title: Female spontaneously hypertensive rats are more dependent on ANG (1-7) to mediate effects of low-dose AT1 receptor blockade than males.
abstract: ANG (1-7) contributes to the blood pressure (BP)-lowering effect of angiotensin receptor blockers (ARBs) in male experimental animals. Females have greater ANG (1-7) concentrations than males; however, the contribution of ANG (1-7) to ARB-mediated decreases in BP in females is unknown. The current study tested the hypothesis that female spontaneously hypertensive rats (SHR) have a larger ANG (1-7) contribution to the BP-lowering effects of the ARB candesartan than male SHR. Twelve-week-old male and female SHR were randomized to receive candesartan (0.5 mg·kg(-1)·day(-1); 7 days), candesartan plus ANG II (200 ng·kg(-1)·min(-1); 7 days), the ANG (1-7) antagonist A-779 (48 μg·kg(-1)·h(-1)) plus candesartan and ANG II. Candesartan decreased basal BP in males and females (baseline vs. candesartan: 142 ± 2 vs. 122 ± 3 and 129 ± 1 vs. 115 ± 1 mmHg, respectively; P < 0.05); however, the decrease was greater in males. ANG II increased BP in males in the presence of candesartan (149 ± 2 mmHg; P < 0.05); candesartan blocked ANG II-induced increases in BP in females (116 ± 1 mmHg). Pretreatment with A-779 abolished candesartan-mediated decreases in BP in females, but not males. A-779 also exacerbated ANG II-induced proteinuria (26 ± 6 vs. 77 ± 11 μg·kg(-1)·day(-1), respectively; P < 0.05) and nephrinuria (20 ± 5 vs. 202 ± 58 μg·kg(-1)·day(-1), respectively; P < 0.05) in candesartan-treated female SHR, with no effect in males. In conclusion, females are more sensitive to the BP-lowering effect of ARBs during ANG II infusion, whereas males are more sensitive under basal conditions. In addition, ANG (1-7) has a greater contribution to ARB-mediated decreases in BP, protein, and nephrin excretion in females relative to males.
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia;
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Zimmerman
authors.affiliation: Georgia Prevention Center, Georgia Regents University, Augusta, Georgia; and Sport and Exercise Science Research Institute, University of Ulster, Northern Ireland, United Kingdom.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia; jensullivan@gru.edu.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Sullivan
mesh_terms: D000803:Angiotensin I / Q000502:physiology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000502:physiology; D012737:Sex Factors; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000803:Angiotensin I; D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C092006:7-Ala-angiotensin (1-7); C110936:Havcr1 protein, rat; C113267:nephrin; C118790:angiotensin I (1-7); C081643:candesartan
keywords: ANG (1-7); SHR; blood pressure; gender; renin-angiotensin system