Alterations in Rat Aortic Alpha1-Adrenoceptors and Alpha1-Adrenergic Stimulated Phosphoinositide Hydrolysis in Intraperitoneal Sepsis

摘要

Sepsis and septic shock are major causes of death in the United States among critically ill patients. Despite sophisticated and aggressive surgical and medical interventions, the mortality rate in septic shock remains between 40 and 60%. In dissecting the pathophysiology of sepsis and endotoxemia, numerous investigators have noted diminished peripheral vascular responsiveness to norepinephrine in both humans and in animal models of sepsis and endotoxemia. Furthermore, an attenuated response to exogenously applied norepinephrine (NE) has been noted in isolated aorta by several groups of investigators using a variety of models of sepsis and endotoxemia. The mechanism of this phenomenon remains unknown, but could reside in part in the signal transduction apparatus. We recently found that NE-induced contraction of rat aorta, which is mediated by alpha1-adrenoceptors, appears to correlate with the breakdown of phosphoinositides (PI). It is proposed that IP3 mobilizes intracellular calcium while DAG activates protein kinase C. Phorbol esters, which mimic the effects of endogenous DAG, are potent inducers of rat aortic contraction. Phorbol esters induce vasoconstriction in part by the mobilization of extracellular calcium in a nitrendipine-sensitive fashion. In this paper we report significant alterations in aortic PI metabolism in rat intraperitoneal sepsis. We also discovered diminution of aortic alpha1-adrenoceptors. These results suggests that experimental sepsis in the rat induces alterations in receptor-coupled signal transduction in the aorta. Keywords: Biochemistry; Reprints. (kt)