Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin

Abstract

To investigate the role of vasodilator prostanoids in the CO2-induced relaxation of cerebral arterioles, the present study examined the effect of exogenous prostaglandin (PG) E2 and nonprostanoid vasodilators, adenosine and sodium nitroprusside, on the indomethacin-impaired pial arteriolar response to CO2 in newborn piglets. Reactivity of pial arterioles (52-131 microns diam) was determined using a closed cranial window with intravital microscopy. Cortical prostanoid synthesis was assessed by analyzing for select prostanoids in cerebrospinal fluid sampled from under the cranial window. Inhalation of 7% CO2 caused an elevation of cortical 6-keto-PGF1 alpha and thromboxane (Tx) B2 and increased pial arteriolar diameter by 34 +/- 5%. Two cyclooxygenase inhibitors, indomethacin (5 mg/kg i.v.) and ibuprofen (30 mg/kg i.v.), abolished the CO2-induced elevation of cortical prostanoids. Indomethacin, but not ibuprofen, blocked the CO2-induced increase in pial arteriolar diameter. The indomethacin-impaired vasodilator response to CO2 was restored when PGE2 (0.1-1 microM) was applied topically to the cortical surface. Adenosine (1-100 microM) and sodium nitroprusside (0.5 microM) only partially restored the vasodilator response to CO2. The data suggest that vasodilator prostanoids facilitate cerebrovascular relaxation to CO2 and may play a permissive role in the relaxation response of vascular smooth muscle. The fact that adenosine (adenosine 3',5'-cyclic monophosphate-mediated dilator) and sodium nitroprusside (guanosine 3',5'-cyclic monophosphate-mediated dilator), were partially effective suggests a role for those intracellular signaling pathways. We speculate that receptor activation of intracellular pathways may alter Ca2+ sensitivity of the contractile apparatus in such a way that the relaxation response to CO2 can occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Changes in pH and PCO2 on Wall Tension in Isolated Rat Intrapulmonary Arteries

“…The magnitude of the relaxation was very similar to that which we observed previously in phenylephrine preconstricted aortic rings (Sweeney et al 1998a) and is in agreement with the widely reported relaxant effect of acidosis in systemic vessels (Tobian et al 1959;Kontos et al 1977a,b;Wagerle & Mishra, 1988;Nielsen et al 1991;Austin & Wray, 1993;Fukuda et al 1993;Wagerle & Degiulio, 1994;Tian et al 1995;Peng et al 1998). In isohydric hypercapnia, however, the tension in PGF2á preconstricted carotid arteries was unchanged.…”

Selective Inhibitors Differentially Affect Cyclooxygenase-Dependent Pial Arteriolar Responses in Newborn Pigs

“…In this species, hypercapnia-induced dilation of pial arterioles was impaired after light/dye endothelial injury, indicating endothelial involvement (14,26). Additionally, vasodilation was found to be one of the numerous COX-dependent responses since inhibition of COX with indomethacin consistently abolished the vascular response (9,27,28). The role of COX-derived prostanoids in the mechanism of vasodilation to hypercapnia has been proposed as a "permissive role" since supplementation of exogenous prostacyclin could restore arteriolar responsiveness following indomethacin or light-dye injury (9,26).…”

Indomethacin lowers optic nerve oxygen tension and reduces the effect of carbonic anhydrase inhibition and carbon dioxide breathing

“…11 Ibuprofen decreases pial vessel diameter in newborn pigs but does not affect the CO 2 reactivity of these vessels. 24 Indomethacin may therefore change the vessel reactivity through affecting other processes than the prostaglandin synthesis, 27 but it may also be a more potent drug in inhibiting cyclo-oxygenase. 28 The inhibiting effect of indomethacin on CO 2 reactivity in cerebral vessels have been reversed by directly adding prostaglandins.…”

“…28 The inhibiting effect of indomethacin on CO 2 reactivity in cerebral vessels have been reversed by directly adding prostaglandins. 24 Thus, it is likely that prostaglandins at least facilitate CO 2 induced vasodilation. 24 We have previously shown that measurements of the oxygen tension in the normal pig vitreous can be obtained using the 20 mm oxygen electrodes, employed in the present study.…”

“…24 Thus, it is likely that prostaglandins at least facilitate CO 2 induced vasodilation. 24 We have previously shown that measurements of the oxygen tension in the normal pig vitreous can be obtained using the 20 mm oxygen electrodes, employed in the present study. 7 15 The vitreous acts as a diffusion medium with very low metabolism and oxygen gradient (about 2 mm Hg per mm in vitreous).…”