Angiotensin AT1 receptor antagonism and protection against cardiovascular end-organ damage.
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.
Nishikawa
K
K
Pharmaceutical Research Division, Takeda Chemical Industries Ltd, Osaka, Japan.
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D002561:Cerebrovascular Disorders / Q000517:prevention & control; D004195:Disease Models, Animal; D006973:Hypertension / Q000517:prevention & control; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D009392:Nephrectomy; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D019808:Losartan; C077793:candesartan cilexetil