The role of NO-cGMP pathway and potassium channels on the relaxation induced by clonidine in the rat mesenteric arterial bed.
The mechanisms involved in the vasodilation action of clonidine have not yet been completely elucidated. We investigated the potential mechanisms that seem to be involved in the clonidine vasodilator effect using rat isolated mesenteric arterial bed (MAB). In precontracted MAB, clonidine (10-300 pmol) induced a dose-dependent relaxation, that was inhibited by endothelium removal (deoxycholic acid - 2.5 mM) and reduced by the alpha(2) adrenoceptor inhibitors yohimbine (1-3 microM) and rauwolscine (1 microM). The endothelium-dependent vasodilation induced by clonidine was reduced by the nitric oxide (NO) synthase inhibitor L-NAME (0.3 mM) and guanylyl cyclase inhibitor ODQ (10 microM) but was not affected by indomethacin (3-10 microM) alone. High K+ (25 mM) solution reduced the vasodilator effect of clonidine that was further attenuated by L-NAME. In the presence of high K+ plus L-NAME, the residual vasodilator effect of clonidine was further reduced by indomethacin (3 microM). The Ca(2+)-dependent K+ channel (K+(Ca2+)) inhibitors, charybdotoxin (ChTx; 0.1 microM) plus apamin (0.1 microM), also reduced the vasodilation induced by clonidine, however this response was not further reduced in the presence of L-NAME as observed with acetylcholine (10 pmol). In the presence of ATP-dependent K+ channel (K+(ATP)) blocker, glibenclamide (10 microM), the inhibitory effect of ChTx plus apamin plus L-NAME was increased. In contrast, the vasodilation induced by clonidine was not affected by voltage-dependent K+ channels (K(V)) blocker, 4-aminopyridine (4-AP, 1 mM). In conclusion, our results demonstrate that clonidine activates alpha(2)-adrenoceptors in rat MAB and that the endothelium-dependent vasodilation is mediated by activation of NO-cGMP pathway, hyperpolarization due to activation of K+(Ca) and K+(ATP) channels. Prostaglandins might participate in the vasodilator effect of clonidine when NO and EDHF mechanisms are blunted.
Pimentel
A M L
AM
Departamento de Farmacologia e Psicobiologia, Instituto de Biologia, Centro Biomédico, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro 87, Rio de Janeiro, Brazil.
Costa
C A
CA
Carvalho
L C R M
LC
Brandão
R M
RM
Rangel
B M
BM
Tano
T
T
Soares de Moura
R
R
Resende
A C
AC
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001685:Biological Factors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011453:Prostaglandins; D018341:Receptors, Adrenergic, alpha-2; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D003000:Clonidine; D011188:Potassium