NO contributes to abnormal vascular calcium regulation and reactivity induced by peritonitis-associated septic shock in rats.
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.
Chen
Shiu-Jen
SJ
Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Kang-Ning Rd., Neihu, Taipei, Taiwan. sjchen@knjc.edu.tw
Li
Shaio-Yun
SY
Shih
Chih-Chin
CC
Liao
Mei-Huei
MH
Wu
Chin-Chen
CC
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002432:Cecum / Q000473:pathology; D007211:Indoles; D008026:Ligation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D009638:Norepinephrine / Q000494:pharmacology*; D010538:Peritonitis / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000494:pharmacology; D012772:Shock, Septic / Q000503:physiopathology*
C504876:2-aminoethoxydiphenylborane; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D007211:Indoles; D012433:Ryanodine; D009569:Nitric Oxide; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; C000543:cyclopiazonic acid