Cardiovascular actions of the κ‐agonist, U‐50,488H, in the absence and presence of opioid receptor blockade

Abstract

1 The cardiovascular actions of U-50,488H, a K-receptor agonist, were studied in rat isolated perfused hearts, and in anaesthetized rats, over concentrations or doses generally above those required to produce K-receptor-mediated effects. 2 U-50,488H dose-dependently decreased left-ventricular peak systolic pressure and beating rate in vitro and reduced blood pressure and heart rate in vivo. 3 Over the concentration range of 1-30UM in vitro, and the dose-range of 0.5-32,umolkg-1 in vivo, U-50,488H prolonged the P-R, QRS and Q-T intervals of the ECG. 4 The effects of U-50,488H were not antagonized by an opioid receptor antagonist, naloxone (1 pM or 8/,amolkg-1). Similarly, the opioid receptor antagonist, MR 2266, at 8 pmolkg-1 did not significantly reduce the cardiovascular actions of U-50,488H in vivo. 5 The actions of U-50,488H on responses to electrical stimulation were also studied. Over the dose range of 0.5-32,amol kg-1, U-50,488H altered thresholds and effective refractory period. It had a biphasic action on thresholds for induction of ventricular fibrillation. Thresholds were decreased at lower doses (0.5-4pmol kg 1) but increased at higher doses (8-32 pmol kg l). The effects of lower doses were blocked by naloxone. Effective refractory period and threshold pulse width only increased with dose. 6 In conclusion, U-50,488H at high concentration, had direct depressant actions on cardiac contractility, electrical excitability and the ECG. These depressant effects were not antagonized by the opioid receptor antagonists, naloxone and MR 2266, and probably do not involve opioid receptors. Furthermore, some of the observed effects were those expected to result from sodium channel blockade.

An examination of the cardiac actions of PD117,302, a κ-opioid receptor agonist

“…The rate of intraventricular pressure development (þdP/dt max ) was not affected by PD117,302. These effects are dissimilar to other κ agonists examined in isolated hearts (Pugsley et al, 1992a(Pugsley et al, , 1998. Naloxone had no effect (data not shown).…”

“…In all vehicle control (n¼ 5) and 8.0 mmol/kg naloxone treated (n ¼4, data not shown) animals blood pressure and heart rate were stable over the duration of the drug infusion period, as has been observed with this naloxone dose previously (Pugsley et al, 1992a(Pugsley et al, , 1992b. PD117,302, in the absence and presence of naloxone, produced a marked dose-dependent reduction in both blood pressure and heart rate ( Fig.…”

“…A number of structurally similar arylacetamide κ agonist drugs including ( À )PD129,290, ( þ)PD129,289, U-62,066E and U-50,488H all dosedependently decreased blood pressure (BP) and heart rate (HR) and at high doses these compounds prolonged the PR, QRS and Q-T intervals of the ECG. Neither Mr2266 nor naloxone reduced these cardiovascular actions (Pugsley et al, 1992a(Pugsley et al, , 1992b(Pugsley et al, , 1993(Pugsley et al, , 1995(Pugsley et al, , 1998. Consistent with neuronal studies, the primary basis for the cardiac effects is due to inhibition of voltage-gated sodium currents with electrophysiological properties similar to local anesthetics .…”

“…Doses of drug (0.25-4.0 mmol/kg, intravenously) were infused over a 5 min period, at a rate of 1.0 mmol/kg/min, and recordings were made at the end of the infusion time prior to the next dose. The bolus dose of naloxone was sufficient to provide sustained opioid receptor blockade without influencing ECG, blood pressure or heart rate (Pugsley et al, 1992a). Heart rate was calculated from the R-R interval of the recorded ECG traces recorded on a Grass polygraph (Model 7D, Quincy, Mass., U.S.A.) while the P-R, QRS, Q-T and RSh intervals were measured directly.…”

Molecular analysis of the Na+ channel blocking actions of the novel class I anti‐arrhythmic agent RSD 921

“…Several arylbenzacetamide k opioid receptor agonists such as U-50,488H and (7)Cl-977 have been shown to reduce the incidence and severity of ischaemic and electrical arrhythmias in rats (Pugsley et al, 1992a,b). Pugsley et al (1992c) showed that these arylacetamide compounds were still anti-arrhythmic in the presence of speci®c k opioid receptor blockade. Further studies showed that the observed antiarrhythmic ecacy of these compounds was maintained when enantiomeric pairs such as (+) PD 129,290 (which lacks anity for the k receptor) and (7) PD 129,289 (which has high anity for the k receptor) were examined (Pugsley et al, 1993b).…”