title: Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats.
abstract: The renin-angiotensin system is a far more complex enzymatic cascade than realized previously. Mounting evidence suggests sex-specific differences in the regulation of the renin-angiotensin system and arterial pressure. We examined the hemodynamic responses, angiotensin II receptor subtypes, and angiotensin-converting enzyme 2 gene expression levels after graded doses of angiotensin II in males and females. Mean arterial pressure was measured via telemetry in male and female rats in response to a 2-week infusion of vehicle, low-dose (50 ng/kg per minute SC) or high-dose (400 ng/kg per minute SC) angiotensin II. The effect of concurrent infusion of the angiotensin II type 2 receptor (AT(2)R) blocker (PD123319) was also examined. The arterial pressure response to high-dose angiotensin II was attenuated in females compared with males (24+/-8 mm Hg versus 42+/-5 mm Hg; P for the interaction between sex and treatment <0.002). Remarkably, low-dose angiotensin II decreased arterial pressure (11+/-4 mm Hg; P for the interaction between sex and treatment <0.02) at a dose that did not have an effect in males. This decrease in arterial pressure in females was abolished by AT(2)R blockade. Renal AT(2)R, angiotensin-converting enzyme 2, and left ventricular AT(2)R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT(2)R ratio of approximately 1 in females. Angiotensin II infusion did not affect renal AT(2)R mRNA expression but resulted in significantly less left ventricular mRNA expression. Renal angiotensin-converting enzyme 2 mRNA expression levels were greater in females than in males treated with high-dose angiotensin II (approximately 2.5 fold; P for the interaction between sex and treatment <0.05). In females, enhancement of the vasodilatory arm of the renin-angiotensin system, in particular, AT(2)R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation.
authors: Department of Physiology, Monash University, Clayton, Victoria, Australia.
authors: Amanda K
authors: AK
authors: Sampson
authors: Karen M
authors: KM
authors: Moritz
authors: Emma S
authors: ES
authors: Jones
authors: Rebecca L
authors: RL
authors: Flower
authors: Robert E
authors: RE
authors: Widdop
authors: Kate M
authors: KM
authors: Denton
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000235:genetics*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II