The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers

TY - JOUR

T1 - The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers

AU - Birk, Steffen

AU - Sitarz, John Thomas

AU - Petersen, Kenneth Ahrend

AU - Oturai, Peter Sandor

AU - Kruuse, Christina Rostrup

AU - Fahrenkrug, Jan

AU - Olesen, Jes

PY - 2007/5/3

Y1 - 2007/5/3

N2 - 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 pmol 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 (133)Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO(2) (P(et)CO(2)) and vital parameters were recorded throughout the 2 hour study period. PACAP38 decreased rCBF in all regions of interest (ROIs) by approximately 3-10%, though not uniformly significant. P(et)CO(2) decreased significantly during PACAP38 infusion compared to placebo (P=0.032), peak decrease was 8.9+/-3.8%. After correction for P(et)CO(2), rCBF remained unchanged in most ROIs. 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 P(et)CO(2) are important dose-limiting factors to consider in future clinical studies.

AB - 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 pmol 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 (133)Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO(2) (P(et)CO(2)) and vital parameters were recorded throughout the 2 hour study period. PACAP38 decreased rCBF in all regions of interest (ROIs) by approximately 3-10%, though not uniformly significant. P(et)CO(2) decreased significantly during PACAP38 infusion compared to placebo (P=0.032), peak decrease was 8.9+/-3.8%. After correction for P(et)CO(2), rCBF remained unchanged in most ROIs. 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 P(et)CO(2) are important dose-limiting factors to consider in future clinical studies.

KW - Adolescent

KW - Adult

KW - Cerebrovascular Circulation

KW - Cross-Over Studies

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Female

KW - Heart Rate

KW - Humans

KW - Injections, Intravenous

KW - Male

KW - Pituitary Adenylate Cyclase-Activating Polypeptide

KW - Reference Values

KW - Vasodilator Agents

U2 - 10.1016/j.regpep.2006.12.010

DO - 10.1016/j.regpep.2006.12.010

M3 - Journal article

C2 - 17320198

SN - 0167-0115

VL - 140

SP - 185

EP - 191

JO - Regulatory Peptides

JF - Regulatory Peptides

IS - 3

ER -