Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide.
The aim of the present study was to explore the mechanisms underlying angiotensin II AT2 receptor modulation of AT1 receptor-mediated vasoconstriction in the rat isolated uterine artery, since previous studies have suggested that AT2 receptors may oppose AT1 receptor-mediated effects. Segments of uterine artery were obtained from Sprague-Dawley rats and mounted in small vessel myographs. Concentration-response (CR) curves to angiotensin II (0.1 nm-0.1 microM) were constructed in the absence and presence of PD 123319 (AT2 antagonist; 1 microM), HOE 140 (bradykinin B2 antagonist; 0.1 microM), Nomega-nitro-l-arginine (NOLA) (NOS inhibitor; 30 microM), as well as combinations of these inhibitors. Contractile responses to angiotensin II were expressed as a percent of the response to a K+ depolarizing solution. PD 123319 (1 microM) potentiated angiotensin II-induced contractions; reflected by a significant four-fold leftward shift of the angiotensin II CR curve. HOE 140 (0.1 microM) significantly increased the pEC50 of the angiotensin II CR curve. The combination of HOE 140 plus PD 123319 did not produce additive potentiation. NOLA (30 microM) significantly enhanced sensitivity to angiotensin II, seen as a five-fold leftward shift of the curve, and an augmented maximum contractile response. Combinations of PD 123319 (1 microM) plus NOLA, and of HOE 140 (0.1 microM) plus NOLA, both induced a similar magnitude of potentiation. Cyclic GMP measurements confirmed angiotensin II-induced activation of the nitric oxide (NO) pathway. In conclusion, AT2 receptor-mediated inhibition of angiotensin II-induced contraction of the rat uterine artery involves NO production; a component of which occurs through a bradykinin B2 receptor pathway.
Hannan
Ruth E
RE
Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
Davis
Elizabeth A
EA
Widdop
Robert E
RE
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000502:physiology*; D014599:Uterus / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D009569:Nitric Oxide; D001920:Bradykinin