cardiovascular-agents and alpha-beta-methyleneadenosine-5--triphosphate

We examined the effects of ATP on intrinsic pump activity in lymph vessels isolated from the rat. ATP caused significant dilation with a cessation of lymphatic pump activity. Removal of the endothelium or pretreatment with Nomega-nitro-L-arginine methyl ester (L-NAME) significantly reduced ATP-induced inhibitory responses of lymphatic pump activity, whereas reduction was not suppressed completely by 10(-6) M ATP. L-arginine significantly restored ATP-induced inhibitory responses in the presence of L-NAME. ATP-induced inhibitory responses in lymph vessels with endothelium were also significantly, but not completely, suppressed by pretreatment with glibenclamide. 8-Cyclopentyl-1,3-dipropylxanthine (a selective adenosine A1 receptor antagonist), but not suramine (a P2X and P2Y receptor antagonist) or 3,7-dimethyl-1-proparglyxanthine (a selective adenosine A2 receptor antagonist), significantly decreased ATP-induced inhibitory responses. alpha,beta-methylene ATP (a selective P2X and P2Y receptor agonist) had no significant effect on lymphatic pump activity. In some lymph vessels with endothelium (24 of 30 preparations), adenosine also caused dose-dependent dilation with a cessation of lymphatic pump activity. L-NAME significantly reduced the inhibitory responses induced by the lower (3 x 10(-8)-3 x 10(-7) M) concentrations of adenosine. Glibenclamide or 8-cyclopentyl-1,3-dipropylxanthine also significantly suppressed adenosine-induced inhibitory responses. These findings suggest that ATP-induced dilation and inhibition of pump activity of isolated rat lymph vessels are endothelium-dependent and -independent responses. ATP-mediated inhibitory responses may be, in part, related to production of endogenous nitric oxide, involvement of ATP-sensitive K+ channels, or activation of adenosine A1 receptors in lymphatic smooth muscle and endothelium.

Topics: Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Antineoplastic Agents; Arginine; Cardiovascular Agents; Endothelium; Enzyme Inhibitors; Glyburide; Indomethacin; Lymphatic System; Male; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide; Potassium Channels; Rats; Rats, Wistar; Receptor, Adenosine A1; Suramin; Xanthines

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.

Topics: Adenosine Triphosphate; Animals; Capsaicin; Cardiotonic Agents; Cardiovascular Agents; Charybdotoxin; Drug Interactions; Electric Stimulation; Endothelium, Vascular; Glyburide; In Vitro Techniques; Indomethacin; Isotonic Solutions; Male; Mesenteric Arteries; Neurons, Afferent; Ouabain; Pyridoxal Phosphate; Rats; Rats, Wistar; Suramin; Tetraethylammonium; Theophylline; Vasodilation