THRESHOLD DOSE AND TIME COURSE OF NOREPINEPHRINE DEPLETION OF THE MAMMALIAN HEART BY RESERPINE

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts

The heart rate-increasing effect of a challenging dose of 3 mg reserpine given to the heart-lung preparation of the dog is a reliable measure of the cardiac content of intrinsic sympathomimetic catechol amines, especially norepinephrine. There is a close correlation between increase in heart rate decrease in right atrial pressure and content of norepinephrine in the heart. Hexamethonium does not prevent the release of norepinephrine from the heart in the heart-lung preparation. Reserpine in a single dose of 100 µg/kg given i.p. in the dog depletes the heart of norepinephrine in 24 hours without causing any apparent side effect. After 6 days some accumulation becomes detectable, by 10 to 20 days normal stores of norepinephrine are again found. In depleting the heart of norepinephrine reserpine has a marked cumulative action. In the dog a dose of 10 µg/kg given i.p. once a day on 2 successive days and a dose of 3, µg/kg given once a day on 10 successive days lead to a heart depleted of norepinephrine 24 hours after the last dose.

The dose of 3 µg/kg is within the therapeutically useful range and depletion of norepinephrine stores in the circulatory system, and possibly in other systems of the human organism, may be of clinical importance, for example, in general anesthesia.

If the mechanism of action of a substance is considered to involve the release of intrinsic norepinephrine, depletion by reserpine might serve as a pharmacological tool to ascertain this involvement.

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