title: Activation of peripheral opioid µ-receptors in blood vessel may lower blood pressure in spontaneously hypertensive rats.
abstract: OBJECTIVE
  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 μ(1)-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.
  
  
  CONCLUSIONS
  We suggest that loperamide can lower MAP in SHRs via μ(2)-opioid receptor-dependent cAMP-PKA pathway that induces vascular relaxation by opening K(ATP) channels.
authors.affiliation: Department of Cardiology, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan, ROC.
authors.forename: Zhih-Cherng
authors.initials: ZC
authors.lastname: Chen
authors.forename: Ja-Ping
authors.initials: JP
authors.lastname: Shieh
authors.forename: Hsien-Hui
authors.initials: HH
authors.lastname: Chung
authors.forename: Ching-Hsia
authors.initials: CH
authors.lastname: Hung
authors.forename: Hung Jung
authors.initials: HJ
authors.lastname: Lin
authors.forename: Juei-Tang
authors.initials: JT
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D009019:Morphinans / Q000494:pharmacology; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D054086:KATP Channels; D009019:Morphinans; D010726:Phosphodiesterase Inhibitors; D017450:Receptors, Opioid, mu; C015482:protein kinase modulator; C058450:cyprodime; D010656:Phenylephrine; D009270:Naloxone; D008139:Loperamide; C034643:naloxonazine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005905:Glyburide