cGMP and cAMP in prostaglandin-induced pial artery dilation and increased CSF opioid concentration.
It has been observed that prostaglandins (PG) PGE2 and PGI2 increased cortical periarachnoid cerebrospinal fluid (CSF) methionine enkephalin (Met-enk) and leucine enkephalin (Leu-enk) concentrations in the newborn pig. It was also observed that PG-induced pial artery dilation was associated with elevated CSF guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) levels in the piglet. However, other studies have not always supported a role for cGMP in PG dilation. The present study used a pharmacological approach to test the hypothesis that both cGMP and cAMP contribute to PG-induced pial dilation and associated elevated CSF opioid concentration. PGE2 produced pial vasodilation that was blunted by the Rp diastereomer of bromoguanosine 3',5'-cyclic monophosphothioate [Rp-8-BrcGMPS (10(-5)M)], a cGMP antagonist (9 +/- 1, 16 +/- 1, and 23 +/- 1 vs. 4 +/- 1, 6 +/- 1, and 9 +/- 1% for 1, 10, and 100 ng/ml PGE2 before and after Rp-8-BrcGMPS, respectively). PGE2 elevated CSF Met-enk concentration, and these biochemical changes were also blunted by Rp-8-BrcGMPS (1,001 +/- 23, 1,424 +/- 54, and 1,973 +/- 56 vs. 804 +/- 41, 988 +/- 52, and 1,222 +/- 21 pg/ml for control, 10, and 100 ng/ml PGE2 in the absence and presence of Rp-8-BrcGMPS, respectively). Similar biochemical and vascular effects of Rp-8-BrcGMPS were observed for PGI2. Additionally, the Rp diastereomer of bromoadenosine 3',5'-cyclic monophosphothioate [Rp-8-BrcAMPS (10(-5)M)], a cAMP antagonist, blunted PGE2 dilation (10 +/- 1, 15 +/- 1, and 24 +/- 1 vs. 5 +/- 1, 8 +/- 1, and 12 +/- 1% for 1, 10, and 100 ng/ml PGE2 before and after Rp-8-BrcAMPS, respectively). PGE2-associated increases in CSF Met-enk and Leu-enk were similarly blunted by Rp-8-BrcAMPS. These data show that both cGMP and cAMP contribute to PG-induced pial dilation and that PG-associated elevated CSF cGMP and cAMP levels result in increased CSF Met-enk and Leu-enk concentration.
Armstead
W M
WM
Department of Anesthesia, University of Pennsylvania, Children's Hospital of Philadelphia 19104, USA.
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004723:Endorphins / Q000134:cerebrospinal fluid*; D005260:Female; D008297:Male; D009994:Osmolar Concentration; D010841:Pia Mater / Q000098:blood supply*; D011453:Prostaglandins / Q000494:pharmacology*; D013237:Stereoisomerism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects
D004723:Endorphins; D011453:Prostaglandins; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D000242:Cyclic AMP; D006152:Cyclic GMP