benzofurans and Hypertension--Renovascular

Basilar vascular smooth muscle cells (BASMCs) hyperplasia is a prominent feature of cerebrovascular remodeling and stroke during the development of hypertension. Tanshinone IIA (Tan) has been reported to exhibit a protective effect against the pathological features of hypertension. Previous studies have shown that phosphoinostitide-3 kinase (PI3K)/3'-phosphoinostitide dependent kinase (PDK1)/AKT pathway is involved in the regulation of proliferation of various cell types. Therefore, there may be a crosstalk between Tan antihypertension processes and PI3K/PDK1/AKT proliferative effect in BASMCs. To test this hypothesis, we used a 2-kidney, 2-clip hypertension model to examine the effect of Tan on PI3K/PDK1/AKT pathway by cellular, molecular, and biochemical approaches. Our results revealed that the abundance of PDK1 in plasma was paralleled with an increase in blood pressure and the cross-sectional area of basilar artery in hypertensive rats. Tan decreased blood pressure and hypertension-induced PDK1 phosphorylation but produced no effect on the phosphorylation of PI3K. Moreover, Tan attenuated endothelin 1 induced the activation of PDK1/AKT pathway in rat BASMCs. Tan could inhibit cell cycle transition by regulating the expression of cyclin D1 and p27, in turn, prevent proliferation of BASMCs. Our study provides a novel mechanism by which Tan prevents cerebrovascular cell proliferation during hypertension, and thus Tan may be a potential therapeutic agent for cerebrovascular remodeling and stroke.

Topics: Animals; Basilar Artery; Benzofurans; Blood Pressure; Cell Cycle; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Endothelin-1; Hypertension; Hypertension, Renovascular; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Rats; Rats, Sprague-Dawley

The effect of blockade of the renin-angiotensin system on kidney function using non-peptide angiotensin AT1 receptor antagonists was investigated in renovascular hypertensive rats. An angiotensin converting enzyme inhibitor, captopril and two angiotensin AT1 receptor antagonists, losartan and GR138950 (1-([3-bromo-2[2-[[(trifluoro-methyl)sulphonyl]amino]phenyl]-5 benzofuranyl]methyl)-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxamide) were administered in Na+-deplete two-kidney, two-clip Goldblatt hypertensive rats over a 3-day period. Captopril, losartan (30 mg/kg body weight) and GR138950 (5 mg/kg body weight) significantly (P < 0.001) lowered the systolic blood pressure in the hypertensive rats from 290 +/- 5, 252 +/- 9 and 238 +/- 13 mmHg to 152 +/- 17, 148 +/- 9 and 123 +/- 6 mmHg, respectively. The magnitude of reduction in blood pressure in these three groups of rats was similar and occurred with comparable marked increases in plasma levels of urea and creatinine indicative of acute renal failure. These findings demonstrate an important role for angiotensin II in the maintenance of renal function during blood pressure reduction in renovascular hypertensive states during restriction of dietary Na+ intake.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Captopril; Hypertension, Renovascular; Kidney; Kidney Function Tests; Losartan; Male; Rats; Rats, Wistar