Activation of Peripheral Opioid µ-Receptors in Blood Vessel May Lower Blood Pressure in Spontaneously Hypertensive Rats

Abstract

Background/Aims: The role of opioid receptors in the regulation of vascular function remains unclear. In the current study, we evaluated the ability of loperamide, a peripheral opioid receptor agonist, to regulate blood pressure in spontaneously hypertensive rats (SHRs) and examined the mechanism(s) by which loperamide exerts its effects. Methods: In male SHRs, mean arterial pressure (MAP) was measured and hemodynamic analysis was recorded. Additionally, the isometric tension of aortic rings isolated from SHRs was determined. Results: Loperamide dose-dependently decreased MAP in SHRs but not in the normal group of Wistar-Kyoto rats. This reduction of MAP in conscious SHRs was abolished by the selective opioid µ-receptor antagonist cyprodime, but not by naloxonazine, the µ₁-opioid receptor antagonist. However, cardiac output was not altered by loperamide in anesthetized SHRs. Moreover, loperamide-induced relaxation in isolated aortic rings precontracted with phenylephrine or vasopressin. This relaxation was abolished by cyprodime, but not by naloxonazine. Loperamide-induced relaxation was also attenuated by glibenclamide, an ATP-sensitive potassium (K_ATP) channel blocker. Additionally, vasodilatation by loperamide was reduced by an inhibitor of protein kinase A (PKA) and enhanced by an inhibitor of phosphodiesterases. Conclusion: We suggest that loperamide can lower MAP in SHRs via µ₂-opioid receptor-dependent cAMP-PKA pathway that induces vascular relaxation by opening K_ATP channels.

Different blood pressure responses to opioids in 3 rat hypertension models: role of the baseline status of sympathetic and renin–angiotensin systems

“…The hypotensive action of morphine is long established (Cox 1988;Siren and Feuerstein 1992). More recently, both morphine and stimulation of peripheral µ receptors with loperamide was reported to decrease blood pressure in SHR (Chen et al 2011, Mahinda et al 2004. Also endogenous endorphins with affinity for µ receptors were reported to induce hind limb vasodilatation (Champion et al 1997), in agreement with our present finding of decreasing iliac vascular resistance, both after morphine and after biphalin.…”

“…It may differ from the final official version of record. 14 peripherally acting µ-receptor agonist, did not alter the cardiac output in anesthetized SHR (Chen et al 2011). Thus, any substantial contribution of a decrease in cardiac output to biphalin's hypotensive effect remains uncertain.…”

“…More important, opioids were shown to inhibit this hypersensitivity: vasoconstrictor response to electrical stimulation of rat tail artery was blocked by an opioid µ-receptor agonist in arteries derived from SHR but not those from normotensive rats (Wong and Ingenito 1995). Furthermore, stimulation of peripheral µ receptors was reported to decrease blood pressure more effectively in SHR than in normotensive rats (Mahinda et al 2004) or to do so exclusively in SHR ( Chen et al 2011).…”

Drug-Induced Pseudoallergy: A Review of the Causes and Mechanisms

“…The activation of mast cell degranulation by codeine may, therefore, occur through its actions at the opioid receptor [51]. There are 3 recognized types of opioid receptors, namely, mu (μ), delta (δ), and kappa (κ) [53,54]. It has been demonstrated that human mast cells express mRNA for δ- and μ-receptors but not for κ-opioid receptors [51].…”

Role of Musclin in the Pathogenesis of Hypertension in Rat

“…The endothelium was removed by gently rubbing it against the teeth of a pair of forceps. Successful removal of the endothelium was confirmed by histological identification and failure of 1 µmol/L acetylcholine to relax the rings that had been pre-contracted with potassium chloride as described previously [10]. …”