Role of prostaglandins in determining the increased cardiac sympathetic nerve activity in ovine sepsis

Abstract

Booth LC, Ramchandra R, Calzavacca P, May CN. Role of prostaglandins in determining the increased cardiac sympathetic nerve activity in ovine sepsis. Am J Physiol Regul Integr Comp Physiol 307: R75-R81, 2014. First published April 30, 2014 doi:10.1152/ajpregu.00450.2013.-Effective treatment of sepsis remains a significant challenge in intensive care units. During sepsis, there is widespread activation of the sympathetic nervous system, which is thought to have both beneficial and detrimental effects. The sympathoexcitation is thought to be partly due to the developing hypotension, but may also be a response to the inflammatory mediators released. Thus, we investigated whether intracarotid infusion of prostaglandin E2 (PGE2) induced similar cardiovascular changes to those caused by intravenous infusion of Escherichia coli in sheep and whether inhibition of prostaglandin synthesis, with the nonselective cyclooxygenase inhibitor indomethacin, administered at 2 and 8 h after the onset of sepsis, reduced sympathetic nerve activity (SNA), and heart rate (HR). Studies were performed in conscious sheep instrumented to measure mean arterial pressure (MAP), HR, cardiac SNA (CSNA), and renal SNA (RSNA). Intracarotid infusion of PGE2 (50 ng·kg Ϫ1 ·min Ϫ1 ) increased temperature, CSNA, and HR, but not MAP or RSNA. Sepsis, induced by infusion of E. coli, increased CSNA, but caused an initial, transient inhibition of RSNA. At 2 h of sepsis, indomethacin (1.25 mg/kg bolus) increased MAP and caused reflex decreases in HR and CSNA. After 8 h of sepsis, indomethacin did not alter MAP, but reduced CSNA and HR, without altering baroreflex control. These findings indicate an important role for prostaglandins in mediating the increase in CSNA and HR during the development of hyperdynamic sepsis, whereas prostaglandins do not have a major role in determining the early changes in RSNA.sepsis; cardiac sympathetic nerve activity; renal sympathetic nerve activity; PGE2; indomethacin; baroreflex curve; sheep SEPSIS AND SEPTIC SHOCK ARE the chief causes of death in intensive care units with mortality rates of between 30 and 70% when combined with multiorgan failure (2, 20, 21, 28). Although the incidence of sepsis is increasing, our knowledge of the pathology is limited, and current treatments, including volume resuscitation and vasoconstrictors, are only marginally effective. In human septic patients the most common hemodynamic profile is a hyperdynamic circulation, characterized by peripheral vasodilatation and hypotension accompanied by an increased cardiac output (16,17). These changes are accompanied by activation of the sympathetic nervous system, as demonstrated by increased circulating levels of plasma catecholamines in septic humans (12), increased renal sympathetic nerve activity (RSNA) in endotoxemic rats (22,30), and increased SNA to the heart and kidneys in sheep with hyperdynamic sepsis (24). It would be expected that an increase in SNA would be beneficial in sepsis, for example, by maintaining arterial pressure; however there...

Brain–heart interactions: physiology and clinical implications

“…Inflammatory mediators act directly on the heart to cause tachycardia in experimental sepsis [115]. However, the sympathetic outflow to the heart also markedly increases in these conditions [116]. Cardiac sympathetic activation during sepsis may result from disinhibition of the DMH and the RVMM caused by prostaglandin E2 binding to neurons in the medial preoptic hypothalamus [116,117].…”

“…However, the sympathetic outflow to the heart also markedly increases in these conditions [116]. Cardiac sympathetic activation during sepsis may result from disinhibition of the DMH and the RVMM caused by prostaglandin E2 binding to neurons in the medial preoptic hypothalamus [116,117]. This is a dramatic example of the complex and still poorly understood interactions between the brain, autonomic activity and the immune system, which are a burgeoning area of research [118].…”

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“…SNS activation mainly includes cardiac sympathetic nerve activation (CSNA), renal sympathetic nerve activation (RSNA), central nervous system activation, as well as skeletal muscle sympathetic activation ( 12 ). The amount of norepinephrine released in the heart and kidney after SNS activation accounted for 62% of the total norepinephrine in the body, suggesting that CSNA and RSNA play essential roles in the onset and progression of heart failure ( 13 ).…”

Emerging benefits and drawbacks of α2‐adrenoceptor agonists in the management of sepsis and critical illness

“…In sepsis, there is evidence that the combination of hypotension and inflammation results in excessive activation of the sympathetic nervous system, which helps support arterial BP. In early sepsis, before arterial pressure decreased, cardiac SNA progressively increased, and this increase is inhibited by indomethacin, indicating a stimulatory effect of PGs (Booth, Ramchandra, Calzavacca, & May, 2014). At the later stages of sepsis, the high level of cardiac SNA is partly mediated by the arterial baroreflex in response to the decrease in arterial pressure (Ramchandra et al, 2009).…”