel hypotensive agent.

M G Wendling, D W DuCharme, G A Johnson

    Federation Proceedings
    |February 1, 1983
    PubMed
    Summary
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    The novel antihypertensive agent U-54,669F effectively lowers blood pressure in rats and monkeys. This drug reduces norepinephrine levels and peripheral sympathetic function without affecting central nervous system activity.

    Area of Science:

    • Pharmacology
    • Cardiovascular Research
    • Neuroscience

    Background:

    • Hypertension remains a significant global health concern requiring novel therapeutic agents.
    • Understanding the mechanisms of existing antihypertensive drugs is crucial for developing safer and more effective treatments.

    Purpose of the Study:

    • To investigate the antihypertensive effects and mechanism of action of the novel agent U-54,669F.
    • To determine the drug's impact on sympathetic nerve activity, norepinephrine levels, and vascular responses.

    Main Methods:

    • Oral administration of U-54,669F to conscious spontaneously hypertensive and normotensive rats, and conscious monkeys.
    • Assessment of dose-related hypotensive responses, repetitive dosing effects, sympathetic nerve activity, and norepinephrine levels in plasma and tissues.

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  • Evaluation of vascular responses to sympathetic nerve stimulation and orthostatic stress tolerance.

    • Main Results:

    • U-54,669F produced dose-related hypotensive effects in rats and monkeys with sustained efficacy over one week.
    • The drug decreased plasma and tissue norepinephrine levels but did not alter brain norepinephrine.
    • Hypotensive responses were blunted in spinal cats, and vascular responses to sympathetic stimulation were attenuated, suggesting peripheral action.

    Conclusions:

    • U-54,669F exhibits potent antihypertensive properties through peripheral modulation of sympathetic neurogenic function.
    • The agent appears to act peripherally, without significant central nervous system penetration, and does not impair orthostatic stress tolerance at effective hypotensive doses.