Role of PKC in autocrine regulation of rat ventricular K+ currents by angiotensin and endothelin.
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Transient and sustained K(+) currents were measured in isolated rat ventricular myocytes obtained from control, steptozotocin-induced (Type 1) diabetic, and hypothyroid rats. Both currents, attenuated by the endocrine abnormalities, were significantly augmented by in vitro incubation (>6 h) with the angiotensin-converting enzyme inhibitor quinapril or the angiotensin II (ANG II) receptor blocker saralasin. Western blots indicated a parallel increase in Kv4.2 and Kv1.2, channel proteins that underlie the transient and (part of the) sustained currents. Under diabetic and hypothyroid conditions, both currents were also augmented by an endothelin receptor blocker (PD142893) or by an endothelin-converting enzyme inhibitor. Kv4.2 density was also enhanced by PD142893. Incubation (>5 h) with the PKC inhibitor bis-indolylmaleimide augmented both currents, whereas the PKC activator dioctanoyl-rac-glycerol (DiC8) prevented the augmentation of currents by quinapril. DiC8 also prevented the augmentation of Kv4.2 density by quinapril. Specific peptides that activate PKC translocation indicated that PKC-epsilon and not PKC-delta is involved in ANG II action on these currents. In control myocytes, quinapril and PD142893 augmented the sustained late current but had no effect on peak current. It is concluded that an autocrine release of angiotensin and endothelin in diabetic and hypothyroid conditions attenuates K(+) currents by suppressing the synthesis of some K(+) channel proteins, with the effects mediated at least partially by PKC-epsilon. (+info)
Differential expression of AT1 receptors in the pituitary and adrenal gland of SHR and WKY.
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The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT1A, AT1B, and AT2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT1B receptor mRNA was detected in the pituitary and adrenal gland. AT2 receptor mRNA was prominent only in the adrenal gland. When compared with WKY, SHR showed increased AT1A receptor mRNA levels in the pituitary gland at all ages in contrast to reduced pituitary AT1B receptor mRNA levels. In the adrenal gland of SHR, AT1B receptor mRNA levels were decreased at the hypertensive stages when compared with WKY. The reduced expression of adrenal AT1B receptor mRNA was localized selectively in the zona glomerulosa by in situ hybridization. No differences were observed between WKY and SHR in the expression of hypothalamic ANG receptors. ANG significantly increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in dexamethasone-treated SHR but not in WKY. The aldosterone response to ANG was similar in SHR and WKY. Our results suggest a differential gene expression of AT1A and AT1B receptors in the hypothalamo-pituitary-adrenal axis of SHR and normotensive WKY and imply the participation of AT1 receptors in an exaggerated endocrine stress response of SHR to ANG. (+info)
Mechanism of increased angiotensin II levels in glomerular mesangial cells cultured in high glucose.
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Previous studies have shown that glucose increases angiotensin II (AngII) levels in rat glomerular mesangial cells and that AngII mediates the inhibitory effects of high glucose on matrix degradation in these cells. The present study addresses the following questions: (1) What are the mechanisms for the generation of AngII in mesangial cells? (2) What are the effects of glucose on AngII generation by these mechanisms? Experiments employed primary mesangial cells from normal Sprague-Dawley rats. The levels of immunoreactive angiotensinogen (AGT), angiotensin I (AngI), and angiotensin II (AngII) were measured by ELISA. AGT mRNA expression was determined by Northern blot analysis. Incubation of cells for 24 h in high glucose (30 mM) increased AGT levels by 1.5-fold and increased AGT mRNA expression; this was accompanied by a 1.5-fold increment in AngI and 1.7-fold increment in AngII levels. Renin activity (measured as AngI generation in the presence of excess AGT) and ACE levels and activity were not altered by high glucose. In further experiments, the effect of high glucose on formation of Ang peptides from exogenous AngI in mesangial cell extracts was examined using HPLC. Exogenous AngI was converted into various Ang peptides, including AngII, Ang(1-9), Ang(1-7), and Ang(3-8). A significant increase in formation of AngII from AngI was observed in cells incubated in high glucose. In addition, AngII production from exogenous Ang(1-9) in cell extracts was also stimulated by high glucose. These findings demonstrate that glucose increases mesangial AngII levels via an increase in AGT and AngI. In addition, this study provides new information that Ang(1-9) is produced by mesangial cells, can be converted to AngII, and that this conversion is also stimulated under high-glucose conditions. (+info)
Disparate roles of AT2 receptors in the renal cortical and medullary circulations of anesthetized rabbits.
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The contributions of angiotensin II type 1 (AT1) and type 2 (AT2) receptors to the control of regional kidney blood flow were determined in pentobarbital-anesthetized rabbits. Intravenous candesartan (AT1 antagonist; 10 microg/kg plus 10 microg x kg(-1) x h(-1)) reduced mean arterial pressure (12%) and increased total renal blood flow (29%) and cortical laser-Doppler flux (18%) but not medullary laser-Doppler flux. Neither intravenous PD123319 (AT2 antagonist; 1 mg/kg plus 1 mg x kg(-1) x h(-1)) nor saline vehicle significantly affected these variables, and the responses to candesartan plus PD123319 were indistinguishable from those of candesartan alone. In vehicle-treated rabbits, renal-arterial infusions of angiotensin II (1 to 25 ng x kg(-1) x min(-1)) and angiotensin III (5 to 125 ng x kg(-1) x min(-1)) dose-dependently reduced renal blood flow (up to 51%) and cortical laser-Doppler flux (up to 50%) but did not significantly affect medullary laser-Doppler flux or arterial pressure. Angiotensin(1-7) (20 to 500 ng x kg(-1) x min(-1)) had similar effects but of lesser magnitude. CGP42112A (20 to 500 ng x kg(-1) x min(-1)) did not significantly affect these variables. After PD123319 administration, angiotensin II and angiotensin III dose-dependently increased medullary laser-Doppler flux (up to 84%), and reductions in renal blood flow in response to angiotensin II were enhanced. Candesartan abolished renal hemodynamic responses to the angiotensin peptides, even when given in combination with PD123319. We conclude that AT2 receptor activation counteracts AT1-mediated vasoconstriction in the renal cortex but also counteracts AT1-mediated vasodilatation in vascular elements controlling medullary perfusion. These mechanisms might have an important effect on the control of medullary perfusion under conditions of activation of the renin-angiotensin system. (+info)
Renin, angiotensin, sodium and organ damage.
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Angiotensin II and sodium balance affect the status of each other and both--either separately or together--can lead to an increase in blood pressure. They also can cause vascular and cardiac damage due to direct effects and effects mediated by the blood pressure increase. This paper reviews the important interactions among these three variables. Acute blood pressure elevation during sleeping but not during waking hours causes cardiac hypertrophy in rats. Similarly, lowering of blood pressure with an angiotension converting enzyme (ACE) inhibitor during sleep but not when awake causes regression of cardiac hypertrophy in rats with 2kidney (K)-1clip (C) Goldblatt hypertension. If angiotensin is given to rats on a low (0.4%) NaCl diet, blood pressure rises but there is less cardiac hypertrophy. Cardiac hypertrophy is greatest after angiotensin administration in rats on a high (4%) NaCl diet. In both the 2K-1C and 1K-1C Goldblatt models, a high salt intake reduces the blood pressure lowering effect of captopril and losartan and prevents regression of cardiac hypertrophy. Combined administration of an ACE inhibitor and an angiotensin type 1 (AT1) receptor blocker to rats on a low (0.2%) NaCl diet produces a syndrome that leads to death with cardiac involution. All features of the syndrome are reversed or prevented by 4% NaCl intake. It is hypothesised that the interaction between angiotensin II and sodium intake can be explained by differences in the way protons produced by contracting cells are neutralized. The sodium hydrogen exchanger and the sodium 2 bicarbonate cotransporter are stimulated by the AT1 and angiotensin type 2 (AT2) receptor, respectively. If the ratio of receptors is altered in favour of the AT2 receptor, then less cardiac hypertrophy will result from the same workload. Review of the clinical literature reveals that many of these results in rats have correlations in clinical medicine. Thus high night time blood pressure is associated with a greater morbidity and high salt intake causes cardiac hypertrophy and vascular stiffness independent of blood pressure levels. When deciding on treatment in human hypertension these results have important clinical implications. (+info)
Angiotensin inhibition reduces glomerular damage and renal chemokine expression in MRL/lpr mice.
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Beneficial effects of angiotensin II inhibition during inflammatory renal disease may involve both hemodynamic and nonhemodynamic mechanisms. To analyze whether angiotensin II inhibition has protective effects on lupus-like, autoimmune-mediated renal damage in MRL/lpr mice, four groups of mice were treated orally for 6 weeks with: 1) vehicle, 2) enalapril (3.0 mg/kg per day), 3) candesartan cilexetil (5.0 mg/kg), or 4) amlodipine (10 mg/kg) as a blood pressure control (n = 9-12/group). All antihypertensive treatments lowered blood pressure to a similar level compared with vehicle group (enalapril: 99.8 +/- 8.3 mm Hg; candesartan: 101 +/- 9 mm Hg; amlodipine: 103.8 +/- 6.7 mm Hg; vehicle: 113.5 +/- 4.6 mm Hg). Vehicle-treated mice developed a moderate glomerular injury with albuminuria (35.1 +/- 39.0 microg/mg of creatinine). Glomerular lesions consisted of immune complex deposition and mesangial expansion with increased mesangial cell proliferation. Amlodipine treatment had no significant protective effects. In contrast to vehicle- and amlodipine-treated mice, those subjected to angiotensin II blockade with enalapril or candesartan had reduced albuminuria, glomerular expansion, and mesangial proliferation. This was associated with significantly reduced renal chemokine mRNA expression compared with vehicle treatment. Our results show that inhibition of angiotensin II has protective effects on the glomerular damage of MRL/lpr mice that extend beyond hemodynamics and involve down-modulation of glomerular inflammation, reduction of mesangial cell proliferation, and decrease in chemokine expression. (+info)
Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients.
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OBJECTIVES: We investigated the vascular effects of candesartan in hypertensive patients. BACKGROUND: The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The plausible mechanisms are that angiotensin II promotes superoxide anion generation, endothelial dysfunction, inflammation, and impaired fibrinolysis. The effects of candesartan on these conditions have not been clearly observed. METHODS: We administered placebo or candesartan 16 mg daily during two months to 45 patients with mild-to-moderate hypertension. This was a randomized, double-blind, placebo-controlled, crossover study in design. RESULTS: Candesartan did not significantly change lipoprotein levels. However, compared with placebo, candesartan significantly reduced plasma levels of malondialdehyde from 1.50 +/- 0.07 to 1.29 +/- 0.09 microM (p = 0.009); improved the percent flow-mediated dilator response to hyperemia from 5.17 +/- 0.24 to 6.22 +/- 0.26% (p < 0.001); and, furthermore, reduced plasma levels of monocyte chemoattractant protein (MCP-1) from 213 +/- 8 to 190 +/- 7 pg/ml (p = 0.003), tumor necrosis factor-alpha from 2.93 to 2.22 pg/ml (p = 0.026), and plasminogen activator inhibitor type 1 from 74 +/- 4 to 53 +/- 4 ng/ml (p < 0.001) but not C-reactive protein (CRP), matrix metalloproteinase protein, and fibrinogen. There were no significant correlations between these changes and reduction of systolic blood pressure (BP) (-0.247 < or = r < or = 0.195) and between these changes and reduction of diastolic BP (-0.262 < or = r < or = 0.197). There were no significant correlations between markers of inflammation and flow-mediated dilation percent or reduction of oxidant stress (-0.119 < or = r < or = 0.127). Furthermore, we observed no significant correlations between CRP and MCP-1 levels (r = -0.162). CONCLUSIONS: Inhibition of the angiotensin II type 1 (AT1) receptor in hypertensive patients reverses endothelial dysfunction, measured as an improvement in flow-mediated dilation and fibrinolysis and reduction of oxidant stress and inflammatory cytokines, suggesting that AT1 receptor blocker therapy has antiatherogenic effects. (+info)
The existence of two forms of hypertensin.
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Two types of hypertensin have been demonstrated by means of counter-current distribution. The first type is the product of the action of the enzyme, renin, upon its substrate and has been designated hypertensin I. It can be rapidly converted to a second approximately equally pressor compound, hypertensin II, apparently through the action of an enzyme in the plasma which requires halide or nitrate for activation. A highly purified preparation containing horse hypertensins I and II caused an elevation of blood pressure when injected into human beings. (+info)