Differential regulation by AT(1) and AT(2) receptors of angiotensin II-stimulated cyclic GMP production in rat uterine artery and aorta.
1. In the present study we determined whether angiotensin II (Ang II) could increase cyclic GMP levels in two blood vessels that exhibit markedly different angiotensin II receptor subtype expression: rat uterine artery (UA; AT(2) receptor-predominant) and aorta (AT(1) receptor-predominant), and investigated the receptor subtype(s) and intracellular pathways involved. 2. UA and aorta were treated with Ang II in the absence and presence of losartan (AT(1) antagonist; 0.1 microm), PD 123319 (AT(2) antagonist; 1 microm), NOLA (NOS inhibitor; 30 microm), and HOE 140 (B(2) antagonist; 0.1 microm), or in combination. 3. Ang II (10 nm) induced a 60% increase in UA cyclic GMP content; an effect that was augmented with PD 123319 and HOE 140 pretreatment, and abolished by cotreatment with losartan, as well as by NOLA. 4. In aorta, Ang II produced concentration-dependent increases in cyclic GMP levels. Unlike effects in UA, these responses were abolished by PD 123319 and by NOLA, whereas losartan and HOE 140 caused partial inhibition. 5. Thus, in rat UA, Ang II stimulates cyclic GMP production through AT(1) and, to a less extent, AT(2) receptors. In rat aorta, the Ang II-mediated increase in cyclic GMP production is predominantly AT(2) receptor-mediated. In both preparations, NO plays a critical role in mediating the effect of Ang II, whereas bradykinin has differential roles in the two vessels. In UA, B(2) receptor blockade may result in a compensatory increase in cyclic GMP production, whilst in aorta, bradykinin accounts for approximately half of the cyclic GMP produced in response to Ang II.
Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
Ruth E
RE
Hannan
Tracey A
TA
Gaspari
Elizabeth A
EA
Davis
Robert E
RE
Widdop
D000804:Angiotensin II; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D066298:In Vitro Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D014599:Uterus / Q000098:blood supply*; D014662:Vasoconstrictor Agents
D057912:Angiotensin II Type 2 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D006152:Cyclic GMP