Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy.

Suzuki, Jun–ichi; Matsubara, Hiroaki; Urakami, Masaya; Inada, Mitsuo

doi:10.1161/01.res.73.3.439

Cited by 234 publications

(164 citation statements)

References 34 publications

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“…This finding is supported by other in vivo studies. In a previous work on spontaneously hypertensive rats, Suzuki and co-workers [38] found increased levels of AT1 receptors in this model of cardiac hypertrophy. Normalisation of blood pressure with AT1 receptor blockers regressed cardiac hypertrophy and completely reversed the increase in receptor message and density.…”

Section: Discussionsupporting

confidence: 49%

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

et al. 2006

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Aims/hypothesis The angiotensin II (type 1) (AT1) receptor mediates many biological effects of the renin-angiotensin system (RAS), leading to remodelling of cardiac tissue. The present study was designed to analyse changes in the function and expression of the AT1 receptor as principal effector of the RAS in myocardium from type 2 diabetic patients compared with non-diabetic myocardium as control. In addition, we determined the effect of treatment with ACE inhibitors or AT1 receptor blockers on expression levels of the receptor in diabetic patients. Methods Gene expression of the AT1 receptor was analysed by quantitative RT-PCR and protein expression was determined by immunoblot analysis in human right atrial myocardium. We investigated functional coupling of the receptors by measuring contractility in isolated trabeculae stimulated with increasing concentrations of angiotensin II. Results Diabetic myocardium showed a significant increase in protein expression (170±16% of control) and median mRNA expression (186% of control) of the AT1 receptor.The additional receptors were functionally coupled, resulting in a stronger inotropic response upon stimulation with angiotensin II (89±5.5% vs 29±1.6% in controls), whereas receptor affinity was similar in both groups. However, myocardium from diabetic patients treated with ACE inhibitors or AT1 receptor blockers showed no increase in AT1 receptor expression. Conclusions/interpretation AT1 receptor expression in myocardium of type 2 diabetic patients is dynamic, depending on the level of glycaemic control and the activity of the RAS. These findings could at least in part explain the strong therapeutic benefit of RAS inhibition in diabetic patients.

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Section: Discussionsupporting

confidence: 49%

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

et al. 2006

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“…22 This increase in cardiac ACE gene expression may have contributed to an increase in angiotensin II-mediated signaling in the heart. Expression of the AT 1 receptor has been shown to be upregulated in several models of cardiac hypertrophy, 39 although the functional relevance of this change was not clear. However, myocardial expression of the AT 1A receptor gene was not altered in LVH rats, consistent with our previous results.…”

Section: Discussionmentioning

confidence: 99%

Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension

et al. 2011

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Although thiazide diuretics are commonly used to supplement angiotensin receptor blockers for treatment of hypertension, the mechanism underlying the therapeutic effects of this drug combination remains unclear. We investigated the antihypertensive and cardioprotective effects of combination therapy with losartan (LOS) and hydrochlorothiazide (HCTZ), in comparison with those of either drug alone, in Dahl salt-sensitive hypertensive rats. Rats fed a high-salt diet from 6 weeks of age were treated with LOS, HCTZ, both drugs (COMB) and vehicle from 6 to 11 weeks. The salt-induced increase in systolic blood pressure was attenuated moderately by LOS and to a greater extent by HCTZ and COMB. Left ventricular (LV) hypertrophy and fibrosis, diastolic dysfunction, as well as angiotensin-converting enzyme and angiotensin II type 1A (AT 1A ) receptor gene expression were attenuated similarly by LOS and HCTZ and more so by COMB. LOS downregulated expression of the AT 1A receptor gene, without affecting that of the AT 2 receptor gene, in the aorta. In contrast, neither HCTZ nor COMB affected aortic expression of the AT 1A receptor gene, but both markedly upregulated that of the AT 2 receptor gene. The salt-induced decrease in the plasma concentration of nitric oxide metabolites was attenuated substantially by LOS and abolished by both HCTZ and COMB. In conclusion, the combination of LOS and HCTZ attenuated hypertension, as well as LV remodeling and diastolic dysfunction, more effectively than did LOS or HCTZ alone in rats with salt-sensitive hypertension. Modulation of the cardiac and vascular renin-angiotensin system may have contributed to these beneficial effects of the drug combination.

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“…Increased expression of renin, angiotensinogen, ACE, and AT 1 mRNA in the hearts of SHRSP has been reported. 29 The amount of aldosterone produced by the heart is very small compared with the amount of plasma or adrenal aldosterone with CYP11B2 mRNA levels in the heart 100-fold lower than in adrenal gland. Such a ratio is comparable to that of ACE mRNA, of which the total quantity is Ϸ150-fold lower in the heart than in the lung, one of the main sources of this enzyme.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Aldosterone Production in Genetically Hypertensive Rats

et al. 2000

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Abstract-Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [ 14 C]deoxycorticosterone to [ 14 C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2-and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats. (Hypertension. 2000;36:495-500.)Key Words: heart Ⅲ rats, inbred strains Ⅲ aldosterone Ⅲ hypertrophy Ⅲ cytochrome p450 Ⅲ mRNA A ldosterone receptors are present in cardiac myocytes, endocardial endothelial cells, and cardiac fibroblasts. 1 The peripheral infusion of aldosterone in rats causes cardiac hypertrophy and cardiac fibrosis without increasing the blood pressure. 2 In cultured neonatal rat fibroblasts or cardiomyocytes, aldosterone increases collagen synthesis and protein synthesis. 3,4 Physiologically significant amounts of mineralocorticoids are believed to be synthesized only in the adrenal cortex. However, extra-adrenal steroid 21-hydroxylation and 11␤-hydroxylation occur in a variety of human tissues. Circulating progesterone is converted to deoxycorticosterone (DOC) and DOC sulfate in adult and fetal human extra-adrenal tissues. 5 The extra-adrenal expression of steroid 21-hydroxylase and 11␤-hydroxylase by a benign testicular Leydig cell tumor has also been reported. 6 We reported that aldosterone, synthesized in the vasculature, is in part controlled by angiotensin (Ang) II and participates in the development of vascular hypertrophy that correlates with Ang II concentration. 7,8 We performed the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibitor, and Ang ...

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Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy.

Cited by 234 publications

References 34 publications

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension

Cardiac Aldosterone Production in Genetically Hypertensive Rats

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