The
opioids methionine enkephalin and
leucine enkephalin contribute to hypoxic pial artery dilation in the newborn pig, and
adenosine 3',5'-cyclic monophosphate (cAMP) analogs have been shown to elevate cerebrospinal fluid (CSF)
opioid concentration. The present study was designed to investigate the contribution of cAMP to hypoxic dilation and to determine whether an endogenous activator of
adenylate cyclase, pituitary
adenylate cyclase-activating
peptide (
PACAP), could modulate the cAMP-induced release of
opioids to contribute to hypoxic pial dilation in piglets equipped with closed cranial windows. An alpha level of P < 0.05 was considered significant in all statistical tests. Moderate and severe
hypoxia (PO2 approximately 35 and 25 mmHg, respectively) induced pial artery dilation that was attenuated by the Rp diastereomer of
8-bromoadenosine 3',5'-cyclic monophosphothioate (Rp-8-BrcAMPS), a cAMP antagonist (24 +/- 1 and 36 +/- 2% vs. 21 +/- 1 and 30 +/- 1% for moderate
hypoxia and 34 +/- 1 and 46 +/- 2% vs. 24 +/- 1 and 32 +/- 1% for severe
hypoxia before and after Rp-8-BrcAMPS, respectively). These responses were associated with an increased CSF cAMP (1,046 +/- 25, 1,366 +/- 28, and 1,735 +/- 47 fmol/ml for control, moderate, and severe
hypoxia, respectively). Hypoxic pial dilation was also accompanied by an increase in CSF
methionine enkephalin (1,101 +/- 62, 3,283 +/- 119, and 3,835 +/- 129 pg/ml for control, moderate, and severe
hypoxia, respectively). Hypoxic dilation additionally increased CSF
PACAP (1,727 +/- 86, 2,268 +/- 157, and 7,980 +/- 238 pg/ml for control, moderate, and severe
hypoxia, respectively).
PACAP (10(-8) and 10(-6) M) elicited pial dilation that was associated with increased CSF cAMP and blunted by Rp-8-BrcAMPS.
PACAP-induced dilation was also accompanied by increases in the
opioid methionine enkephalin (1,059 +/- 23, 1,483 +/- 34, and 2,108 +/- 77 pg/ml for control and 10(-8) and 10(-6) M
PACAP, respectively). These data show that cAMP contributes to hypoxic pial artery dilation.
Hypoxia increases CSF
PACAP, whereas
PACAP elevates CSF
opioid concentration. These data, therefore, suggest that
PACAP modulates cAMP-induced
opioid release, thereby contributing to hypoxic pial dilation.