Substance P, a member of the tachykinin family, is found primarily in sensory nerves. In the heart, substance P-containing nerve fibers surround coronary vessels, making them ideally positioned to sense changes in coronary pressure and/or flow. Recent studies have identified substance P as being protective acutely following ischemia-reperfusion due to its ability to induce coronary blood vessel vasodilation. In addition, studies conducted on non-cardiac tissue have reported substance P to be protective against cell death through a mechanism involving activation of anti-apoptotic AKT pathway. However, the possibility of substance P being similarly cardioprotective has not been reported. Accordingly, the purpose of this study was to test the hypothesis that substance P attenuates cardiomyocyte cell death following ischemia/reperfusion. A rat isolated heart preparation was used to study the effect of substance P following global ischemia/reperfusion, while a rat left ventricular tissue slice culture preparation was used to study the effect of substance P in ischemia without reperfusion. Coronary flow was significantly increased during reperfusion and LDH release was less in substance P pretreated ischemia/reperfusion hearts compared with no-treatment ischemia/reperfusion hearts. In the cultured slice preparation, substance P was shown to be effective in decreasing hypoxic-induced LDH release, apoptosis (TUNEL), and necrosis (PAS), as well as increasing AKT activation (phosphorylation) in a dose dependent manner. Inhibition of the substance P receptor (NK1) or p-AKT resulted in an increased release of LDH, apoptosis, and necrosis in hypoxic slices incubated with substance P, thus abolishing the protective effect of substance P. These findings indicate that, in addition to its coronary vasodilatory effect, substance P is cardioprotective via a cardiomyocyte antiapoptotic mechanism
