Volume 126, Issue 1, Page 111

British Journal of Pharmacology

January 1999, Volume 126, Issue 1, Pages 111 - 120

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Original Article

Role of iNOS in the vasodilator responses induced by L-arginine in the middle cerebral artery from normotensive and hypertensive rats
Ana M. Briones, María J. Alonso, Jesús Marín & Mercedes Salaices¹
Departmento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029-Madrid, Spain

¹Author for correspondence

Keywords

Rat middle cerebral artery;   inducible NO synthase;   L-arginine;   lipopolysaccharide;   dexamethasone;   polymyxin B;   protein kinase C

Abstract

1   The substrate of nitric oxide synthase (NOS), L-arginine (L-Arg, 0.01 µM-1 mM), induced endothelium-independent relaxations in segments of middle cerebral arteries (MCAs) from normotensive Wistar-Kyoto (WKY) and hypertensive rats (SHR) precontracted with prostaglandin F₂ (PGF₂). These relaxations were higher in SHR than WKY arteries.
2   L-N^G-nitroarginine methyl ester (L-NAME) and 2-amine-5,6-dihydro-6-methyl-4H-1,3-tiazine (AMT), unspecific and inducible NOS (iNOS) inhibitors, respectively, reduced those relaxations, specially in SHR.
3   Four- and seven-hours incubation with dexamethasone reduced the relaxations in MCAs from WKY and SHR, respectively.
4   Polymyxin B and calphostin C, protein kinase C (PKC) inhibitors, reduced the L-Arg-induced relaxation.
5   Lipopolysaccharide (LPS, 7 h incubation) unaltered and inhibited these relaxations in WKY and SHR segments, respectively. LPS antagonized the effect polymyxin B in WKY and potentiated L-Arg-induced relaxations in SHR in the presence of polymyxin B.
6   The contraction induced by PGF₂ was greater in SHR than WKY arteries. This contraction was potentiated by dexamethasone and polymyxin B although the effect of polymyxin B was higher in SHR segments. LPS reduced that contraction and antagonized dexamethasone- and polymyxin B-induced potentiation, these effects being greater in arteries from SHR.
7   These results suggest that in MCAs: (1) the induction of iNOS participates in the L-Arg relaxation and modulates the contraction to PGF₂; (2) that induction is partially mediated by a PKC-dependent mechanism; and (3) the involvement of iNOS in such responses is greater in the hypertensive strain.

Received 11 June 1998; Revised 30 September 1998; Accepted 9 October 1998