Cardiovascular depressant effects of the kappa opioid receptor agonists U50488H and spiradoline mesylate

The cardiovascular effects of the selective kappa opioid receptor agonists U50488H and spiradoline mesylate were examined in pentobarbital-anesthetized mongrel dogs and chloralose-anesthetized cats. In the dog studies, U50488H (0.01-3.0 mg/kg, i.v.) produced a dose-related depression in mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular dp/dt, and heart rate. These effects were completely reversed by a 1 mg/kg, i.v. dose of the opioid receptor antagonist naloxone. A second kappa agonist, spiradoline mesylate, also produced a naloxone-reversible cardiovascular depression. Furthermore, the compound did not interfere with the positive inotropic or hypertensive effects of norepinephrine (1 μg/kg, i.v.), showing that the cardiovascular depressant effects of the kappa agonist are unrelated to interference with alpha- or beta-adrenergic receptor mechanisms. In normal cats anesthetized with chloralose, which produces less depression of sympathetic tone than does pentobarbital, spiradoline mesylate did not decrease the MAP in i.v. doses up to 1.0 mg/kg. However, a dose-related increase in sympathetic nerve discharge (SND) was observed (+290% at 1.0 mg/kg). In contrast, in baroreceptor-denervated cats, spiradoline mesylate caused a dose-related hypotensive effect with no change in SND. These results show that the cardiovascular effects of the kappa agonists are peripherally mediated and that reflex sympathetic activity, if uncompromised, can produce a full compensation.