We systematically modified isoproterenol's chemical structure to reduce chronotropic, arrhythmogenic, and vascular side effects. Experiments on dogs showed that the resulting drug, dobutamine, had an inotropic efficacy as great as that of epinephrine due to a direct action on /?, cardiac receptors. However, unlike epinephrine, dobutamine's effect on a and ft, vascular receptors was slight. At equivalent inotropic doses, dobutamine had less than a fourth of the chronotropic effect of isoproterenol. Desmethylimipramine (DMI), which blocks the sympathetic nerve fiber uptake mechanism, had no effect on dobutamine's actions. In contrast, DMI antagonized dopamine's inotropic effect, and marked chronotropic and pressor responses occurred when we used doses of dopamine large enough to elicit a direct inotropic effect. Dobutamine increased the contractility of isolated cat papillary muscles more but the automaticity less than did isoproterenol. In ischemic dog hearts, dobutamine lacked significant arrhythmic activity, whereas dopamine, norepinephrine, and isoproterenol caused severe ectopic activity. In dogs with experimentally induced low cardiac contractility, low cardiac output, and hypotension, dobutamine produced dose-related increases in cardiac contractility and output, restored arterial blood pressure, and reduced total peripheral resistance slightly. In contrast, isoproterenol failed to restore blood pressure, had only a meager effect on cardiac contractility and output, caused extreme tachycardia, and lowered peripheral resistance more than did dobutamine. Norepinephrine, which did not increase cardiac contractility or output as much as dobutamine, excessively elevated peripheral resistance and arterial blood pressure.
KEY WORDSadrenergic receptors arrhythmias dopamine cardiogenic shock isoproterenol myocardial infarction norepinephrine cat papillary muscles dogs• Isoproterenol has great inotropic efficacy; moreover, it does not cause the vasoconstriction and the rise in arterial blood pressure associated with the naturally occurring catecholamines, norepinephrine, epinephrine (1) and dopamine, if a narrow dose range is exceeded (2-6). However, the therapeutic value of isoproterenol for the treatment of acutely depressed cardiac contractility is limited by its chronotropic activity. Isoproterenol administration like that of the naturally occurring catecholamines involves a considerable risk of arrhythmia (7). Moreover, the strong activity of isoproterenol on the f3 2 receptors (1) of the peripheral vasculature is disadvantageous because these receptors predominate in skeletal muscles, which constitute nearly half of the body's mass. Consequently, vig- Circulation Research, Vol. 36, January 1975 orous stimulation of y3 2 receptors wastefully diverts a large portion of the cardiac output to skeletal muscle, lowers peripheral resistance to the point of reducing diastolic pressure, and hence lowers effective coronary perfusion pressure (8).To attenuate these undesirable features, we systematically modifi...