In line with the promotion by the Faculty of Medicine of integration between basic and clinical sciences, this laboratory has developed a new line of research on cardiovascular sciences. We are now focussing our efforts on septic shock, a major health problem, still poorly understood, for which the outcome is often fatal. Clinicians have very few means of stopping the vicious circle leading to cardiovascular failure, disseminated intravascular coagulation, multiple organ failure and death. The objective of this basic research project is to develop a procedure that can be efficacious in preventing terminal cardiovascular failure in late diagnosed septic patients. In the first stage, we aimed at dissecting the mechanisms responsible for the decrease in ventricular performance occurring during the hypo-dynamic phase of septic shock. We have now identified two factors that are overproduced during sepsis and that significantly decrease the intrinsic ventricular contractility and its response to beta-adrenergic stimulation. Broadly, the next steps in our research program will be:

• To characterize the molecular mechanisms by which these factor decrease contractility.

• To characterize the time course for the overproduction of these factors after bacterial infection.

• To assess "in vivo" the efficacy of inhibiting the biological effects of these two factors in restoring proper hemodynamics in our animal model of septic shock.

The laboratory is ready to address these issues, and is well equipped to carry out experiments at all levels from in vivo to cellular work. Graduate students at the M.Phil. and Ph.D. level will have the opportunity to address the problem from a broad range of perspectives, and will find the critical mass and the support they need to succeed in becoming independent investigators.

This research is funded by the Research Grant Council of Hong Kong and by the Committee on Research and Conference Grants of the University of Hong Kong.

REPRESENTATIVE PUBLICATIONS

• Mittra, S. and Bourreau, J.P (2006) G(s) and G(i) coupling of adrenomedullin in adult rat ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 290: H1842-H1847.

• Tu, J., Shan, Q.X., Jin, H.F. et al. (2004) Endothelin-1-mediated coronary vasoconstriction deteriorates myocardial depression in hearts isolated from lipopolysaccharide-treated rats: Interaction with nitric oxide. Clin. Exp. Pharmacol. Physiol. 31: 571-574.

• Mittra, S., Hyvelin, J.M., Shan, Q.X., et al. (2004) Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis? Am. J. Physiol. Heart Circ. Physiol. 286: H1034-H1042.

• Hyvelin, J.M., Shan, Q.X. and Bourreau, J.P. (2002) Adrenomedullin: A cardiac depressant factor in septic shock. J. Car. Surg. 17: 328-335

• Chan, H.Y., Yao, X.Q., Tsang, S.Y., et al. (2002) Isoproterenol amplifies 17 beta-estradiol-mediated vasorelaxation: role of endothelium/nitric oxide and cyclic AMP. Cardiovasc. Res. 53: 627-633.

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