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

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 microM) relaxed noradrenaline (10 microM) pre-contracted arteries from LPS-treated but not from control rats. This effect of L-arginine was reversed by two inhibitors of NO synthase: N omega-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 microM) 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 microM). 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.