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1-α-Acetylmethadol (LAAM) and its major metabolites (1-α-acetylnormethadol and 1-α-acetyldinormethadol) produce a biphasic inotropic response in vitro in guinea pig atrium. Lower concentrations increase contractile height and higher concentrations decrease it. The positive inotropic response was blocked by dl -propranolol and attenuated by pretreatment of the animal with 6-OH-dopamine. These results indicate that endogenous norpinephrine mediates the positive inotropic response to LAAM and congeners. The narcotic agonist decreased the positive inotropic response to increasing concentrations of Ca 2+ . This finding suggests that LAAM decreases availability of extracellular Ca 2+ , thereby producing a negative inotropic response.

There are many experimental conditions under which an interaction between aigitalis and the sympathetic nervous system can be demonstrated. In the absence of viable sympathetic function, digitalis toxicity is decreased and the mode of death in experimental animals is changed from ventricular fibrillation to cardiac arrest. The interaction between digitalis and the sympathetic nervous system does not appear to be active in nature. That is, no causal relationship between either changes in adrenergic neuron transport or changes in sympathetic nerve activity and the development of cardiac arrhytmias has been demonstrated. The interaction that occurs appears to be passive. Endogenous norepinephrine which is released tonically serves to maintain certain specialized tissues of the heart in a state such that lower doses of digitalis which are non-toxic in sympathectomized animals can effect electrical changes which result in cardiac arrhythmias.

The drug 1-α-acetylmethadol (LAAM) is a long-acting, orally effective narcotic agonist. It has been proposed as a replacement for methadone in the medical treatment of persons addicted to narcotic analgesics. The purpose of the present investigation was to determine whether or not LAAM possesses chronotropic properties. The results reported here indicate that high concentrations of the major metabolites of the drug (1-α-acetylnormethadol, 1-α-acetyldinormethadol) as well as high concentrations of the parent compound produce significant negative chronotropic effects on isolated right atria of guinea pigs. These effects could not be blocked by the prior administration of naloxone, a narcotic antagonist. LAAM also decreases the positive chronotropic efficacy of norepinephrine.

The cardiovascular responses to 1-α-acetylmethadol (LAAM) and its two major metabolites, 1-α-acetylnormethadol (N-LAAM) and 1-α-acetyldinormethadol (DN-LAAM), were examined in anesthetized dogs. LAAM, N-LAAM, and DN-LAAM caused significant decreases (p < 0.05) in mean arterial blood pressure (BP), heart rate (HR), and myocardial contractile force (CF). N-LAAM appeared to be approximately 10 times more potent than LAAM or DN-LAAM in producing these effects. The cardiovascular responses to LAAM were also studied in vagotomized (VAGOT), chemically sympathectomized (SYMX), and vagotomized + chemically sympathectomized (VAGOT + SYMX) dogs. VAGOT had little effect on the responses to LAAM, SYMX and VAGOT + SYMX caused a decrease in the magnitude of the bradycardia produced by LAAM relative to that observed in intact animals and also increased the threshold dose required to produce significant decreases in BP; however, statistically significant (p < 0.05) decreases in BP, HR, and CF were observed. The data suggest that part of the hypotension and bradycardia produced by LAAM may be the result of sympathetic nervous system depression, but there also appears to be a direct component to the cardiovascular effects of LAAM and congeners.