Am. J. Respir. Crit. Care Med., Volume 163, Number 2, February 2001, 362-367

Phosphorylation-dependent Alteration in Myofilament Ca²⁺ Sensitivity but Normal Mitochondrial Function in Septic Heart

BENOÎT TAVERNIER, ALEXANDRE MEBAZAA, PHILIPPE MATEO, STANISLAS SYS, RENÉE VENTURA-CLAPIER, and VLADIMIR VEKSLER

INSERM U-446, Laboratoire de Cardiologie Cellulaire et Moléculaire, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Département d'Anesthésie-Réanimation Chirurgicale 2, Hôpital Claude Huriez, Lille, France; Département d'Anesthésie-Réanimation, Hôpital Lariboisière, Paris, France; and Laboratory of Cardiovascular Physiology, RUCA, Antwerp, Belgium

The subcellular mechanisms responsible for myocardial depression during sepsis remain unclear. Recent data suggest a role for impaired energy generation and utilization, resulting in altered contractile function. Here, we studied the energetic and mechanical properties of skinned fibers isolated from rabbit ventricle in a nonlethal but hypotensive model of endotoxemia. Thirty-six hours after lipopolysaccharide (LPS) injection (in the presence of altered myocardial contractility), mitochondrial respiration, coupling between oxidation and phosphorylation, and creatine kinase function were similar in preparations from endotoxemic (LPS) and control animals. The maximal Ca²⁺-activated force was similar in LPS and control preparations. However, the Ca²⁺ concentration corresponding to half-maximal force (pCa₅₀, where pCa = log₁₀[Ca²⁺]) was 5.55 ± 0.01 (n = 11) in LPS fibers versus 5.61 ± 0.01 (n = 10) in control fibers (p < 0.01). Both protein kinase A (PKA) and alkaline phosphatase treatment led to the disappearance in the difference between control and LPS pCa₅₀ values. Incubation of control fibers with the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) did not change the Ca²⁺ sensitivity after subsequent skinning, whereas isoproterenol decreased pCa₅₀ from 5.62 ± 0.01 to 5.55 ± 0.01 (p < 0.01). These data suggest that during sepsis, cardiac mitochondrial and creatine kinase systems remain unaltered, whereas protein phosphorylation decreases myofibrillar Ca²⁺ sensitivity and may contribute to the depression of cardiac contractility.

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