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The effects of dobutamine ([+/-]-4-[2-[[3-(p-hydroxyphenyl)-1-methyl propyl] amino] ethyl] pyrocatechol hydrochloride), a new synthetic cardioactive sympathomimetic amine, were examined on direct and continuous measurements of left ventricular (LV) diameter (D), pressures (P), velocity of shortening (V), dP/dt, dP/dt/P, arterial pressure, cardiac output, and regional blood flows in the left circumflex coronary, mesenteric, renal, and iliac beds in healthy, conscious dogs. At the highest dose of dobutamine examined, 40 mug/kg/min, the drug increased dP/dt/P from 65+/-3 to 128+/-4 s(-1) and isolength velocity from 72+/-4 to 120+/-7 mm/s without affecting LV end diastolic D significantly. Mean arterial P rose from 92+/-2 to 104+/-3 mm Hg and heart rate from 78+/-3 to 111+/-7 beats/min, while LV end systolic D fell from 24.1+/-1.4 to 19.9+/-1.8 mm, reflecting a rise in stroke volume from 30+/-4 to 42+/-3 ml. Cardiac output rose from 2.41+/-0.23 to 4.35+/-0.28 liter/min, while calculated total peripheral resistance declined from 0.042+/-0.005 to 0.028+/-0.003 mm Hg/ml/min. The greatest increases in flow and decreases in calculated resistance occurred in the iliac and coronary beds, and the least occurred in the renal bed. Propranolol blocked the inotropic and beta(2) dilator responses while vasoconstricting effects mediated by alpha adrenergic stimulation remained in each of the beds studied. When dobutamine was infused after a combination of practolol and phentolamine, dilatation occurred in each of the beds studied. These observations indicate that dobutamine is a potent positive inotropic agent with relatively slight effects on preload, afterload, or heart rate, and thus may be a potentially useful clinical agent. The one property of this drug which is not ideal is its tendency to cause a redistribution of cardiac output favoring the muscular beds at the expense of the kidney and visceral beds.

Isolated cat right ventricular papillary muscles were used to study the effects of antibodies with high affinity for ouabain and acetyl strophanthidin on myocardium exposed to these cardioactive steroids. Antibodies with average intrinsic affinity constants for ouabain and acetyl strophanthidin of the order of 10(8) M(-1) were raised in rabbits challenged by repeated injection of a conjugate of ouabain covalently linked to a poly D,L-alanyl derivative of human serum albumin. Effects were assessed in terms of time-course and extent of inotropy reversal, influence of experimentally induced ventricular failure, digitalis-antibody concentration relations, influence of digitalis-antibody complex on response to additionally added digitalis, and relation of antibody effects on digitalis-induced automaticity and contracture to reversal of inotropy. Specific antibody (but not control antibody) in 1.1-1.5-fold molar excess over cardioactive steroid concentrations blocked positive inotropic effects of ouabain and acetyl strophanthidin, and gradually reversed established contractile effects of these agents with a mean time for half-reversal of ouabain-induced inotropy of 124+/-6 (SEM) min and 37+/-3 min for half-reversal of acetyl strophanthidin-induced inotropy. Papillary muscles from cats with right ventricular failure induced by chronic pulmonary artery constriction responded similarly. Both normal and failing muscles returned to but not below levels of contractility existing before cardioactive steroid exposure, and time for half-reversal of inotropy by antibody was significantly shorter than time for half-reversal after removal of ouabain or acetyl strophanthidin by muscle bath washout alone. Presence of ouabain- or acetyl strophanthidin-antibody complex did not alter the myocardial contractile response to subsequently added cardioactive steroids. Spontaneous automaticity occurring as a toxic response to ouabain or acetyl strophanthidin in eight muscles was rapidly reversed by specific antibody at a time when positive inotropic effects were still fully manifest. Early contracture was also reversed by specific antibody. These studies provide further support for the concept that cardiac glycoside-specific antibodies are capable of reversing established cellular effects of cardioactive steroids.

1 In dogs respired with 10% oxygen: 90% nitrogen, only five out of 16 dogs survived repeated intravenous doses of isoprenaline (either 0.5 or 1.0 mug/kg) and only one out of six dogs survived repeated isoprenaline inhalations from a pressurized aerosol.2 In dogs respired with 15% oxygen: 85% nitrogen, five out of six dogs survived repeated intravenous doses of isoprenaline (2.5 mug/kg).3 The fatal response in these animals consisted of a fall in heart rate, arterial and pulse pressures. Sinus rhythm persisted even after the arterial pressure had fallen, though occasionally a slow A-V nodal rhythm or irregular ventricular ectopic beats occurred. Ventricular fibrillation did not occur.4 Eight out of 10 dogs brought to the verge of a fatal response with 10% oxygen: 90% nitrogen and repeated doses of isoprenaline (2.5 mug/kg) were resuscitated by the administration of 100% oxygen and, when necessary, cardiac massage.5 A group of five dogs survived the combined effects of repeated doses of isoprenaline (2.5 mug/kg) and respiration with 10% oxygen: 90% nitrogen when the time interval between doses was 11 min, instead of the usual 5 minutes.6 Control of pH by infusion of sodium bicarbonate did not protect the dogs from the combined effects of hypoxia and repeated isoprenaline challenge.7 After a 60 min period of continuous isoprenaline infusion in dogs breathing room air, only one of 10 dogs survived artificial respiration with 10% oxygen: 90% nitrogen and repeated challenge with intravenous isoprenaline (1.0 mug/kg) at 5 min intervals. At the higher infusion levels of isoprenaline (0.1 and 1.0 mug kg(-1) min(-1)), two dogs out of four died after the hypoxic mixture was started but before any isoprenaline challenge was given.8 The possible relevance of these findings in dogs to the recently observed increase in mortality in young asthmatics is discussed.