RESUMO
BACKGROUND: Blood pressure-independent (BP) effects of angiotensin (Ang) II and endothelin (ET) on coronaries (remodeling) in high renin hypertension are incompletely understood. METHODS: We studied the effects of subdepressor doses of Ang II receptor (AT1) blockade with losartan (10 mg/kg/day gavage) and endothelin A receptor (ETA) blockade with LU135252 (30 mg/kg/day) on the coronaries of rats harboring human renin and angiotensinogen genes (dTGR). Nontransgenic Sprague-Dawley rats were controls. The rats were treated between the ages of 6 and 10 weeks. Coronary cross-sectional area [CSA; 0.79 x (external diameter2 - internal diameter2)], cell proliferation, and infiltration of monocytes/macrophages were determined. RESULTS: Monotherapy did not lower BP while combination treatment did (p < 0.05). All treatments reduced mortality (p < 0.01). CSA was decreased by all treatments compared to vehicle, independent of blood pressure (p < 0.05). Extensive proliferation by PCNA staining and infiltration of ED-1-positive cells was diminished by both treatment and the combination. CONCLUSIONS: The data show that Ang II promotes coronary inflammation and remodeling, in part independent of blood pressure but dependent upon ET signaling. Combination treatment directed at both pathways may improve outcome, independent of blood pressure reduction.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensinogênio/genética , Vasos Coronários/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A , Hipertensão/patologia , Renina/genética , Animais , Animais Geneticamente Modificados , Aorta/patologia , Pressão Sanguínea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Humanos , Hipertensão/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Autopsy specimens of human coronary arteries were collected from 65 men and women ranging in age from 40-76 years of age. We made 209 coronary artery sections, which were graded in terms of severity of atherosclerosis by means of the Stary classification. Sections were stained using an antibody directed against the angiotensin II type 1 (AT1) receptor. We found that in non-atherosclerotic sections, staining was confined to vascular smooth muscle cells in the media. However, with the advent of atherosclerosis, AT1 receptor expression was also present in atherosclerotic plaque and involved other cell types including inflammatory cells and myofibroblasts. We identified a remarkable correlation between AT1 receptor staining and the severity of coronary atherosclerosis as well as intima-media thickness. These human data correspond well to animal models of atherosclerosis indicating an upregulation of AT1 receptor expression in atherosclerotic tissue.
