Tempol selectively attenuates angiotensin II evoked vasoconstrictor responses in spontaneously hypertensive rats.
OBJECTIVE
To assess whether superoxide anions mediate vasoconstrictor responses to agonists in blood vessels of spontaneously hypertensive rats (SHRs).


METHODS
The effect of the superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol), on responses to angiotensin II (Ang II), endothelin-1, phenylephrine and potassium chloride was determined in aortic rings and perfused mesenteric vascular beds (MVB) of adult male rats of the Sprague-Dawley, Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) strains. The effect of tempol on Ang II-evoked superoxide production was assessed in aortic rings.


RESULTS
There were no differences in the maximum tension (Emax) attained in response to agonists, but the negative logarithm of the concentration required to produce 50% of the maximal response (EC50) for Ang II was lower (P < 0.05) in aortic rings of SHRs. In the MVBs of SHRs, the Emax but not the EC50 values attained in response to Ang II, endothelin-1 and phenylephrine were greater. Tempol significantly and selectively reduced the Emax of Ang II in both aorta and MVB preparations with intact endothelium. The reduction in Emax attained in response to Ang II was more pronounced in SHRs (P < 0.01) than in WKY rats (P < 0.05) or Sprague-Dawley rats (P < 0.05). The inhibitory effect of tempol was absent when a nitric oxide synthase inhibitor was included or endothelium was denuded. A significant increase in lucigenin chemiluminescence evoked by Ang II in both intact and endothelium-denuded aortic rings of SHRs was abolished when tempol was included in the buffer.


CONCLUSIONS
These data suggest that increased superoxide anions mediate vasoconstrictor responses to Ang II, but not to other agonists, in an endothelium-dependent manner, by quenching vasodilatory mediator, nitric oxide. This may account for the exaggerated vasoconstrictor responses to Ang II in SHRs.
Department of Pharmacology and the Cardiovascular Risk Factor Reduction Unit (CRFRU), College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
Shailesh
S
Shastri
Venkat
V
Gopalakrishnan
Ramarao
R
Poduri
Hui
H
Di Wang
D000804:Angiotensin II / Q000187:drug effects* / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008163:Luminescent Measurements; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008955:Models, Cardiovascular; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D003497:Cyclic N-Oxides; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013113:Spin Labels; D013481:Superoxides; D000804:Angiotensin II; D010656:Phenylephrine; D011189:Potassium Chloride; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester