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Hypertension alters role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after LPS in rat cerebral arteries

¹Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid; ²Departamento de Farmacología Terapéutica i Toxicología, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona; and ³Departamento de Ciencias de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcón, Madrid, Spain

Submitted 12 June 2003 ; accepted in final form 25 February 2004

This study was performed to investigate the role of reactive oxygen species and inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) metabolites in the lipopolysaccharide effect on bradykinin-induced relaxation in middle cerebral arteries from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). LPS exposure (10 µg/ml for 1–5 h) reduced bradykinin relaxation; this effect appeared earlier and was greater in arteries from SHR than WKY rats. LPS also reduced the relaxation to the NO donor diethylamine (DEA)-NO; however, LPS modified neither the bradykinin relaxation after inhibiting NO synthesis with N^G-monomethyl-L-arginine (0.1 mM) nor endothelial NOS expression. In arteries from WKY rats, the respective iNOS and COX-2 inhibitors aminoguanidine (0.1 mM) and NS-398 (10 µM) and the superoxide anion scavenger SOD (100 U/ml) reduced the LPS effect on bradykinin relaxation; however, the thromboxane A₂ (TxA₂)PGH₂ receptor antagonist SQ-29548 (1 µM) and the H₂O₂ scavenger catalase (1,000 U/ml) did not modify the LPS effect. In arteries from SHR, all of these drugs reduced the LPS effect. LPS exposure (5 h) increased superoxide anion levels in arteries from both strains and TxA₂ levels only in SHR. COX-2 expression rose to a similar level in arteries from both strains after 1 and 5 h of LPS incubation, whereas expression of Cu/Zn- and Mn-SOD only increased after 5 h. In conclusion, in segments from WKY rats, LPS reduced bradykinin-induced relaxation through increased production of NO (from iNOS) and superoxide anion. The greater LPS effect observed in arteries from SHR seems to be related to higher participation of reactive oxygen species and contractile prostanoids (probably TxA₂).

lipopolysaccharide; inducible nitric oxide synthase; cyclooxygenase-2; rat; reactive oxygen species

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