title: Exploring the mechanism of endothelial involvement in acidosis-induced vasodilatation of aortic tissues from normal and diabetic rats.
abstract: Acidosis modulates physiologic and pathophysiologic processes but the mechanism of acidotic vasodilatation remains unclear. We therefore explored this in aortic rings from normal and streptozotocin-induced diabetic Sprague-Dawley rats. Phenylephrine (PE)-induced contraction in endothelium-intact and -denuded rings were recorded under normal and acidotic pH with or without drug probes. Acidosis exerted a relaxant effect in endothelium-intact and -denuded euglycaemic and diabetic tissues. l-NAME or methylene blue partially inhibited acidotic relaxation in these endothelium-intact but not the -denuded tissues, with greater inhibition in the diabetic tissues, indicating that acidosis induces relaxation by endothelium-dependent and -independent mechanisms, the former being EDNO-cGMP mediated. Indomethacin had no effect on the tissues, indicating that cyclooxygenase products are neither involved in acidosis-induced vasodilatation nor in the modulation of phenylephrine-contraction. In euglycaemic tissues under normal pH, no K(+) channel blocker altered phenylephrine-contraction, but all (except glibenclamide) enhanced diabetic tissue contraction, indicating that normally, these channels (K(ir), K(V), BK(Ca), K(ATP)) do not modulate phenylephrine-contraction, but they (except K(ATP)) are expressed in diabetes where they attenuate phenylephine-induced contraction and modulate acidosis. Only the K(ir) channel modulates acidotic relaxation in euglycaemic tissues. Only tetraethylammonium and iberiotoxin enhanced phenylephrine-induced contraction in endothelium-denuded diabetic tissues indicating that BK(Ca) attenuates phenylephrine-contraction and that acidotic relaxation in this condition is modulated by a tetraethylammonium-sensitive mechanism. In conclusion, acidosis causes vasodilatation in normal and diabetic tissues via endothelium-dependent and -independent mechanisms differentially modulated by a combination of a NO-cGMP process and K(+) channels, some of which are dormant in the normal state but activated in diabetes mellitus.
authors.affiliation: International Medical University, Commonwealth Plaza, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Jian Loong
authors.initials: JL
authors.lastname: Yeo
authors.forename: Boris Teng Chuan
authors.initials: BT
authors.lastname: Tan
authors.forename: Francis I
authors.initials: FI
authors.lastname: Achike
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000138:Acidosis / Q000503:physiopathology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D017609:Barium Compounds / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D015309:Glucose Clamp Technique; D005905:Glyburide / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D017609:Barium Compounds; D002712:Chlorides; D010455:Peptides; C024986:barium chloride; D019789:Tetraethylammonium; C064719:iberiotoxin; D015761:4-Aminopyridine; D005905:Glyburide; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin