Effects of indomethacin and diclofenac on cerebral blood flow in hypercapnic conscious rats

Quintana, Antonio García; Raczka, Ewa; Quintana, Miguel A.

doi:10.1016/0014-2999(88)90674-7

Cited by 22 publications

(10 citation statements)

References 8 publications

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“…These observations suggest that PG may not have a critical role in the regulation of basal cerebral hemodynamics in the newborn animal, as has been suggested for other major organs in the adult (29, 32, 45-47, 52, 53, 58), This, however, does not preclude the important contribution of PG to CBF regulation during adaptive physiologic responses (1 -14, 32, 44, 59). Finally, our findings clearly indicate, as previously suggested (20,60), that it is necessary to compare the cerebrovascular effects of a range of NSAID before attributing a particular role to the PG. …”

Section: -----------supporting

confidence: 84%

Differences in the Effects in the Newborn Piglet of Various Nonsteroidal Antiinflammatory Drugs on Cerebral Blood Flow but Not on Cerebrovascular Prostaglandins

et al. 1991

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ABSTRACT. To characterize the role of prostaglandins (PG) in the regulation of basal cerebral blood flow (CBF) in the newborn, we determined the effects of four nonsteroidal antiinflammatory drugs, indomethacin (3 mg/kg, n = 8 and 10 mglkg, n = 5), aspirin (65 mg/kg, n = 6), ibuprofen (30 mg/kg, n = 8), and naproxen (15 mg/kg, n = 6), on CBF, cerebral metabolism, and cerebrovascular PG in conscious 1-to 3-d-old piglets. Drugs and vehicle (n = 8) were injected i.v., and measurements were made 5 min before and 20 and 60 min after injections. Neither the vehicle nor any of the nonsteroidal antiinflammatory drugs exerted significant effects on mean arterial blood pressure and on blood gases and pH. All four drugs, with the exception of indomethacin at the lower dose (3 mg/kg), decreased PG to nearly undetectable levels within 20 min; the low dose of indomethacin caused a small decrease (18-32%) in PG at 60 min. However, the effects of these agents on CBF were diverse. CBF increased after the administration of aspirin, decreased to almost the same extent after both low and high doses of indomethacin, and did not change after the administration of ibuprofen and naproxen. Cerebral metabolic rate for oxygen was increased by aspirin but was unaltered by the other drugs. The data suggest that PG may not play a critical role in the regulation of basal CBF in the newborn animal and that certain nonsteroidal antiinflammatory drugs may have additional actions unrelated to the inhibition of PG synthesis. (Pediatr Res 30: 106-111,1991) Abbreviations PG, prostaglandin CBF, cerebral blood flow BP, blood pressure NSAID, nonsteroidal antiinflammatory drugThe role of PG in the regulation of CBF during various hemodynamic disturbances, such as hypertension, hypotension, hypoxia, and asphyxia, has been reported by various investigators (1-14). However, the significance of PG in the regulation of basal CBF remains controversial (1 5-19). In most studies ex-

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Section: -----------supporting

confidence: 84%

Differences in the Effects in the Newborn Piglet of Various Nonsteroidal Antiinflammatory Drugs on Cerebral Blood Flow but Not on Cerebrovascular Prostaglandins

et al. 1991

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“…Similar differences between the effectiveness of these two COX inhibitors were reported previously: indomethacin but not diclofenac inhibited the cerebral hyperemic response to hypercapnia (Quintana et al, 1988) and to acetazolamide-induced extracellular acidosis (Wang et al, 1993) in rats. Both compounds, in doses used in our present and the above cited studies, were shown to inhibit prostanoid production in the rat brain (Abdel-Halim et al, 1978).…”

Section: Discussionsupporting

confidence: 84%

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

et al. 2007

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The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous L-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute L-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous L-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI 2 , PGE 2 and PGD 2 ) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA 2 and PGF 2α ) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic L-NAME treatment. Although urinary excretion of PGI 2 and PGE 2 metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.

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“…In contrast to the effects of indomethacin, L-NNA and L-NAME have no effect on the response to hypercapnic acidosis in this vascular bed (newborn pig) (Parfenova et al 1994). In several other studies and in different species, including humans, indomethacin has been shown to inhibit the response to hypercapnia in a variety of vascular beds (Pickard & Mackenzie 1973, Eriksson et al 1983a, McCalden et al 1984, Norins et al 1992, You et al 1994, Wang et al 1994b, but indomethacin has effects unrelated to the inhibition of prostanoid production (McCalden et al 1984, Quintana et al 1988, Wagerle & Degiulio 1994, and the data are therefore dif®cult to interpret, as also indicated above. Furthermore, in other studies prostanoids did not increase during hypercapnic acidosis (Ellis et al 1982, Jackson et al 1983, Eriksson et al 1983b, McCalden et al 1984, and indomethacin was without effect on the vasodilator response to hypercapnia (Kontos et al 1967, Wei et al 1980, Busija & Heistad 1983, Toda et al 1993.…”

Section: The Role Of the L-arginine/no Pathway And Prostaglandinsmentioning

confidence: 99%

pH and smooth muscle

Aalkjær

Peng

1997

Acta Physiologica Scandinavica

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In this paper, the control of vascular smooth muscle intracellular pH (pHi) and the mechanisms of importance for the vasodilation to acidosis are reviewed. The three transport pathways of importance for the control of pHi are a sodium-coupled bicarbonate transport, a Na,H-exchanger and a Cl,HCO3- exchange. While the two latter pathways are present in all smooth muscle cells studied, the sodium-coupled bicarbonate transport may be present in two forms which are either coupled to chloride efflux or are independent of chloride. The chloride-independent pathway seems electroneutral, indicating a 1:1 stoichiometry. All three transporters can be activated by vasoactive hormones and the second messengers involved are under intense investigation. With respect to the mechanisms involved in the vasodilation to acidosis, there seems to be a nitric oxide-dependent pathway as well as a direct effect of acidosis on the smooth muscle cells. In some preparations, prostanoids may also be involved. The direct vasodilator effect of acidosis is probably mediated through reduction of extracellular pH and the acidosis is associated with a reduction of the intracellular calcium concentration, which could explain the reduction of smooth muscle tone.

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Effects of indomethacin and diclofenac on cerebral blood flow in hypercapnic conscious rats

Cited by 22 publications

References 8 publications

Differences in the Effects in the Newborn Piglet of Various Nonsteroidal Antiinflammatory Drugs on Cerebral Blood Flow but Not on Cerebrovascular Prostaglandins

Differences in the Effects in the Newborn Piglet of Various Nonsteroidal Antiinflammatory Drugs on Cerebral Blood Flow but Not on Cerebrovascular Prostaglandins

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

pH and smooth muscle

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