ACTION OF GUANETHIDINE AND RESERPINE UPON THE ISOLATED MAMMALIAN HEART

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts
² Department of Pharmacology, University of Helsinki, Helsinki, Finland

Guanethidine was studied in the heart-lung preparation of normal and reserpine-pretreated dogs (0.5 mg/kg, 48 and 24 hours prior to isolation of the heart). In the normal heart it had a rate-increasing effect which, in the dose range of 1 to 30 mg, lasted for more than 2 hours. The intensity of the effect upon the pacemaker of the heart was due to norepinephrine release and to an acute increase in sensitivity of the pacemaker to norepinephrine caused by the releasing agent. The dose-response curve of the rate-increasing effect of guanethidine began at a higher dose level, was steeper and had a higher maximum than that of reserpine. The maximally effective dose of guanethidine (mw 198) was 30 mg as compared to that of 3 mg for reserpine (mw 608.7). The amounts of norepinephrine released in about 2 hours by 10 to 30 mg of guanethidine and by 3 mg of reserpine, respectively, were of the same order of magnitude.

In the heart-lung preparation of reserpine-pretreated dogs, guanethidine, in the dose range of 1 to 10 mg, had no or very little rate-increasing effect. The dose of 6 mg caused a tenfold increase in the sensitivity of the pacemaker to administered norepinephrine. Reserpine, in a dose of 10 mg, had no sensitizing activity. In the absence of norepinephrine release, guanethidine, in a dose of 3 mg or more, impaired the force of contraction. In equimolar doses it had greater negative inotropic activity than reserpine.

In the intact rat, intraperitoneal injection of 20 mg of guanethidine per kg caused a depletion of the cardiac norepinephrine stores in about 5 hours. Replenishment of the stores required more than 3 days. An equipotent dose of reserpine of 5 mg/kg caused depletion in about 2 hours and replenishment required more than 6 days.