title: Functional cross-talk between endothelial muscarinic and alpha2-adrenergic receptors in rabbit cerebral arteries.
abstract: Interactions between two classes of receptors have been observed in several cell lines and preparations. The aim of this work was to assess the impact of simultaneous stimulation of endothelial muscarinic and alpha2-adrenergic receptors (alpha2-AR) on vascular reactivity. Rabbit middle cerebral arteries were isolated and changes in isometric tension were recorded in the presence of indomethacin. Inhibition of nitric oxide (NO) synthase with Nomega-nitro-L-arginine (L-NOARG, 100 micromol l(-1)) revealed alpha-AR-dependent contractions. Pre-addition of acetylcholine (ACH, 1 micromol l(-1)) augmented oxymetazoline (OXY, 10 micromol l(-1), alpha2-AR agonist)-, but decreased phenylephrine (PE, 10 micromol(-1), alpha1-AR agonist)-induced contraction (P<0.05). The effects of ACH were endothelium-dependent. Vessels were precontracted with 40 mmol l(-1) KCl-physiological salt solution (PSS) in the absence of L-NOARG, or PE or OXY in the presence of L-NOARG. In the presence of high external K+ or PE, ACH induced a potent relaxation (P<0.05). In the presence of OXY, however, ACH mediated contraction (P<0.05). After pertussis toxin (PTX, inactivator of Galpha(i/o) proteins) pre-treatment, alpha2-AR-dependent contractions were abolished. Forty mmol l(-1) KCl-PSS induced contraction was not altered by PTX whereas ACH-induced relaxation was augmented (P<0.05). To investigate if endothelin-1 (ET-1) intervened in the endothelium-dependent contractile response to ACH in the presence of OXY-dependent tone, vessels were incubated in the presence of BQ123 (1 micromol l(-1)), an ETA receptor antagonist. OXY-mediated tone was not affected by BQ123; however, ACH-induced contraction was reversed to a relaxation (P<0.05). These data indicate that activation of endothelial alpha2-AR triggers an endothelium-dependent, ET-1 mediated, contraction to ACH. This suggests that activation of alpha2-AR affects muscarinic receptor/G protein coupling leading to an opposite biological effect.
authors.affiliation: Institut de Cardiologie de Montréal, Centre de Recherche, Québec, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Thorin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010109:Oxymetazoline / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D011817:Rabbits; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D018341:Receptors, Adrenergic, alpha-2; D011976:Receptors, Muscarinic; D014665:Vasodilator Agents; D010566:Virulence Factors, Bordetella; D019335:Nitroarginine; D010109:Oxymetazoline; D019001:Nitric Oxide Synthase; D037342:Pertussis Toxin; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)