Serotonin (5-hydroxytrypamine; 5-HT) is known to cause complex dose-dependent effects within the cardiovascular system by altering vascular resistance and arterial pressure resulting in pressor or depressor outcomes. Increased circulating levels of 5-HT has been reported in chronic cardiovascular diseases. Therefore, it is important to understand the mechanisms by which 5-HT regulates cardiovascular system function under chronic conditions. Previous work in our laboratory found low doses of infused 5-HT causes a sustain fall in arterial pressure. The focus of my work was to understand the hemodynamic mechanisms that cause 5-HT-induced hypotension. A significant finding from my work was determining the activated 5-HT7 receptor is essential in mediating the chronic fall in arterial pressure with low doses of 5-HT. Rats lacking a functional 5-HT7 receptor (pharmacologically or genetically removed) resulted in no 5-HT-induced observed depressor response. At the systemic hemodynamic level, a decrease in total peripheral resistance (TPR) during 5-HT infusion was the result of an elevation in skeletal muscle blood flow mediated by the 5-HT7 receptor, which was measured with Doppler flow probes. Additionally, administration of 5-HT infusion relaxed splanchnic veins, via 5-HT7 receptor stimulation, when measured using novel imaging methodology. An increase in vascular capacitance from splanchnic venodilation is expected to affect arterial pressure by decreasing stroke volume (SV) and cardiac output. However, both SV and CO were elevated from the start and throughout the duration of 5-HT infusion, indicating that changes in vascular capacitance were unlikely to contribute to chronic 5-HT-hypotension. Previous evidence suggested chronic (but not acute) 5-HT-induced hypotension was dependent on activation of nitric oxide synthase. However, the magnitude of the pressor response to a nitric oxide synthase inhibitor was not significantly different between the control or 5-HT infused groups, concluding 5-HT-induced nitric oxide synthase may not be contributing. Collectively, my work provides insight into the unique cardiovascular pharmacology of the 5-HT7 receptor, a member of the 5-HT receptor family whose chronic cardiovascular effects have been little studied up to now. Future work should include: characterizing the impact of 5-HT7 receptor activation by endogenous 5-HT on chronic cardiovascular diseases such as hypertension and heart failure; and evaluating whether it is possible to capitalize on the unique cardiovascular effects of 5-HT7 receptor stimulation for therapeutic purposes.
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