Angiotensin receptor subtype 1 mediates angiotensin II enhancement of isoproterenol-induced cyclic AMP production in preglomerular microvascular smooth muscle cells.
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In a previous study, we found that angiotensin (Ang) II enhances beta-adrenoceptor-induced cAMP production in cultured preglomerular microvascular smooth muscle cells (PMVSMCs) obtained from spontaneously hypertensive rats. The purpose of the present investigation was to identify the Ang receptor subtypes that mediate this effect. In our first study, we compared the ability of Ang II, Ang III, Ang (3-8), and Ang (1-7) to increase cAMP production in isoproterenol (1 microM)-treated PMVSMCs. Each peptide was tested at 0.1, 1, 10, 100, and 1000 nM. Both Ang II and Ang III increased intracellular (EC50s, 1 and 11 nM, respectively) and extracellular (EC50s, 2 and 14 nM, respectively) cAMP levels in a concentration-dependent fashion. In contrast, Ang (3-8) and Ang (1-7) did not enhance either intracellular or extracellular cAMP levels at any concentration tested. In our second study, we examined the ability of L 158809 [a selective Ang receptor subtype 1 (AT1) receptor antagonist] to inhibit Ang II (100 nM) and Ang III (100 nM) enhancement of isoproterenol (1 microM)-induced cAMP production in PMVSMCs. L 158809 (10 nM) abolished or nearly abolished (p <.001) Ang II and Ang III enhancement of isoproterenol-induced intracellular and extracellular cAMP levels. In contrast, PD 123319 (300 nM; a selective AT2 receptor antagonist) did not significantly alter Ang II enhancement of isoproterenol-induced intracellular or extracellular cAMP levels. We conclude that AT1 receptors, but not AT2, Ang (3-8), nor Ang (1-7) receptors mediate Ang II and Ang III enhancement of beta-adrenoceptor-induced cAMP production in cultured PMVSMCs. (+info)
Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation.
(2/1828)
BACKGROUND: The blockade of angiotensin II (Ang II) formation has protective effects on cardiovascular tissue; however, the role of Ang II in atrial electrical remodeling is unknown. The purpose of this study was to investigate the effects of candesartan and captopril on atrial electrical remodeling. METHODS AND RESULTS: In 24 dogs, the atrial effective refractory period (AERP) was measured before, during, and after rapid atrial pacing. Rapid atrial pacing at 800 bpm was maintained for 180 minutes. The infusion of saline (n=8), candesartan (n=5), captopril (n=6), or Ang II (n=5) was initiated 30 minutes before rapid pacing and continued throughout the study. In the saline group, AERP was significantly shortened during rapid atrial pacing (from 149+/-11 to 132+/-16 ms, P<0.01). There was no significant difference in AERP shortening between the saline group and the Ang II group. However, in the candesartan and captopril groups, shortening of the AERP after rapid pacing was completely inhibited (from 142+/-9 to 147+/-12 ms with candesartan, from 153+/-15 to 153+/-14 ms with captopril, P=NS). Although rate adaptation of the AERP was lost in the saline group, this phenomenon was preserved in the candesartan and captopril groups. CONCLUSIONS: The inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing. These results indicate for the first time that Ang II may be involved in the mechanism of atrial electrical remodeling and that the blockade of Ang II may lead to the better therapeutic management of human atrial fibrillation. (+info)
Angiotensin II inhibits rat arterial KATP channels by inhibiting steady-state protein kinase A activity and activating protein kinase Ce.
(3/1828)
We used whole-cell patch clamp to investigate steady-state activation of ATP-sensitive K+ channels (KATP) of rat arterial smooth muscle by protein kinase A (PKA) and the pathway by which angiotensin II (Ang II) inhibits these channels. Rp-cAMPS, an inhibitor of PKA, did not affect KATP currents activated by pinacidil when the intracellular solution contained 0.1 mM ATP. However, when ATP was increased to 1.0 mM, inhibition of PKA reduced KATP current, while the phosphatase inhibitor calyculin A caused a small increase in current. Ang II (100 nM) inhibited KATP current activated by the K+ channel opener pinacidil. The degree of inhibition was greater with 1.0 mM than with 0.1 mM intracellular ATP. The effect of Ang II was abolished by the AT1 receptor antagonist losartan. The inhibition of KATP currents by Ang II was abolished by a combination of PKA inhibitor peptide 5-24 (5 microM) and PKC inhibitor peptide 19-27 (100 microM), while either alone caused only partial block of the effect. In the presence of PKA inhibitor peptide, the inhibitory effect of Ang II was unaffected by the PKC inhibitor Go 6976, which is selective for Ca2+-dependent isoforms of PKC, but was abolished by a selective peptide inhibitor of the translocation of the epsilon isoform of PKC. Our results indicate that KATP channels are activated by steady-state phosphorylation by PKA at normal intracellular ATP levels, and that Ang II inhibits the channels both through activation of PKCepsilon and inhibition of PKA. (+info)
Reactive oxygen species-mediated homologous downregulation of angiotensin II type 1 receptor mRNA by angiotensin II.
(4/1828)
Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of angiotensin (Ang) II through Ang II type 1 receptor (AT(1)-R). However, the role of ROS in the regulation of AT(1)-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT(1)-R by Ang II. Ang II (10(-6) mol/L) decreased AT(1)-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells. Preincubation of vascular smooth muscle cells with N:-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT(1)-R mRNA. The effect of NAC was due to stabilization of the AT(1)-R mRNA that was destabilized by Ang II. The Ang II-induced AT(1)-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as by PD98059. Exogenous H(2)O(2) also suppressed AT(1)-R mRNA. These results suggest that the production of ROS and the activation of ERK are critical for the downregulation of AT(1)-R mRNA. The generation of ROS through stimulation of AT(1)-R not only mediates signaling of Ang II but also may play a crucial role in the adaptation process of AT(1)-R to the sustained stimulation of Ang II. (+info)
Use of positron emission tomography to study AT1 receptor regulation in vivo.
(5/1828)
Increased sodium intake and enhanced sodium sensitivity are implicated in the pathogenesis of hypertension and in the control of a major regulator of BP, the type 1 angiotensin receptor (AT(1) receptor). An in vivo technique to study changes of renal AT(1) receptors by dietary sodium was developed that uses positron emission tomography (PET). PET revealed that renal cortical AT(1) receptor binding was increased in sodium-loaded compared with sodium-deprived dogs, which correlated with ex vivo estimations of AT(1) receptor numbers. Plasma renin activity, angiotensin II, and aldosterone were inversely related to changes in AT(1) receptor binding. These results demonstrate, for the first time in vivo, that the renal AT(1) receptor is inversely related to the activity of the renin angiotensin system, which may provide a compensatory mechanism to prevent inappropriate fluctuations in arterial BP. The ability to measure AT(1) receptor binding in vivo has potential significance for clinical studies of AT(1) receptors, because PET is a noninvasive imaging technique that is readily applicable in humans. (+info)
Angiotensin II type 1 and 2 receptors in conduit arteries of normal developing microswine.
(6/1828)
OBJECTIVE: To identify vascular cells capable of responding to angiotensin II (Ang II) generated in conduit arteries, we examined the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) in the thoracic aorta (TA) and abdominal aorta (AA) and branches in 90-day fetal, 3-week postnatal, and 6-month adult microswine. METHODS AND RESULTS: By autoradiography ((125)I-[Sar(1)Ile(8)]-Ang II with or without AT1R- or AT2R-selective analogues or (125)I-CGP 42112), there were striking rostrocaudal differences in (1) AT2R binding at all ages (prominent in AA wall and branches, sparse in TA wall and branches) and (2) a non-AT2R binding site for CGP 42112 (consistently evident in postnatal TA and branches but absent in AA and branches). Furthermore, patterns of AT2R distribution in infradiaphragmatic arteries were developmentally distinct. In fetal AAs, high-density AT2Rs occupied the inner 60% of the medial-endothelial wall. In postnatal AAs, AT2Rs were sparse in the medial-endothelial wall but prominent in a circumferential smooth muscle alpha-actin-negative cell layer at the medial-adventitial border, occupying approximately 20% to 25% of the AA cross-sectional area. AT1R density in the TA and AA medial-endothelial wall increased with age, whereas AT2R density decreased after birth. CONCLUSIONS: A novel AT2R-positive cell layer confined to postnatal infradiaphragmatic arteries physically links adventitial and medial layers, appears optimally positioned to transduce AT2R-dependent functions of local Ang II, and suggests that adventitial Ang II may elicit regionally distinct vascular responses. (+info)
Angiotensin II type 1 receptor blockade to control blood pressure in postmenopausal women: influence of hormone replacement therapy.
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BACKGROUND: Hypertension is twice as common in postmenopausal than in premenopausal women. This study evaluated the effectiveness of a blockade of the renin-angiotensin-aldosterone system (RAAS) with candesartan cilexetil (CC) to control blood pressure (BP) in hypertensive menopausal women, and the influence of hormone replacement therapy (HRT). METHODS: This was designed as a prospective, open-label and non-comparative study. Included were 618 hypertensive menopausal women grade I/II according to the Sixth Report of the Joint National Committee (VI-JNC), with an average age 52+/-4.7 years (95% CI 52.3-53.0) and with a last menstrual period (LMP) at least one year before. BP was determined by measurement in four visits during six months of follow-up, according to the recommendations of the OMS/SIH. Optimal control of BP was considered as BP <140/90 mm Hg. RESULTS: A statistically significant decrease in systolic (SBP; 19.9+/-11.2) and diastolic (DBP; 11.5+/-7.3) blood pressure mm Hg values was observed (P<0.01). The control of BP increased significantly over time to 61.2% (P<0.01). In multivariate analysis, only age was associated with control of BP (beta= -0.062; P=0.004). Of the women not controlled in the second visit, 12.5 mg of hydrochlorothiazide (HCTZ) were added to 31.5% (N=122), with 80% more BP control achieved in visit 3 than in the non-supplement group (OR=1.8; 95% CI 1.04-3.05; P<0.03). One hundred and three (16.7%) patients were receiving HRT for 2.01+/-2.23 years (95% CI 1.55-2.46). HRT did not affect the control of BP. No severe adverse reactions were reported. CONCLUSIONS: Candesartan cilexetil significantly reduced SBP and DBP and increased control (61.2%) of BP in hypertensive menopausal women. Only age had an inverse association with control of BP. In this study, HRT did not affect the control of BP. (+info)
Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies.
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BACKGROUND: Blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies. Additionally, this beneficial effect is not dependent on blood pressure control. METHODS: To assess and compare the effects of lisinopril (up to 40 mg/day), candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8+/-2.4 g/g) and normal or slightly reduced renal function (CCr 95+/-33 mL/min) were enrolled in a six month multicenter, prospective, open, randomized, active-controlled and parallel-group trial with 1:1:1 allocation. Blood pressure goal was set at or below 125/75 mm Hg for all patients, with additional antihypertensive medication prescribed if required. RESULTS: Renal function, estimated by creatinine clearance, remained stable throughout the study. Hyperkalemia (K>5.5 mmol/L) was detected in 3.1% of all measurements in follow-up, and was more frequent in patients treated with lisinopril alone or lisinopril plus candesartan (P<0.001) than in those on candesartan alone. No other relevant adverse event was recorded. The blood pressure goal (<125/75 mm Hg) was achieved by week 4 in all treatment groups (P<0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% confidence intervals CI) decreased in patients treated with lisinopril alone to -33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32-63), in patients treated with the combination of both to -60% (CI -44-77) to -54% (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively. All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with candesartan alone at two and six months (P=0.004 and P=0.023, respectively) and than treatment with lisinopril only at two months (P=0.03). CONCLUSION: Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated. (+info)