Effects Of Ketanserin On Endotoxic Shock And Baroreflex Function In Rodent

Backgrounds and Objectives: Sepsis is a major cause of morbidity and mortality in critically ill adults. Although a great progress was made on the treatment of septic shock, experimental strategies neutralizing proinflammatory cytokines (monoclonal antibodies against TNF, IL-1-receptor antagonists and TNF-receptor fusion proteins) are a successful therapeutic approach against several inflammatory disorders. However, these cytokine-based strategies have produced modest effects in clinical trials. The mortality rate associated with severe sepsis and septic shock remains unacceptably high at 30% to 50%. Therefore, it is important to find new strategies for the septic shock treatment.Ketanserin, an antihypertensive drug with a central sympathoinhibitory action, is a selective 5-HT2A receptor antagonist with additionalα1-adrenoceptor-blocking properties. Studies have demonstrated that ketanserin effectively lowers blood pressure (BP), decreases blood pressure variability (BPV) and enhances BRS in SHR. However, clinical application of ketanserin was not limited to anti-hypertension. Research demonstrated that intracoronary administration of ketanserin augments coronary collateral flow and decreases myocardial ischemia during balloon angioplasty. This could be of clinical significance in the management of acute ischemic syndromes. Another clinical research showed that treated with 2% ketanserin ointment for 8 weeks, observed a significant decrease in relative wound area compared with the placebo group in chronic leg ulcers patients. These results indicate that ketanserin is a valuable therapy for difficult-to-treat leg ulcers. This effect of ketanserin is through blocked of 5-HT2A receptor and improved microcirculation. Recently, a research showed that ketanserin has a beneficial effect in endotoxemia by improved microcirculation. However, ketanserin was used as a treatment in septic shock was rarely reported. Our previous study demonstrated that ketanserin could protect the organ damage in hypertension by restoring arterial baroreflex function.Arterial baroreflex function (ABR) is one of the most important mechanisms in the regulation of cardiovascular activities. Baroreflex function, expressed as baroreflex sensitivity (BRS), was found as an important determinant of cardiac death after acute myocardial infarction. There is also established evidence of abnormal BRS in animal models of stroke and patients with chronic cerebrovascular disease. Indeed, it was found that BRS was impaired after acute stroke. Poststroke patients with impaired BRS had a poor prognosis. However, to our knowledge, there is no report about BRS on predicting stroke. The first aim of this study was therefore, to investigate whether BRS can be a new predictor for stroke incidence. Our previous study showed that ABR function plays an important role in the development of septic shock. It was found that the survival time of conscious sinoaortic denervated (SAD) rats (BRS = 0.198±0.035 ms/mmHg) was significant shorted by LPS (101±11.5 min vs. (148±6.5 min). This result was also observed in post-cecal ligation and puncture rats. These reports demonstrated that ABR dysfunction was associated to a poor prognosis in septic shock. So we hypothesized that ketanserin has a beneficial effect in septic shock through restoration of baroreflex function.Methods: The study was based on the model of endotoxin-induced shock rodent. Kunming mice were injected with LPS (30mg/kg, i.p.) to induce septic shock. Ketanserin was administered (0.3-10mg/kg, i.p.) immediately after injected with LPS. Survival time was monitored and cytokines were analyzed after the onset of LPS. In IL-10 deficient mice, the anti-shock effect of ketanserin was still existed. The effect of ketanserin on survival time was observed after sinoaortic denervation in Kunming mice. Baroreflex sensitivity (BRS) was measured after treated with LPS or followed with ketanserin in WKY rats.Results:1. Kunming mice were injected with LPS (30mg/kg, i.p.) to induce septic shock, then injected ketanserin (0.3-10mg/kg, i.p.) immediately after injected with LPS. Results showed that ketanserin could significantly increase survival rate dose-dependently.2. At 0.3-10.0 mg/kg, ketanserin significantly decreased serum TNF-αin serum in LPS-induced shock mice. Serum IL-1βwas significantly decreased. At 10.0 mg/kg, ketanserin also significantly increased serum IL-10. Moreover, ketanserin prevented the organ damage induced by LPS.3. In comparison to the wild-type littermates, serum TNF-αwas significantly higher in IL-10 deficient mice. Treatment with ketanserin (10 mg/kg) significant decreased serum TNF-αin wild-type mice, as well as in IL-10 deficient mice. It is suggested that increasing IL-10 is not a major action of ketanserin that produces its protective effects on LPS-induced shock.4. LPS increased heart rate, and elicited a rapid reduction in MAP, followed by a rebound and then a secondary decrease. Ketanserin did not alter the effects of LPS on MAP and heart rate, but significantly prolonged the survival time.5. LPS significantly decreased BRS. In rats treated with 1.0 mg/kg ketanserin, LPS also decreased BRS. However, ketanserin significantly attenuated the depression of BRS induced by LPS6. In sham-operated mice, ketanserin (1.0 mg/kg) significantly reduced LPS-induced mortality. Such an effect was attenuated by SAD. Conclusion: These findings demonstrate that restoration of baroreflex function is an effective therapy in treating septic shock by ketanserin.