Pharmacological characteristics of endothelium-derived hyperpolarizing factor-mediated relaxation of small mesenteric arteries from db/db mice.
Endothelial dysfunction is considered as a major risk factor of cardiovascular complications of type I and type II diabetes. Our previous studies have demonstrated that endothelial dysfunction in the small mesenteric arteries from 12-16 week old type II diabetic mice was associated with decreased bio-availability of nitric oxide whereas endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation was preserved. The objective of the present study was to characterize EDHF-mediated relaxations of small mesenteric arteries from db/db mice. A depolarizing concentration of KCl or tetraethylammonium (TEA, 10 mM) significantly inhibited the EDHF-mediated relaxation to acetylcholine and bradykinin in small mesenteric arteries from both db/+ and db/db mice. Charybdotoxin or iberiotoxin alone and a combination of ouabain and barium significantly reduced the maximal relaxation to acetylcholine in small mesenteric arteries from db/db mice and charybdotoxin or iberiotoxin either alone or in combination with apamin reduced the sensitivity to the EDHF-mediated component of the relaxation response to bradykinin. 17-octadecynoic acid, but not catalase, significantly reduced the sensitivity to EDHF-mediated responses to bradykinin in db/db mice; 17-octadecynoic acid had no effect on acetylcholine-mediated relaxations. No differences were, however, detected for mRNA expression levels of calcium-activated potassium channels or connexins 37, 40, 43 and 45. Collectively, these data suggest that bradykinin-induced, EDHF-dependent relaxation in small mesenteric arteries from db/db mice is mediated via cytochrome P450 product that activates the large conductance calcium-activated potassium (BK(Ca) or Slo) channel, whereas the acetylcholine-induced, EDHF-mediated relaxation involves neither cytochrome P450 product nor hydrogen peroxide.
Pannirselvam
Malarvannan
M
The Heart and Stroke/Richard Lewar Center of Excellence in Cardiovascular Research, University of Toronto, Canada.
Ding
Hong
H
Anderson
Todd J
TJ
Triggle
Chris R
CR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D001920:Bradykinin / Q000494:pharmacology; D017630:Connexins / Q000032:analysis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000737:chemistry / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D001685:Biological Factors; D017630:Connexins; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012333:RNA, Messenger; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000109:Acetylcholine; D001920:Bradykinin