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(Hypertension. 2008;52:666.)
© 2008 American Heart Association, Inc.

Original Articles

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

Amanda K. Sampson; Karen M. Moritz; Emma S. Jones; Rebecca L. Flower; Robert E. Widdop; Kate M. Denton

From the Departments of Physiology (A.K.S., R.L.F., K.M.D.) and Pharmacology (E.S.J., R.E.W.), Monash University, Clayton, Victoria; and the School of Biomedical Sciences (K.M.M.), University of Queensland, Queensland, Australia.

Correspondence to Kate M. Denton, Department of Physiology, Building 13F, Monash University, Victoria, Australia 3800. E-mail kate.denton{at}med.monash.edu.au

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 (AT₂R) 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 AT₂R blockade. Renal AT₂R, angiotensin-converting enzyme 2, and left ventricular AT₂R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT₂R ratio of 1 in females. Angiotensin II infusion did not affect renal AT₂R 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 (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, AT₂R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation.

Key Words: basic science • gender differences • gene expression/regulation • hypertension • angiotensin receptors

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This article has been cited by other articles:

				D. J. Campbell Can the Study of Female Rats Help Our Understanding of Women? Hypertension, December 1, 2008; 52(6): e142 - e142. [Full Text] [PDF]

				A. K. Sampson, K. M. Moritz, E. S. Jones, R. E. Widdop, and K. M. Denton Response to Can the Study of Female Rats Help Our Understanding of Women? Hypertension, December 1, 2008; 52(6): e143 - e143. [Full Text] [PDF]

				K. Sandberg Response to Can the Study of Female Rats Help Our Understanding of Women? Hypertension, December 1, 2008; 52(6): e144 - e144. [Full Text] [PDF]

				K. Sandberg and H. Ji Why Can't a Woman Be More Like a Man?: Is the Angiotensin Type 2 Receptor to Blame or to Thank? Hypertension, October 1, 2008; 52(4): 615 - 617. [Full Text] [PDF]