Tempol augments angiotensin II-induced AT2 receptor-mediated relaxation in diabetic rat thoracic aorta.
OBJECTIVE
To assess angiotensin II type 2 receptor-mediated responses in thoracic aorta of streptozotocin-induced diabetic rats.


METHODS
The concentration-dependent relaxation response (in the presence of an AT1 receptor blocker) to angiotensin II (Ang II) was studied in phenylephrine (PE) or potassium chloride (KCl) precontracted rat thoracic aortic rings isolated from male Sprague-Dawley rats pretreated with streptozotocin (65 mg/kg i.p.) or vehicle 8 weeks prior to the study.


RESULTS
Ang II-induced relaxation response (% relaxation), evident only in the presence of an AT1 receptor blocker, was significantly enhanced in aortic rings isolated from diabetic (55%) compared to control (25%) rats. Tempol (100 micromol/l) augmented the relaxation response in aortic rings isolated from diabetic (80%) but not control (28%) rats. N-nitro-l-arginine methyl ester (L-NAME) (100-300 micromol/l) [a nitric oxide (NO) synthase inhibitor] partially inhibited the relaxation response in diabetic (25%) and control (15%) rats. However, l-NAME (100 micromol/l) and glipizide or butanedione monoxime (1 micromol/l) (ATP-sensitive K channel blockers) together completely blocked the relaxation response. [H]Ang II saturation binding at the AT2 receptor was enhanced in aortic membranes from diabetic [maximum binding capacity, (Bmax)=1.14 +/- 0.06 fmol/mg protein] compared to control rats (Bmax=0.75 +/- 0.03 fmol/mg protein), with no change in the dissociation equilibrium constant (Kd) value (2.55 +/- 0.12 versus 2.22 +/- 0.15 nmol/l).


CONCLUSIONS
The results suggest enhanced AT2-receptor density and function [mediated by a nitric oxide and ATP-sensitive K channel-dependent relaxation response (in presence of an AT1 receptor blocker)] in thoracic aorta isolated from diabetic rats. This could be a compensatory mechanism, which may be therapeutically exploited.
Cardiovascular and Receptorology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Phase-X, Sector 67, S.A.S.Nagar (Mohali)--160 062, Punjab, India.
K H S
KH
Arun
Chamanlal L
CL
Kaul
Ramarao
R
Poduri
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006943:Hyperglycemia / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D014316:Tritium; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000975:Antioxidants; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D044139:Receptor, Angiotensin, Type 2; D013113:Spin Labels; D014662:Vasoconstrictor Agents; D014316:Tritium; D000804:Angiotensin II; D013482:Superoxide Dismutase; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester