Alteration by lipopolysaccharide of the relationship between intracellular calcium levels and contraction in rat mesenteric artery

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Abstract
1 The aim of this work was to investigate the effect of lipopolysaccharide (LPS) treatment on the relationship between the cytosolic Ca2+ ion concentration ([Ca2+]i) and contraction in rat resistance arteries, and the involvement of the L-arginine-nitric oxide (NO)-guanosine 3′-5′ cyclic monophosphate (cyclic GMP) pathway in these effects. 2 [Ca2+]i and tension were simultaneously recorded in small mesenteric arteries removed from rats 4 h after intraperitoneal injection of E. coli LPS (30 mg kg−1) or solvent. Cyclic GMP was assayed in vessels submitted to identical treatments. 3 Basal [Ca2+]i was higher in vessels from LPS-treated rats compared to controls. LPS did not modify the concentration-contraction curve of noradrenaline. However, the increase in basal [Ca2+]i produced by LPS resulted in a shift of the noradrenaline [Ca2+]i-contraction curve to higher [Ca2+]i concentrations. 4 L-Arginine (300 μm) relaxed noradrenaline (10 μm) pre-contracted arteries from LPS-treated but not from control rats. This effect of L-arginine was reversed by two inhibitors of NO synthase: Nω-nitro-l-arginine-methyl-ester (L-NAME, 1 mM) and S-methyl-isothiourea (SMT, 0.1 mM). Both the relaxing effect of L-arginine and its reversal by L-NAME or SMT occurred without any change in [Ca2+]i. 5 LPS treatment did not modify the cyclic GMP content of the small mesenteric arteries. In arteries removed from LPS-treated rats but not from controls, addition of L-arginine (300 μm) was associated with a significant increase in cyclic GMP content, an effect which was prevented by both L-NAME (1 mM) and SMT (0.1 mM). 6 L-NAME (1 mM) produced a greater reduction in cyclic GMP content than SMT (0.1 mM) in control vessels exposed to L-arginine (300 μm). Under the same conditions, SMT produced a larger decrease in cyclic GMP level than L-NAME in arteries taken from LPS-treated rats, consistent with selective inhibition by SMT of the inducible NO-synthase after LPS. 7 These results show that LPS produced two effects in small mesenteric arteries: (i) alterations in Ca2+ handling and a decreased sensitivity of myofilaments to Ca2+, (ii) induction of NO-synthase activity resulting in exogenous L-arginine-dependent production of NO and cyclic GMP accumulation. Both effects are likely to be involved in the hyporeactivity induced by LPS in resistance arteries.