Mechanisms of augmented vasoconstriction induced by 5-hydroxytryptamine in aortic rings from spontaneously hypertensive rats.
OBJECTIVE
To test whether development of enhanced vasoconstriction to 5-hydroxytryptamine (5-HT; serotonin) in SHR was temporally related to hypertension, elevated vascular superoxide (O(2)(-)) levels, decreased NO bioavailability, or increased contractile effects of cyclooxygenase or rho-kinase and/or PKC.


METHODS
We examined systolic blood pressure (SBP), vascular O(2)(-), and 5-HT-induced contractile responses of aortic segments from 4- and 8-week-old WKY and SHR.


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 O(2)(-) 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
Development of augmented vascular contractile responses to 5-HT in SHR is preceded by hypertension. It is associated with increased vascular O(2)(-) levels and reduced modulatory effects of NO, and is unlikely to be due to enhanced activity of rho-kinase, PKC or cyclooxygenase.
Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
K
K
Budzyn
R M
RM
Ravi
A A
AA
Miller
C G
CG
Sobey
D000818:Animals; D001158:Arteries; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012701:Serotonin / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D012701:Serotonin; D011451:Prostaglandin-Endoperoxide Synthases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D010100:Oxygen