Mechanism of prolonged vasorelaxation to ATP in the rat isolated mesenteric arterial bed.
1. This study investigated the mechanism of prolonged relaxation to ATP in the rat isolated perfused mesenteric arterial bed. 2. In methoxamine pre-constricted preparations, ATP elicited dose-dependent, endothelium-dependent, rapid relaxation at 5 pmol - 0.05 micromol (R(max) 76+/-5.6%, pD(2) 9.2+/-0.2), and contraction, followed by prolonged endothelium-independent vasorelaxation at 0.05, 0.5 and 5 micromol (56+/-3.0, 87+/-2.9 and 85+/-4.6%). Suramin (100 microM), attenuated rapid (pD(2) 7.8+/-0.1) and prolonged relaxation to ATP. The selective P2 receptor antagonist PPADS (10 microM) reduced prolonged, but not rapid relaxation. Neither phase of relaxation was affected by 8-sulphophenyltheophylline (1 microM) or indomethacin (10 microM). 3. alpha,beta-methylene ATP (alpha,beta-meATP; 10 microM) attenuated prolonged relaxation to ATP (relaxations at 0.05 and 0.5 micromol were 25+/-8.3 and 48+/-9.0%, respectively). alpha,beta-meATP blocked contractions and revealed rapid relaxation to ATP at 0.05 - 5 micromol. 4. Capsaicin pre-treatment did not affect either phase of vasorelaxation to ATP. alpha,beta-meATP (10 microM) had no effect on vasorelaxation mediated by electrical stimulation of capsaicin-sensitive sensory nerves. 5. High K(+) (25 mM) attenuated prolonged relaxation to ATP (21+/-2.6 and 64+/-5.8%, at 0.05 and 0.5 micromol, respectively), but had no effect on rapid relaxation. Ouabain (1 mM), an inhibitor of Na(+)/K(+)-ATPase, and glibenclamide (10 microM), an inhibitor of K(ATP) channels, also attenuated prolonged relaxation to ATP. Charybdotoxin (100 nM), a selective inhibitor of K(Ca) channels, and tetraethylammonium (10 mM) had no effect on rapid or prolonged relaxations. 6. These results show that the prolonged phase of vasorelaxation to ATP in the rat isolated mesenteric arterial bed, which may be mediated by P2Y receptors, is endothelium-independent, involves activation of Na(+)/K(+)-ATPase and K(ATP) channels, and is inhibited by alpha,beta-meATP. Neither prolonged nor rapid vasorelaxation to ATP involves capsaicin-sensitive sensory nerves, adenosine P1 receptors, prostanoids or K(Ca) channels.
Ralevic
V
V
School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH. vera.ralevic@nottingham.ac.uk
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007552:Isotonic Solutions / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013498:Suramin / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D007552:Isotonic Solutions; C051865:Krebs-Ringer solution; D018999:Charybdotoxin; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D010042:Ouabain; D011732:Pyridoxal Phosphate; D013498:Suramin; D019789:Tetraethylammonium; C031433:8-(4-sulfophenyl)theophylline; D000255:Adenosine Triphosphate; D013806:Theophylline; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D002211:Capsaicin; D005905:Glyburide; D007213:Indomethacin