Mechanisms of augmented vasoconstriction induced by 5-hydroxytryptamine in aortic rings from spontaneously hypertensive rats

Background and purpose: To test whether development of enhanced vasoconstriction to 5-hydroxytryptamine (5-HT; serotonin) in SHR was temporally related to hypertension, elevated vascular superoxide (O2−) levels, decreased NO bioavailability, or increased contractile effects of cyclooxygenase or rho-kinase and/or PKC. Experimental approach: We examined systolic blood pressure (SBP), vascular O2−, and 5-HT-induced contractile responses of aortic segments from 4- and 8-week-old WKY and SHR. Key results: SBP was 35% higher in SHR than WKY at 4 weeks and 60% higher at 8 weeks. Contractile responses to 5-HT were similar in WKY and SHR at 4 weeks, but were markedly augmented in SHR at 8 weeks. The NO synthase inhibitor, l-NAME, enhanced contractile responses to 5-HT markedly in both strains at 4 weeks and in WKY at 8 weeks, but only very modestly in SHR at 8 weeks. These functional differences were associated with higher O2− levels in SHR versus WKY at 8 weeks, but not at 4 weeks. The rho-kinase inhibitor, Y-27632, and the PKC inhibitor, Ro 31-8220, each only modestly attenuated contractions in WKY and SHR in each age group, and their effects in each strain were more pronounced at 8 weeks. The cyclooxygenase inhibitor, indomethacin, had no effect on contractile responses. Conclusions and implications: Development of augmented vascular contractile responses to 5-HT in SHR is preceded by hypertension. It is associated with increased vascular O2− levels and reduced modulatory effects of NO, and is unlikely to be due to enhanced activity of rho-kinase, PKC or cyclooxygenase