The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers

PACAP38 is an endogenous peptide located in trigeminal perivascular nerve fibers in the brain. It reduces neuronal loss and infarct size in animal stroke models and has been proposed a candidate substance for human clinical studies of stroke. The effect on systemic hemodynamics and regional cerebral blood flow (rCBF) is not well understood. We here present the first study of the effect of PACAP38 on cerebral hemodynamics in humans. PACAP (10 pnnol kg(-1) min(-1)) or placebo (0.9% saline) was infused for 20 min into 12 healthy young volunteers in a cross over, double blind study. rCBF was measured with SPECT and Xe-133 inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO2 (PetCO2) and vital parameters were recorded throughout the 2 hour study period. PACAP38 decreased rCBF in all regions of interest (ROIs) by similar to 3-10%, though not uniformly significant. PetXO2 decreased significantly during PACAP38 infusion compared to placebo (P=0.032), peak decrease was 8.9 +/- 3.8%. After correction for PetCO2, rCBF remained unchanged in most Rots. Heart rate increased 61.9 +/- 22.4% (P < 0.0001 vs. placebo). These findings suggest that PACAP38 has no major direct effect on rCBF in healthy volunteers. The marked increase in heart rate and the reduction in rCBF caused by decreased PetCO2 are important dose-limiting factors to consider in future clinical studies. (c) 2007 Elsevier B.V. All rights reserved.