Effects of Indomethacin on Myogenic Contractile Activation and Responses to Changes in O₂ and CO₂ in Isolated Feline Cerebral Arteries

Abstract

Summary:We used an isolated, pressurized, and per fused feline middle cerebral artery preparation to mea sure how changes in intraluminal pressure and alterations in O2 and CO2 affect vessel diameter and myogenic con tractile activation before and after treatment with indo methacin (I ND). Vessel diameters were measured over the pressure range 60-140 mm Hg. The arteries were then exposed to low O2 (50 torr) and/or high CO2 (65 torr) and diameters remeasured over the same range. Under con trol conditions, the arteries exhibited myogenic contrac tile activation. Exposure to low O2, high CO2, or a mix ture of low 02/high CO2, increased vessel diameter but did not change the vessels' myogenic contractile respon siveness to changes in pressure. Arteries exposed to IND Arachidonic acid derivatives produced by the ce rebral arteries have many effects on the cerebrovas culature (Pickard and Walker, 1985). Investigations into how these derivatives, particularly prostaglan dins and prostacyclin, affect cerebrovascular regu lation have relied extensively upon the use of the cyclo-oxygenase inhibitor, indomethacin (IND) (Pickard and Walker, 1985). However, many of the findings have been contradictory. In animal studies, results have varied depending upon the species as well as the experimental model used (Leffler et aI., 1985). In some studies IND significantly reduced basal CBF (Pickard and MacKenzie, 1973; McCulReceived October 9, 1991; final revision received March 20, 1992; accepted March 24, 1992. Address correspondence and reprint requests to Dr. Jane A. 866decreased in diameter but retained myogenic contractile activity. In the presence of IND, vessels dilated to both low O2 and a mixture of low 02/high CO2, but did not dilate to high CO2 alone. Under all conditions, vessels retained myogenic contractile activity. Results obtained under control conditions and low O2 confirm those of others using similar systems. Myogenic contractile activ ity in the presence of high CO2 or a mixture of low Ozl high CO2 has not been previously reported. The dilation to low O2 but not to high CO2 in the presence of IND suggests that this drug's effects in cerebral arteries are not limited solely to inhibition of prostaglandin synthesis.

Carbonic Anhydrase I Inhibition By Nitric Oxide: Implications For Mediation Of The Hypercapnia‐Induced Vasodilator Response

“…In several studies and in different species, including humans, indomethacin has been shown to inhibit the response to hyper‐ capnia in a variety of vascular beds; 40–45 however, the effects of indomethacin are unrelated to the inhibition of prostanoid production 44,46 …”

Use of indomethacin in brain-injured patients with cerebral perfusion pressure impairment: preliminary report

“…12 Although the standard therapy observed before and during indomethacin infusion did not appear to effect significant changes, the fact that in three cases mannitol reestablished its action on ICP and CPP during indomethacin infusion was consistent with the view that indomethacin could have a beneficial effect on cerebral autoregulation. 9 Third, it is also probable that the beneficial effects of indomethacin infusion could be due to nonvascular actions on baseline ICP in pathological conditions such as ischemic and vasogenic edema. 1,4,14 Decreased production of cerebrospinal fluid following endothelin potentiation has been recently demonstrated.…”

Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis

“…22 Alternative mechanisms include interference with the regulation of cerebrovascular tone mediated by extracellular pH, 23 a reduction of cerebral temperature, 24 as well as a direct non-prostaglandin-mediated vasoconstrictive effect. 25 Our study was not designed to dissect this complexity, although we did show evidence of decreased prostanoid formation without effects on body temperature.…”