ryanodine and Peritonitis

Calcium plays an important role in determining vascular smooth muscle tone. Norepinephrine (NE)-induced vascular contraction contains two components: 1) Ca2+ release from the sarcoplasmic reticulum as the fast phase and 2) Ca2+ influx via a voltage-dependent calcium channel as the slow phase. This study used functional isometric tension recording to evaluate mediators contributing to abnormal NE-induced Ca2+ handling and reactivity in isolated thoracic aortas from septic rats. Sepsis was induced by cecal ligation and puncture (CLP), and thoracic aortas were removed at 18 h after CLP. Our results showed that rats that received CLP for 18 h manifested severe hypotension and vascular hyporeactivity to NE in vivo. This vascular hyporeactivity to NE was also observed in the aorta obtained from CLP-induced sepsis rat. Both the fast and slow phases of NE-induced contraction were reduced in aortas from sepsis rats. To clarify what possible mediators contribute to the abnormal Ca2+ handling in aortas from sepsis animals, inhibitors of Ca2+ channel and release were used. Inhibition by 2-aminoethoxy-diphenyl borane, ryanodine, and cyclopiazonic acid of the NE-induced contraction in Ca2+-free solution was greater in the aorta from sepsis rats and inhibitions of cyclopiazonic acid and ryanodine, but not of 2-aminoethoxy-diphenyl borane, were attenuated by NOS inhibitor N[omega]-nitro-l-arginine methyl ester. In addition, the attenuation of NE-induced contraction by nifedipine in the aorta was also greater in the CLP group. Our results suggest that abnormal NE-induced Ca2+ handling associated with vascular hyporeactivity in the CLP-induced sepsis is caused by a major decrease in sarcoplasmic reticulum function and a minor impairment of voltage-dependent Ca2+ channels on membrane to Ca2+ handling, at least, in the aorta, and this could be attributed to an overproduction of NO in sepsis.

Topics: Animals; Aorta, Thoracic; Boron Compounds; Calcium; Calcium Channel Blockers; Cecum; Indoles; Ligation; Male; Muscle Contraction; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Peritonitis; Rats; Rats, Wistar; Ryanodine; Shock, Septic