In sepsis, lipopolysaccharide (LPS) depresses cardiac function by inducing production of nitric oxide (NO) and its second messenger cGMP. LPS also stimulates ANG II production. We hypothesized that ANG II modulates the cardiac response to LPS. Adult rabbit cardiac myocytes incubated with LPS (10 ng/ml) had increased cardiac cGMP after 6 h (but not within 1 h) [527 ± 43 vs. 316 ± 27 (SE) fmol/mg protein in controls, n = 16 each group, P < 0.05]. This was associated with depressed cell shortening with no alterations in Ca²⁺ transients (indo 1 fluorescence), indicating a decreased myofilament responsiveness to Ca²⁺. ANG II (100 nM) alone had no effect. However, ANG II with LPS produced higher cGMP levels (1,025 ± 113 fmol/mg protein, n = 16, P < 0.05 vs. LPS alone), more severe contractile depression, impaired Ca²⁺ handling, and decreased mitochondrial activity (MTS assay). We conclude that ANG II and LPS have synergistic effects on the activation of NO-cGMP pathways to induce dose-dependent impairments in excitation-contraction coupling in cardiac myocytes.

sepsis; guanosine 3',5'-cyclic monophosphate; contractility; intracellular calcium

This article has been cited by other articles:

				H. L. Li, J. Suzuki, E. Bayna, F.-M. Zhang, E. Dalle Molle, A. Clark, R. L. Engler, and W. Y. W. Lew Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT1 receptors Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H461 - H467. [Abstract] [Full Text] [PDF]

				J. Schwobel, T. Fischer, B. Lanz, and M. Mohaupt Angiotensin II receptor subtypes determine induced NO production in rat glomerular mesangial cells Am J Physiol Renal Physiol, December 1, 2000; 279(6): F1092 - F1100. [Abstract] [Full Text] [PDF]