Role of activation of calcium-sensitive K+ channels and cAMP in opioid-induced pial artery dilation.
The present study was designed to investigate the role of activation of Kca+2 channels and cAMP in opioid-induced pial artery dilation in newborn pigs equipped with closed cranial windows. Methionine enkephalin, an endogenous mu agonist, elicited dilation that was modestly attenuated by the Kca+2 channel antagonist, iberiotoxin (10(-7) M) (7 +/- 1, 11 +/- 1 and 16 +/- 1 vs. 4 +/- 1, 7 +/- 1, and 11 +/- 1% for methionine enkephalin 10(-10), 10(-8), 10(-6) M in the absence and presence of iberiotoxin, respectively). Dilator responses to leucine enkephalin and dynorphin, endogenous delta and kappa agonists, as well as the synthetic analogues DAMGO, DPDPE, deltorphin and U50488H all were similarly attenuated by iberiotoxin. Dilation in response to methionine enkephalin was accompanied by increased CSF cAMP concentration (1170 +/- 21, 1358 +/- 22, 1473 +/- 26, and 1575 +/- 24 fmol/ml for control, 10(-10), 10(-8), 10(-6) M methionine enkephalin, respectively). Methionine enkephalin-induced dilation was attenuated by Rp 8-bromo cAMPs (10(-5) M), a cAMP antagonist (7 +/- 1, 11 +/- 1 and 17 +/- 1 vs. 2 +/- 1, 4 +/- 1, and 7 +/- 1% for methionine enkephalin 10(-10), 10(-8), and 10(-6) M in the absence and presence of Rp 8-bromo cAMPs, respectively). Dilation by the other endogenous and synthetic opioid analogues was also accompanied by elevated CSF cAMP and attenuated by Rp 8-bromo cAMPs. Additionally, dilation produced by the cAMP analogue, 8-bromo cAMP, was blunted by iberiotoxin. These data show that both cAMP and activation of Kca+2 channels contribute to opioid-induced pial artery dilation. Further, these data suggest that opioids elicit dilation, at least in part, via the sequential release of cAMP and subsequent activation of Kca+2 channels by this second messenger.
Armstead
W M
WM
Department of Anesthesia and Pharmacology, The University of Pennsylvania , USA.
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D004744:Enkephalin, Methionine / Q000494:pharmacology*; D005260:Female; D008297:Male; D015335:Molecular Probes; D010455:Peptides / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists*; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D015335:Molecular Probes; D010455:Peptides; D015221:Potassium Channels; D014665:Vasodilator Agents; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004744:Enkephalin, Methionine; C064719:iberiotoxin; D000242:Cyclic AMP; D002118:Calcium