Spontaneous tone in deoxycorticosterone acetate-salt hypertensive rats
Date
2003-11
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Doctoral
Abstract
This body of work tests the hypothesis that reactive oxygen species (ROS) contribute to the modulation of spontaneous tone observed in aortic rings from deoxycorticosterone acetate (DOCA) salt hypertensive rats. In isolated organ baths, tension developed in rings from hypertensive but not SHAM-normotensive rats in response to increases in preload. Endothelial-denudation and nitric oxide (NO) synthase inhibition with NG-nitro-L arginine methyl ester (L-NAME) increased spontaneous tone. These results indicate that spontaneous tone is related to the preload and that NO plays a protective role opposing tone. Basal superoxide anion (02.-) production was increased in aortic rings from DOCA-salt hypertensive rats. Stretch increased 02.- production even further. Tempol, an 02.- scavenger, or apocynin, an inhibitor of NADPH-oxidase, attenuated hypertension. Spontaneous tone was abolished by superoxide dismutase (SOD), tempol, or apocynin in endothelium-intact rings but not in endothelium-denuded rings nor in L-NAME treated rings. Catalase, the enzyme that breaks down hydrogen peroxide (H202), increased spontaneous tone. Taken together, these findings suggest that O2.- derived from NAD(P)H-oxidase modulates spontaneous tone primarily by scavenging NO, while H202 serves as a protective mechanism.
The cyclooxygenase (COX) inhibitor, valeroyl salicylate, and the thromboxane-prostaglandin (TP) receptor antagonist, SQ 29548, inhibited spontaneous tone. 20-hydroxyeicosatetraenoic acid (20-HETE) production was increased in rings from DOCA-salt hypertensive rats. Inhibition of the CYP4A isozyme with aminobenzotriazole decreased spontaneous tone. Exogenous 20-HETE increased spontaneous tone in an endothelium-dependent manner. These effects were blocked by the COX inhibitor or the TP-receptor antagonist. Thus 20 HETE increases tone, an effect likely mediated by its COX metabolites.
Cromakalim, a KATP channel opener, abolished spontaneous tone in a glibenclamide-sensitive fashion. In aortic cells from DOCA-salt hypertensive rats, ATP-dependent K+(KATP) channel currents were either absent or weak in response to challenges by elevated extracellular K+ and by cromokalim. These findings suggest that the function of KATP channels is impaired in smooth muscle cells from aorta of DOCA-salt hypertensive rats. The data support the hypothesis that a complex array of ROS and metabolites of arachidonic acid (20-HETE and its metabolites) interact in concert with depressed KATP channel activity to modulate spontaneous tone in the DOCA-salt model.
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Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacology
Program
Pharmacology