Chengming Yang

Randomized, double-blind, placebo-controlled trial of oral enalapril in patients with neurally mediated syncope☆☆☆★★★

BACKGROUND The purpose of this study was to study the effect of enalapril on neurally mediated syncope (NMS). Several agents (except for angiotensin-converting enzyme [ACE] inhibitors) have been used to treat patients with NMS. It is unknown whether ACE inhibitors have beneficial effects on NMS. METHODS AND RESULTS Thirty subjects who had reproducible NMS induced with head-up tilt table test (HUT) were randomly assigned and divided in double-blind fashion into placebo and enalapril (an ACE inhibitor) groups. Hemodynamics and plasma catecholamine concentrations were studied. Before administration of enalapril, syncope induced by HUT was associated with vigorous hypotension and bradycardia. Plasma catecholamine concentrations were significantly elevated during NMS compared with the supine position before tilt. Oral enalapril rather than placebo produced a marked reduction in diastolic blood pressure during supine positioning before tilt. Administration of enalapril prevented HUT-induced NMS and increase of plasma catecholamine concentrations in all patients examined. Conversely, placebo had no effect in the majority of patients with NMS (12 of 15 subjects). Follow-up data showed that NMS disappeared in 14 (93%) of 15 patients treated with enalapril. CONCLUSIONS This study demonstrates that ACE inhibitors may efficiently prevent NMS, presumably through inhibition of sympathetic system activation and peripheral hypotensive effect.

D3 Dopamine Receptor Regulation of ETB Receptors in Renal Proximal Tubule Cells From WKY and SHRs

BACKGROUND The dopaminergic and endothelin systems, by regulating sodium transport in the renal proximal tubule (RPT), participate in the control of blood pressure. The D(3) and ETB receptors are expressed in RPTs, and D(3) receptor function in RPTs is impaired in spontaneously hypertensive rats (SHRs). Therefore, we tested the hypothesis that D(3) receptors can regulate ETB receptors, and that D(3) receptor regulation of ETB receptors in RPTs is impaired in SHRs. METHODS ETB receptor expression in RPT cells was measured by immunoblotting and reverse transcriptase-PCR and ETB receptor function by measuring Na(+)-K(+) ATPase activity. D(3)/ETB receptor interaction was studied by co-immunoprecipitation. RESULTS In Wistar-Kyoto (WKY) RPT cells, the D(3) receptor agonist, PD128907, increased ETB receptor protein expression, effects that were blocked by removal of calcium in the culture medium. The stimulatory effect of D(3) on ETB receptor mRNA and protein expression was also blocked by nicardipine. In contrast, in SHR RPT cells, PD128907 decreased ETB receptor expression. Basal D(3)/ETB receptor co-immunoprecipitation was three times greater in WKY than in SHRs. The absolute amount of D(3)/ETB receptor co-immunoprecipitation induced by a D(3) receptor agonist was also greater in WKY than in SHRs. Stimulation of ETB receptors decreased Na(+)-K(+) ATPase activity in WKY but not in SHR cells. Pretreatment with PD128907 augmented the inhibitory effect of BQ3020 on Na(+)-K(+) ATPase activity in WKY but not in SHR cells. CONCLUSIONS D(3) receptors regulate ETB receptors by physical receptor interaction and govern receptor expression and function. D(3) receptor regulation of ETB receptors is aberrant in RPT cells from SHRs.

Renal D3 dopamine receptor stimulation induces natriuresis by endothelin B receptor interactions.

Dopaminergic and endothelin systems participate in the control blood pressure by regulating sodium transport in the renal proximal tubule. Disruption of either the endothelin B receptor (ETB) or D(3) dopamine receptor gene in mice produces hypertension. To examine whether these two receptors interact we studied the Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats by selectively infusing reagents into the right kidney of anesthetized rats. The D(3) receptor agonist (PD128907) caused natriuresis in WKY rats which was partially blocked by the ETB receptor antagonist. In contrast, PD128907 blunted sodium excretion in the SHRs. We found using laser confocal microscopy that the ETB receptor was mainly located in the cell membrane in control WKY cells. Treatment with the D(3) receptor antagonist caused its internalization into intracellular compartments that contained the D(3) receptors. Combined use of D(3) and ETB antagonists failed to internalize ETB receptors in cells from WKY rats. In contrast in SHR cells, ETB receptors were found mainly in internal compartments under basal condition and thus were likely prevented from interacting with the agonist-stimulated, membrane-bound D(3) receptors. Our studies suggest that D(3) receptors physically interact with proximal tubule ETB receptors and that the blunted natriuretic effect of dopamine in SHRs may be explained, in part, by abnormal D(3)/ETB receptor interactions.

Inhibitory effect of D1-like and D3 dopamine receptors on norepinephrine-induced proliferation in vascular smooth muscle cells

The sympathetic nervous system plays an important role in the regulation of blood pressure. There is increasing evidence for positive and negative interactions between dopamine and adrenergic receptors; the activation of the alpha-adrenergic receptor induces vasoconstriction, whereas the activation of dopamine receptor induces vasorelaxation. We hypothesize that the D1-like receptor and/or D3 receptor also inhibit alpha1-adrenergic receptor-mediated proliferation in vascular smooth muscle cells (VSMCs). In this study, VSMC proliferation was determined by measuring [3H]thymidine incorporation, cell number, and uptake of 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT). Norepinephrine increased VSMC number and MTT uptake, as well as [3H]thymidine incorporation via the alpha1-adrenergic receptor in aortic VSMCs from Sprague-Dawley rats. The proliferative effects of norepinephrine were attenuated by the activation of D1-like receptors or D3 receptors, although a D1-like receptor agonist, fenoldopam, and a D3 receptor agonist, PD-128907, by themselves, at low concentrations, had no effect on VSMC proliferation. Simultaneous stimulation of both D1-like and D3 receptors had an additive inhibitory effect. The inhibitory effect of D3 receptor was via protein kinase A, whereas the D1-like receptor effect was via protein kinase C-zeta. The interaction between alpha1-adrenergic and dopamine receptors, especially D1-like and D3 receptors in VSMCs, could be involved in the pathogenesis of hypertension.

Fixed-combination of amlodipine and diuretic chronotherapy in the treatment of essential hypertension: improved blood pressure control with bedtime dosing—a multicenter, open-label randomized study

Previous studies have demonstrated that individual anti-hypertension medications have different effects when administered in the morning vs. the evening. However, the impact of administration timing on fixed combinations of anti-hypertensive medications on blood pressure control is still unknown. In the present study, we examined the administration time-dependent effects of a fixed combination of amlodipine and diuretics (amlodipine complex) on blood pressure in hypertensive subjects. Eighty patients from Chongqing City were enrolled in this study. Subjects were randomly assigned to receive a single pill (amlodipine complex, each tablet containing amlodipine 5 mg and hydrochlorothiazide 25 mg), either in the morning (0800 hours, n=40) or at bedtime (2200 hours, n=40). Blood pressure was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 24 consecutive hours before and after the 12 weeks of treatment. Following treatment, the 24-h mean systolic and diastolic blood pressures were reduced significantly in both the morning and bedtime groups. However, the morning blood pressure surge was reduced to a greater degree in the bedtime group. In addition, the nocturnal blood pressure and the 24 h mean blood pressure were lower in the bedtime group. More patients converted from having a non-dipper to dipper blood pressure in the bedtime group. These findings confirm that amlodipine complexes have different efficiencies depending on treatment time. Administration of amlodipine complexes at bedtime could optimize the anti-hypertensive effect by augmenting blood pressure-lowering effects, increasing the diurnal/nocturnal ratio of blood pressure, normalizing the blood pressure pattern and minimizing the morning blood pressure surge.

Insulin Increases D5 Dopamine Receptor Expression and Function in Renal Proximal Tubule Cells From Wistar-Kyoto Rats

BACKGROUND Ion transport in the renal proximal tubule (RPT) is regulated by numerous hormones and humoral factors, including insulin and dopamine. Previous studies show an interaction between insulin and the D(1) receptor. Because both D(1) and D(5) receptors belong to the D(1)-like receptor subfamily, it is possible that an interaction between insulin and the D(5) dopamine receptor exists in RPT cells from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). METHODS D(5) receptor expression in immortalized RPT cells from WKY and SHRs was quantified by immunoblotting and D(5) receptor function by measuring Na(+)-K(+) ATPase activity. RESULTS Insulin increased the expression of the D(5) receptor. Stimulation with insulin (10(-7) mol/l) for 24 h increased D(5) receptor expression in RPT cells from WKY rats. This effect of insulin on D(5) receptor expression was aberrant in RPT cells from SHRs. The stimulatory effect of insulin on D(5) receptor expression in RPT cells from WKY rats was inhibited by a protein kinase C (PKC) inhibitor (PKC inhibitor peptide 19-31, 10(-6) mol/l) or a phosphatidylinositol 3 (PI3) kinase inhibitor (wortmannin, 10(-6) mol/l), indicating that both PKC and PI3 kinase were involved in the signaling pathway. Stimulation of the D(5) receptor heterologously expressed in HEK293 cells with fenoldopam (10(-7) mol/l/15 min) inhibited Na(+)-K(+) ATPase activity, whereas pretreatment with insulin (10(-7) mol/l/24 h) increased the D(5) receptor-mediated inhibition. CONCLUSIONS Insulin and D(5) receptors interact to regulate renal sodium transport; an aberrant interaction between insulin and D(5) receptor may participate in the pathogenesis of hypertension.

D1-like receptors inhibit insulin-induced vascular smooth muscle cell proliferation via down-regulation of insulin receptor expression.

Objective Vascular smooth muscle cell (VSMC) proliferation is central to the development of vascular diseases, including hypertension, which is regulated by numerous hormones and humoral factors. Our previous study showed that the stimulatory effect of norepinephrine on VSMC proliferation is inhibited by D1-like receptors and the D3 dopamine receptor, a member of the D2-like receptor family. Insulin is a proliferative hormone but it is not known if there is any interaction between insulin and D1-like receptors. We hypothesized that Dl-like receptors may have an inhibitory effect on the insulin-induced VSMC proliferation; aberrant insulin and Dl-like receptor functions could be involved in the pathogenesis of essential hypertension. Methods VSMC proliferation was determined by [3H]-thymidine incorporation; insulin receptor mRNA and protein expressions were determined by RT-PCR, immunoblotting, and immunohistochemistry. Results Insulin increased VSMC proliferation in immortalized aortic A10 cells, determined by [3H]-thymidine incorporation. Although the D1-like receptor, by itself, had no effect on VSMC proliferation, stimulation with fenoldopam, a D1-like receptor agonist, inhibited the stimulatory effect of insulin. The inhibitory effect of fenoldopam on insulin-mediated VSMC proliferation was receptor specific, because its effect could be blocked by SCH23390, a D1-like receptor antagonist. Fenoldopam also inhibited insulin receptor mRNA and protein expression, which was time dependent and concentration dependent. A PKC or MAP kinase inhibitor blocked the inhibitory effect of fenoldopam on insulin receptor expression, indicating that PKC and MAP kinase were involved in the signaling pathway. Conclusion The inhibitory effect of D1-like receptors on insulin-mediated VSMC proliferation may play an important role in the regulation of blood pressure.

Inhibitory effect of ETB receptor on Na(+)-K(+) ATPase activity by extracellular Ca(2+) entry and Ca(2+) release from the endoplasmic reticulum in renal proximal tubule cells.

The kidney is important in the long-term regulation of blood pressure and sodium homeostasis. Stimulation of ETB receptors in the kidney increases sodium excretion, in part, by decreasing sodium transport in the medullary thick ascending limb of Henle and in collecting duct. However, the role of ETB receptor on Na+–K+ ATPase activity in renal proximal tubule (RPT) cells is not well defined. The purpose of this study is to test the hypothesis that ETB receptor inhibits Na+–K+ ATPase activity in rat RPT cells, and investigate the mechanism(s) by which such an action is produced. In RPT cells from Wistar–Kyoto rats, stimulation of ETB receptors by the ETB receptor agonist, BQ3020, decreased Na+–K+ ATPase activity, determined by ATP hydrolysis (control=0.38±0.02, BQ3020=0.26±0.03, BQ788=0.40±0.06, BQ3020+BQ788=0.37±0.04, n=5, P<0.01). The ETB receptor-mediated inhibition of Na+–K+ ATPase activity was dependent on an increase in intracellular calcium, because this effect was abrogated by a chelator of intracellular-free calcium (BAPTA-AM; 5 × 10−3 M 15 min−1), Ca2+ channel blocker (10−6 M 15 min−1 nicardipine) and PI3 kinase inhibitor (10−7 M per wortmannin). An inositol 1,4,5-trisphosphate (IP3) receptor blocker (2-aminoethyl diphenyl borate; 10−4 M 15 min−1) also blocked the inhibitory effect of the ETB receptor on Na+–K+ATPase activity (control=0.39±0.06, BQ3020=0.25±0.01, 2-APB=0.35±0.05, BQ3020+ 2-APB=0.35±0.06, n=4, P<0.01). The calcium channel agonist (BAY-K8644; 10−6 M 15 min−1) inhibited Na+–K+ ATPase activity, an effect that was blocked by a phosphatidylinositol-3 kinase inhibitor (10−7 M 15 min−1 wortmannin). In rat RPT cells, activation of the ETB receptor inhibits Na+–K+ ATPase activity by facilitating extracellular Ca2+ entry and Ca2+ release from endoplasmic reticulum.

[Use of unfractionated heparin and a low-molecular-weight heparin following thrombolytic therapy for acute ST-segment elevation myocardial infarction].

AbstractBackground: Acute myocardial infarction (AMI) is one of the most serious cardiovascular diseases, with acute ST-segment elevation myocardial infarction (STEMI) showing a higher mortality rate than non-ST-segment elevation myocardial infarction (NSTEMI). There is evidence that low-molecular-weight heparin (LMWH) shows greater efficacy than unfractionated heparin (UFH). This open-label, single-centre, randomised study was conducted to compare the efficacy and safety of parnaparin sodium, a LMWH, with UFH in patients with STEMI. Patients and methods: Patients with STEMI were randomised to receive either parnaparin sodium (4250IU aXa subcutaneously every 12 hours for 7 days, initiated 12 hours after thrombolysis) or UFH (100 U/kg intravenous bolus, initiated 12 hours after thrombolytic therapy, followed by 1000 U/hour as a continuous infusion for 3 days, then 7500U subcutaneously every 12 hours for 4 days). Patients were followed up for 45 days (≥14 days in hospital). Results: In total, 186 patients were randomised to receive parnaparin sodium (n = 96) or UFH (n = 90). A significantly greater reduction in the composite primary endpoint (sum of all deaths, first occurrence of recurrent MI, and first occurrence of emergency revascularisation) was seen with parnaparin sodium compared with UFH at day 45 (27.08% vs 42.22%; p = 0.03). A lower incidence of composite endpoint was seen as early as day 2 with parnaparin sodium, but this did not reach significance versus UFH. The rate of individual endpoint events (death, first occurrence of non-fatal recurrent MI and first occurrence of emergency revascularisation) was lower in the parnaparin sodium group than the UFH group at 2, 7, 14 and 45 days, but the differences were not statistically significant. At day 7, the incidences of any bleeding and heparin-induced thrombocytopenia were also lower in the parnaparin sodium group compared with the UFH group (3.13% vs 10.0%; p = 0.06 and 0% vs 3.33%; p = 0.07, respectively). Conclusion: The results of this study indicate that parnaparin sodium is more effective than UFH in reducing composite cardiac events in patients with STEMI following thrombolytic therapy. There was also a lower incidence of bleeding and heparin-induced thrombocytopenia with parnaparin sodium than with UFH. In view of these findings, parnaparin sodium represents an effective, convenient and well tolerated alternative to UFH.

Effects of ACE inhibitor and β-adrenergic blocker on plasma NPY and NPY receptors in aortic vascular smooth muscle cells from SHR and WKY rats

To investigate the effects of the angiotensin-converting enzyme (ACE) inhibitor, peridopril, and the beta-adrenergic blocker, metoprolol, on plasma neuropeptide Y (NPY), and NPY receptors in aortic vascular smooth muscle cells (VSMCs) from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), both strains of rats were fed with different doses of the drugs (peridopril or metoprolol) for 7 days to get the optimal dosages. After that, 18 male SHR and 18 male age-matched WKY rats were divided into three groups: control, peridopril (2mg/kg/day) and metoprolol (2mg/kg/day). After two months of treatment, VSMCs were isolated from the media layer of the aortic wall. Results showed that the SHRs had higher plasma concentrations and binding sites/affinity for NPY as compared to WKY rats. Peridopril dose-dependently decreased plasma NPY concentrations in WKY rats, and the absolute changes of plasma NPY were greater in SHRs than in WKY rats. Metoprolol showed none of these changes. Metoprolol decreased while peridopril increased NPY binding sites/affinity in SHRs. This indicated that lowered plasma NPY concentration and decreased NPY receptor in VSMCs, might play some roles in the anti-hypertensive mechanisms mediated by ACE inhibitor and beta-adrenergic blockers.