Mechanisms of 5-HT1A receptor-mediated reversal of hypovolemic shock

In the United States, trauma is the leading cause of death of young people between the ages of 3 and 33 years. Most trauma deaths are due to injury to the central nervous system (CNS) and/or exsanguination and the ensuing cardiovascular decompensation that follows prolonged hypoperfusion. Currently massive fluid resuscitation combined with vasoconstrictors is the standard therapy for hypovolemic shock. However major side effects of such treatment, including further ischemia, excessive production of toxic oxidative radicals and inflammatory cytokines, result in extensive end organ damage. Alternative therapies to prevent reperfusion injury are limited. Therefore, development of more effective therapies to increase cardiac output and restore perfusion pressure with limited reperfusion injury is a major goal of hypovolemic shock research.; Our laboratory showed that administration of the selective 5-HT 1A receptor agonist, (+)-8-hydroxy-2-n-di[propylamino] tetralin (8-OH-DPAT), after the onset of hypotensive hemorrhage acts within the CNS to reverse the hypotensive, bradycardic and sympathoinhibitory responses that develop following severe hemorrhage in conscious rats. However, it was not known if similar effects could be elicited during hypovolemic shock, and thus whether 5-HT1A agonists might be useful adjuvants to volume restitution. The mechanisms by which 5-HT1A agonists increase pressure are not known. It is also not known whether the sympathoexcitatory effects of 5-HT1A agonists are beneficial in hypovolemic shock. Therefore, this dissertation tested the overall hypothesis that 5-HT1A agonists increase sympathetic activity and thus blood pressure following hemorrhage by disinhibiting the arterial baroreflex. We further hypothesized that the sympathetic-mediated increase in perfusion pressure would contribute to increased renal perfusion.; Results from these studies show that administration of 8-OH-DPAT following acute hemorrhage increases pressure by mechanisms that involve arterial baroreceptor-dependent and independent increases in sympathetic drive. Furthermore, a clinically available partial 5-HT1A agonist, buspirone, was found to have similar sympathoexcitatory effects in hypovolemic animals. Our results also indicate that 8-OH-DPAT increases blood pressure and renal blood flow when administered after development of hypovolemic shock, the latter effect of which was due to increases in both perfusion pressure and renal vasodilation. Together, our observations indicate that 8-OH-DPAT may be a beneficial adjuvant in the treatment of hemorrhagic shock.