Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

Yanes, Licy L.; Romero, Damián G.; Iles, Joshua W.; Iliescu, Radu; Gómez-Sánchez, Celso E.; Reckelhoff, Jane F.

doi:10.1152/ajpregu.00510.2005

Cited by 62 publications

(57 citation statements)

References 22 publications

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“…In fact, reactive oxygen species can modulate calcium handling proteins [48], such as ryanodine receptors, SERCA2a and L-type calcium channels, thereby contributing to slowed calcium transients [49][50][51][52][53]. In the present study, we observed increased levels of oxidative stress and PLBThr" phosphorylation, as reported by others [30,42,46]. Oxidative stress may have contributed to the myocardial contractile dysfunction observed in OVX rats.…”

Section: Discussionsupporting

confidence: 86%

“…Angiotensin II most likely negatively affects excitation-contraction coupling in the myocardium by increasing Superoxide production in the heart [30]. Estrogen may play a more important role in mediating oxidative stress in males than in females [42]. Prolonged exposure to angiotensin II activates the Ca^V^almodulin-dependent protein kinase (CaMK) II by increasing reactive oxygen species [43] which in turn phosphorylates phospholamban at Thrl 7, increasing calcium reuptake by SERCA2a and leading to cell death [44].…”

Section: Discussionmentioning

confidence: 99%

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Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT₁Receptor Activation in Female Rats

Ribeiro

Pavan

Potratz

et al. 2012

Cell Physiol Biochem

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Background/aim:Estrogen deficiency induces myocardial contractile dysfunction and increases cardiovascular disease risk. However, the mechanism underlying this response is unclear. Our aim was to investigate whether AT₁receptor blockade would prevent ovariectomy-induced myocardial contractile dysfunction. Methods: Female rats (8 weeks old, 280 g) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with losartan (OVX + LOS, 15 mg/kg, s.c., in 0.9 % NaCl), placebo (OVX), estrogen replacement (OVX + E2, 1 mg/ kg, once a week, i.m.) and SHAM for 58 days. Results: Losartan and estrogen treatment 1) prevented ovariectomy-induced weight gain and slight hypertrophy, 2) restored the positive inotropic responses to Ca²⁺ and isoproterenol in the isolated papillary muscle in the OVX group, 3) prevented the reduction in SERCA2a levels and the increase in phospholamban (PLB) expression in the OVX group, 4) abolished the increase in superoxide anion that was increased in the OVX group, and 5) normalized the increase in p22^phox expression after ovariectomy. Estrogen treatment but not losartan restored the increase in serum angiotensin converting enzyme activity in the OVX group. Conclusion: This study demonstrated that myocardial contractile dysfunction induced by ovariectomy and expression of key Ca²⁺-handling proteins were prevented by losartan treatment and that AT₁receptor activation is involved in this response.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT₁Receptor Activation in Female Rats

Ribeiro

Pavan

Potratz

et al. 2012

Cell Physiol Biochem

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“…One of the suggested mechanisms underlying this sexual dimorphism is differences in the function of the renin-angiotensin system (RAS). [2][3][4] Angiotensin II (Ang II), the main effector peptide of the RAS, exerts its effects through 2 main receptor subtypes. Stimulation of the angiotensin type 1 receptor (AT 1 R) causes vasoconstriction, sodium reabsorption, and cell proliferation.…”

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confidence: 99%

Sex Differences in the Pressor and Tubuloglomerular Feedback Response to Angiotensin II

et al. 2012

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Abstract-Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT 2 R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT 2 R mechanism that, in part, offsets Ang II-induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT 2 R knockout (AT 2 R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28Ϯ6 mm Hg), male AT 2 R-KO (26Ϯ2 mm Hg), and female AT 2 R-KO (26Ϯ4 mm Hg) mice, however, the response was attenuated in female WT mice (12Ϯ4 mm Hg; P between sex and genotypeϭ0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT 2 R-KO, and female AT 2 R-KO but not in the female WT mice (P between sex and genotype Ͻ0.05; both). In conclusion, these data indicate that an enhanced AT 2 R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II-dependent resetting of TGF activity in females. Thus, the enhancement of the AT 2 R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease. Key Words: sex differences Ⅲ renin-angiotensin system Ⅲ Ang II Ⅲ mean arterial pressure Ⅲ hypertension Ⅲ renal hemodynamics Ⅲ tubuloglomerular feedback M en have a greater prevalence for hypertension and cardiovascular disease than premenopausal women of the same age. 1 The mechanisms underlying these differences in the pathophysiology of cardiovascular disease between men and women remain unclear. One of the suggested mechanisms underlying this sexual dimorphism is differences in the function of the renin-angiotensin system (RAS). [2][3][4] Angiotensin II (Ang II), the main effector peptide of the RAS, exerts its effects through 2 main receptor subtypes. Stimulation of the angiotensin type 1 receptor (AT 1 R) causes vasoconstriction, sodium reabsorption, and cell proliferation. The angiotensin type 2 receptor (AT 2 R) opposes the AT 1 R, causing vasodilation, sodium excretion, and apoptosis. 5,6 Earlier studies have shown that females have a greater AT 2 R:AT 1 R ratio. 7,8 We, and others, have demonstrated previously that the rise in arterial pressure in response to Ang II is blunted in females compared with males. 7,9 -11 Furthermore, we have provided evidence to suggest that arteria...

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“…We have shown previously in other models of hypertension (most are androgen sensitive in the males) that androgens stimulate increases in plasma renin activity and angiotensinogen synthesis. [3][4][5] Thus, one potential mechanism for our findings is activation of the reninangiotensin system in response to the testosterone supplementation in OZRs that mediated the hypertensive response. However, we did not see any increase in blood pressure in the lean Zuckers who also received testosterone supplements.…”

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confidence: 80%

Response to Testosterone and Blood Pressure: Is the Decreased Sodium Excretion the Missing Link?

Reckelhoff

2012

Hypertension

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1Thank you also for your suggestions and for sharing the information from your human studies showing the negative correlation between sodium excretion and total testosterone in your hypertensive cohort.2 Unfortunately, we did not measure sodium excretion in these studies.1 The rats were in sodium balance, so the sodium output would be equivalent to sodium intake. The diet is what determined sodium intake in our study, and because the obese Zucker rats (OZRs) with testosterone supplements were Ϸ250 g lighter in body weight, they ate less than untreated control OZRs, thus would have lower absolute sodium excretion. However, because the OZRs with testosterone supplements had higher blood pressure, we anticipate that they would have had a shift to higher pressures to excrete this amount of sodium (shift to the right in the pressure-natriuresis relationship) compared with untreated controls. We do not know whether testosterone treatment made the hypertension in the OZRs salt sensitive because we did not give them a salt load.We also did not evaluate any of the parameters of the reninangiotensin system because it was not a goal of the present study. We have shown previously in other models of hypertension (most are androgen sensitive in the males) that androgens stimulate increases in plasma renin activity and angiotensinogen synthesis.3-5 Thus, one potential mechanism for our findings is activation of the reninangiotensin system in response to the testosterone supplementation in OZRs that mediated the hypertensive response. However, we did not see any increase in blood pressure in the lean Zuckers who also received testosterone supplements. This would suggest differential effects on the renin-angiotensin system in response to testosterone in obese versus lean animals.

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Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

Cited by 62 publications

References 22 publications

Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT₁Receptor Activation in Female Rats

Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT₁Receptor Activation in Female Rats

Sex Differences in the Pressor and Tubuloglomerular Feedback Response to Angiotensin II

Response to Testosterone and Blood Pressure: Is the Decreased Sodium Excretion the Missing Link?

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Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

Cited by 62 publications

References 22 publications

Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT1Receptor Activation in Female Rats

Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT1Receptor Activation in Female Rats

Sex Differences in the Pressor and Tubuloglomerular Feedback Response to Angiotensin II

Response to Testosterone and Blood Pressure: Is the Decreased Sodium Excretion the Missing Link?

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Product

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Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT₁Receptor Activation in Female Rats

Myocardial Contractile Dysfunction Induced by Ovariectomy Requires AT₁Receptor Activation in Female Rats