PACAP and VIP differentially preserve neurovascular reactivity after global cerebral ischemia in newborn pigs

• Published in: Brain research Vol. 1283; pp. 50 - 57
• Main Authors: Lenti, Laura, Zimmermann, Aliz, Kis, Dávid, Oláh, Orsolya, Tóth, Gábor K, Hegyi, Orsolya, Busija, David W, Bari, Ferenc, Domoki, Ferenc
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 04-08-2009; Elsevier
• Subjects: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arterioles - drug effects; Arterioles - metabolism; Arterioles - physiopathology; Biological and medical sciences; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Cerebral Arteries - drug effects; Cerebral Arteries - metabolism; Cerebral Arteries - physiopathology; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - physiology; Cranial window; Cyclooxygenase Inhibitors - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Excitatory Amino Acid Agonists - pharmacology; Female; Hypercapnia; Hypercapnia - metabolism; Hypercapnia - physiopathology; Indomethacin - pharmacology; Male; Medical sciences; Neurology; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric Oxide Synthase Type I - metabolism; NMDA; Pial arteriole; Piglet; Pituitary Adenylate Cyclase-Activating Polypeptide - metabolism; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacology; Pneumology; Respiratory system : syndromes and miscellaneous diseases; Sus scrofa; Vascular diseases and vascular malformations of the nervous system; Vasoactive Intestinal Peptide - metabolism; Vasoactive Intestinal Peptide - pharmacology; Vasodilation - drug effects; Vasodilation - physiology; NO; MABP; DMSO; N-methyl- d-aspartate; I/R; Pial arteriole; ischemia/reperfusion; Hypercapnia; vasoactive intestinal peptide; dimethyl sulfoxide; analysis of variance; ANOVA; Piglet; reactive oxygen species; NMDA; nitric oxide synthase; cerebrovascular reactivity; Cranial window; nitric oxide; L-NAME; PACAP; cyclooxygenase; N-ω-nitro- l-arginine methyl ester; COX; artificial cerebrospinal fluid; CR; pituitary adenylate cyclase activating polypeptide; NOS; ROS; mean arterial blood pressure; aCSF; SEM; standard error of the mean; VIP; Arteriole; Central nervous system; Carbon dioxide; Cardiovascular disease; Neuropeptide; Encephalon; Vascular disease; Microcirculation; Cerebrovascular disease; Ungulata; Pituitary adenylate cyclase activating peptide; Nervous system diseases; Respiratory disease; Cerebral disorder; Pig; Vertebrata; Mammalia; Newborn animal; Central nervous system disease; Vasoactive intestinal peptide; Brain ischemia; Circulatory system; Artiodactyla
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.06.021

Abstract Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective in numerous models. Impairment of cerebrovascular reactivity (CR) contributes to ischemia/reperfusion (I/R)-induced neuronal damage. We tested whether PACAP and/or VIP preserve CR to I/R-sensitive dilator responses dependent on endothelial and/or neuronal function. Accordingly, changes in pial arteriolar diameters in response to hypercapnia (5–10% CO2 ventilation) or topical N-methyl- d -aspartate (NMDA, 10 − 4  M) were determined before and after I/R via intravital microscopy in anesthetized/ventilated piglets. Local pretreatment with non-vasoactive doses of PACAP (10 − 8  M) and VIP (10 − 9  M) prevented the attenuation of postischemic CR to hypercapnia; to 10% CO2 , the CR values were 27 ± 8% vs 92 ± 5%⁎ vs 88 ± 13%⁎ (vehicle vs PACAP38 vs VIP, CR expressed as a percentage of the response before I/R, mean ± SEM, n = 8–8, ⁎ p < 0.05). PACAP, but not VIP, preserved CR to NMDA after I/R, with CR values of 31 ± 10% vs 87 ± 8%⁎ vs 35 ± 12% (vehicle vs PACAP38 vs VIP, n = 6–6). Unlike PACAP, VIP-induced vasodilation has not yet been investigated in the piglet. We tested whether VIP-induced arteriolar dilation was sensitive to inhibitors of cyclooxygenase (COX)-1 (SC-560, 1 mg/kg), COX-2 (NS-398, 1 mg/kg), indomethacin (5 mg/kg), and nitric oxide synthase (L-NAME, 15 mg/kg). VIP (10 − 8 –10 − 7 –10 − 6  M, n = 8) induced reproducible, dose-dependent vasodilation of 16 ± 3%, 33 ± 6%⁎, and 70 ± 8%⁎. The response was unaffected by all drugs, except that the vasodilation to 10 − 8  M VIP was abolished by SC-560 and indomethacin. In conclusion, PACAP and VIP differentially preserve postischemic CR; independent of their vasodilatory effect.