Spontaneous Tone in Deoxycorticosterone Acetate-Salt Hypertensive Rats
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.
Advisor:Hiebert, Linda M.; Desai, Kaushik; Gopalakrishnan, Venkat; Hickie, Robert A.; Wilson, Thomas W.; McNeill, James Robert
School:University of Saskatchewan
School Location:Canada - Saskatchewan
Source Type:Master's Thesis
Date of Publication:10/23/2008