CHARACTERISTICS AND MECHANISM OF INOTROPIC AND CHRONOTROPIC ACTIONS OF BRETYLIUM TOSYLATE

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

The inotropic and chronotropic effects of bretylium were studied in kitten papillary muscles and guinea-pig left atrial strips. Increases in tension development and pacemaker rate appeared at 3 x 10^-6 to 10^-5 M bretylium and reached their maximum with 10^-4 to 3 x 10^-4 M. At 60 contractions/min optimal concentrations increased tension development by 505 ± 54% in atrial strips and by 81 ± 10% in papillary muscles. The mean maximum increase in pacemaker rate was 44%. Positive inotropic effects of bretylium were associated with increases in the rate of tension development and decreases in the time to peak tension. They persisted during five hours of exposure to the drug. No positive inotropic or chronotropic responses to bretylium were observed in myocardium from reserpine-treated animals or in the presence of 10^-6 M propranolol. Under such conditions bretylium slowed relaxation. Bretylium did not alter inotropic responses to isoproterenol but limited further inotropic action of tyramine. Release of norepinephrine from sympathetic nerve endings in heart muscle by electrical stimulation was inhibited by bretylium concentrations lower than those which released norepinephrine. It is concluded that the marked positive chronotropic and inotropic actions of bretylium on atrial and ventricular muscle are entirely indirect and due to release of endogenous norepinephrine. The inotropic action of bretylium varies both with drug concentration and with the pre-existing rate of sympathetic discharge.

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