Protective effect of continuous intravenous infusion of Isoproterenol on myocardial mitochondria of early septic rats and the corresponding mechanism

Abstract

Objective To investigate the protective effect of continuous intravenous infusion of Isoproterenol (ISO)on myocardial mitochondria of early septic rats and the corresponding mechanism. Methods Thirty Sprague Dawley (SD)rats were randomly divided into 5 groups (6 cases per group): control group, endotoxin group, ISO small-dose group, ISO medium-dose group and ISO large-dose group.Endotoxin group and ISO intervene group received same management apart from drug intervention: receiving intravenous injection of lipopolysaccharide (LPS)10 mg/kg followed by an continuous intravenous infusion of 9 g/L saline 1 mL/h or ISO 0.06 μg/(kg·min), 0.30 μg/(kg·min)and 0.60 μg/(kg·min). Control group received intraperitoneal injection and continuous intravenous infusion with the same amount of 9 g/L saline.The primary endpoint of the study was 24 hours after injection of 9 g/L saline or LPS.Serum creatine kinase (CK)and creatine kinase isoenzyme (CK-MB), oxidative and nitrosative stress levels and swelling of isolated heart mitochondrion were detected.The pathological changes of the myocardium and morphologic changes of the heart mitochondria were observed through light microscope and scanning electron microscope, respectively. Results The levels of CK, CK-MB, nitric oxide (NO)content, inducible nitric oxide synthase (iNOS)activity and malondialdehyde (MDA)content in endotoxin group were increased compared with control group (all P<0.05), while the superoxide dismutase (SOD) activity decreased [(11.543±1.080) U/mg prot vs (9.892±0.815) U/mg prot, P<0.05]. The morphology of the heart mitochondria significantly changed (such as swelling, disordered arrangement, crest fracture, fusion and cavitations, and so on). ISO intervention significantly decreased the levels of CK, CK-MB and mitochondrial swelling (all P<0.05)and increased the SOD activity (all P<0.05). The levels of NO content, iNOS activity and MDA content were significantly decreased in small-dose group[(10.823±2.240) μmol/g prot vs (7.917±2.203) μmol/g prot, (0.045±0.008) U/mg prot vs (0.033±0.003) U/mg prot, (1.663±0.618) mmol/mg prot vs (0.768±0.312) mmol/mg prot, all P<0.05], while the levels of iNOS activity and MDA content were significantly increased in medium- and large-dose group (all P<0.05); compared with medium-dose group, the degree of mitochondrial swelling in large-dose group increased (1.160±0.186 vs 1.393±0.128, P<0.05). The pathological changes of the myocardium mitochondria significantly improved. Conclusions The myocardium and myocardial mitochondria of early septic rats were damaged, continuous intravenous infusion of low-dose ISO revealed protective effect on these damages, and the corresponding mechanism may relate to the decrease of the oxidative and nitrosative stress. Key words: Isoproterenol; Lipopolysaccharide; Sepsis; Oxidative stress; Mitochondrion