A potential role for trace amines in the treatment of septic shock

Sepsis involves an unregulated response to bacterial infection, the inflammatory response leading to persistent hypotension, leading to a precipitous fall in arterial blood pressure. The major trigger for the hypotension in sepsis and septic shock is the release of lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria, which generates a major inflammatory response. LPS activates toll-like receptors (TLR4), leading to the release of an array of inflammatory mediators, which most notably activate inducible nitric oxide (NO) synthase and release copious amounts of NO. This is responsible for the hypotension. Despite the development of a large number of newer drugs for treating sepsis, none has emerged as superior to existing treatments. Early vasopressor therapy remains an integral life-saving strategy to treat the hypotension. Noradrenaline remains the vasopressor of choice; however, it has a number of limitations which are discussed. Improvements in vasopressor therapies are required and research from the authors is used to advance the case for using trace amines, such as β-phenylethylamine (PEA). Although usually regarded as sympathomimetic amines, PEA and related amines such as amphetamine and ephedrine exert vasoconstrictive effects via trace amine-associated receptors (TAARs), particularly when administered by infusion. The sympathomimetic and TAAR vasoconstrictor actions are demonstrated on anesthetized rat blood pressure. Unlike noradrenaline, PEA is not a universal vasoconstrictor; it also dilates other vessels, including mesenteric vascular beds. This would provide a superior profile of activity for use in restoring blood pressure in sepsis. The ability of PEA to reverse the vasodilator action of LPS is demonstrated in a simple in vitro blood vessel model. This review therefore opens the possibility of using trace amines for restoring blood pressure and organ perfusion in septic shock.