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Published on: September 28, 2015
Angiotensin AT1 receptor antagonism and protection against cardiovascular end-organ damage
1Pharmaceutical Research Division, Takeda Chemical Industries Ltd, Osaka, Japan.
Insights
Angiotensin AT1 receptor antagonists, like candesartan cilexetil, protect organs from damage. These drugs reduce stroke and kidney injury, independent of blood pressure changes, by inhibiting tissue growth factors.
Area of Science:
- Cardiovascular Pharmacology
- Renal Physiology
- Hypertension Research
Background:
- Hypertension leads to end-organ damage, including stroke, cardiac hypertrophy, and renal dysfunction.
- Angiotensin II plays a key role in mediating these hypertensive effects through AT1 receptor stimulation.
- Existing treatments primarily focus on blood pressure reduction, but tissue-specific protective mechanisms require further investigation.
Purpose of the Study:
- To review the protective effects of angiotensin AT1 receptor antagonists against cardiovascular and renal end-organ damage.
- To investigate whether these protective effects are independent of blood pressure normalization.
- To explore the role of transforming growth factor-beta1 (TGF-beta1) and extracellular matrix (ECM) components in mediating AT1 antagonist tissue protection.
Main Methods:
- Review of studies using various rat models of hypertension (SHRSP, SHR, DOCA/salt, Dahl, 5/6 nephrectomized).
- Analysis of the effects of candesartan cilexetil and losartan on stroke incidence, cardiac hypertrophy, renal dysfunction, and vascular hypertrophy.
- Measurement of mRNA levels for TGF-beta1 and ECM components (fibronectin, collagen, laminin) in affected tissues.
- In vitro studies examining the direct effects of AT1 antagonists on cultured cardiac myocytes, fibroblasts, mesangial cells, and vascular smooth muscle cells stimulated by angiotensin II.
Main Results:
- Angiotensin AT1 receptor antagonists demonstrated significant protection against stroke, cardiac hypertrophy, renal dysfunction, and vascular hypertrophy in multiple hypertensive rat models.
- Candesartan cilexetil reduced stroke and renal injury in SHRSP and DOCA/salt rats, even at doses that did not lower blood pressure.
- Treatment with candesartan cilexetil inhibited the increased gene expression of TGF-beta1 and ECM components in the heart, kidney, and vascular tissues.
- In vitro studies confirmed that AT1 receptor antagonists directly inhibit angiotensin II-induced hypertrophy and proliferation of various cell types.
Conclusions:
- Angiotensin AT1 receptor antagonists offer significant protection against cardiovascular and renal end-organ damage in hypertensive models.
- Tissue-protective effects of AT1 antagonists are, at least partly, independent of their blood pressure-lowering effects.
- Inhibition of local tissue AT1 receptor stimulation, TGF-beta1, and ECM component gene expression contributes to the protective mechanisms of these drugs.
- Targeting local tissue AT1 receptor signaling represents a promising therapeutic strategy for preventing hypertensive end-organ damage.
Abstract:
This review describes how angiotensin AT1 receptor antagonists (eg, candesartan cilexetil, losartan) effectively protect against end-organ damage including stroke, cardiac hypertrophy, renal dysfunction, glomerulosclerosis, and/or vascular hypertrophy in the models of stroke-prone spontaneously hypertensive rats (SHRSP), SHR, DOCA/salt hypertensive rats, Dahl hypertensive rats and/or 5/6 nephrectomised rats. Particularly in SHRSP and DOCA/salt hypertensive rats, candesartan cilexetil markedly reduced the incidence of stroke and renal injury even at doses which had no effect on blood pressure (BP), suggesting that the tissue protective effects of angiotensin AT1 antagonists are not attributable simply to the normalisation of BP. In the heart, kidney and vascular tissues of SHRSP and the kidney of DOCA/salt hypertensive rats, the mRNA levels for transforming growth factor (TGF)-beta1 and extracellular matrix components (fibronectin, collagen type I, III and IV and laminin) were increased, and the increases of the gene expression were inhibited by treatment with candesartan cilexetil. In addition, there are some reports indicating that angiotensin AT1 receptor antagonists inhibit directly hypertrophy or proliferation of cultured cardiac myocytes and nonmyocytes (fibroblast), cultured mesangial cells and cultured vascular smooth muscle cells, which were stimulated by angiotensin II. These in vitro and in vivo findings suggest that local tissue AT1 receptor stimulation, being accompanied by the increased gene expression of TGF-beta1 and extracellular matrix components may partially contribute to the pathogenesis of cardiovascular end-organ damage.
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