Selective inhibitors differentially affect cyclooxygenase-dependent pial arteriolar responses in newborn pigs

Domoki, Ferenc and Nagy, Krisztina and Temesvári, Péter and Bari, Ferenc (2005) Selective inhibitors differentially affect cyclooxygenase-dependent pial arteriolar responses in newborn pigs. PEDIATRIC RESEARCH, 57 (6). pp. 853-857. ISSN 0031-3998

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Abstract

Cyclooxygenase (COX)-derived prostanoids play an important role in the cerebrovascular control of newborns. In humans and in the widely accepted model of piglets, both the COX-1 and the COX-2 isoforms are expressed in cerebral arteries. However, the involvement of these isoforms in cerebrovascular control is unknown. Therefore we tested if specific inhibitors of COX-1 and/or COX-2 would differentially affect pial arteriolar responses to COX-dependent stimuli in piglets. Anesthetized, ventilated piglets (n = 35) were equipped with a closed cranial window, and changes in pial arteriolar diameters (baseline similar to 100 mu m) to hypercapnia (ventilation with 5-10% CO2, 21% O-2, balance N-2), arterial hypotension (40 mm Hg MABP achieved by blood withdrawal), and Ach (Ach, 10-100 mu M) were determined via intravital microscopy. Arteriolar responses were repeatedly tested 15 min after IV administration of selective COX-1 and COX-2 inhibitors SC-560 and NS-398 (1-1 mg/kg), and nonselective inhibitors indomethacin (0.3-1 mg/kg), acetaminophen (30 mg/kg), and ibuprofen (30 mg/kg). Hypercapnia resulted in concentration-dependent, reversible, (similar to 20-40%) increases in pial arteriolar diameters that were unaffected by NS-398, SC-560, acetaminophen and ibuprofen. In contrast, 0.3 mg/kg indomethacin significantly reduced, 1 mg/kg virtually abolished the vasodilation. Arterial hypotension elicited (similar to 15-20%) vasodilation that was similarly reduced by NS-398 and indomethacin but was unaltered by SC-560. Ach dose-dependently constricted pial arterioles. This response was similarly attenuated by NS-398, indomethacin, and ibuprofen, but left intact by SC-560. We conclude that the assessed COX-dependent vascular reactions appear to depend largely on COX-2 activity. However, hypercapnia-induced vasodilation was found indomethacin-sensitive instead of a COX-dependent response in the piglet.

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