Dobutamine: development of a new catecholamine to selectively increase cardiac contractility.

Abstract

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...

Cardiovascular effects of dobutamine, dopamine and isoproterenol on the whole animal and isolated cross-perfused atrium in dogs.

“…In a whole animal, it was reported that dobutamine-induced cardiac effects were not influenced by desmethylimipramine, an uptake blocker of catecholamines (1). In the present study by use of isolated atria, we confirmed that dobutamine-induced positive chronotropic and inotropic effects were not modified by treatment with imipramine, although tyramine induced ones were markedly suppressed and dopamine-induced ones were slightly but significantly sup pressed as reported previously (9).…”

“…administration of dobutamine to an intact animal produces a lesser increase in systemic blood pressure than that of dopamine (1,2). However, in isolated atria which were perfused with donor's blood, an i.v.…”

“…Indeed, dobutamine directly increases myocardial contractility without inducing marked tachycardia or greatly changing peripheral arterial resistance in intact dogs (1)(2)(3). In the cat papillary muscle, dobutamine increases the con tractility more but the automaticity less than did isoproterenol (1).…”

Dopexamine: a novel agonist at peripheral dopamine receptors and β2‐adrenoceptors

“…Another N-alkylated dopamine analogue, dobutamine, developed as an inotropic agent (Tuttle & Mills, 1975) is inactive as an agonist at vascular DA,-receptors (Robie et al, 1974) and at prejunctional DA2-receptors of the rabbit ear artery (unpublished observations), but is active in stimulating al-, PI-and P2-adrenoceptors (Maccarone et al, 1984).…”

Effects of Dopamine, Dobutamine, Amrinone and Milrinone on Regional Blood Flow in Isoflurane Anesthetized Dogs

“…Dopamine (DA) and dobutamine (DB) induce potent inotropic action through α and β adrenaline receptors on myocardial cell membrane [12,16,32]. However, CA may induce tachycardia and hypoxia in myocardium [33].…”