ET gets HIT--thrombocytotic heparin-induced thrombocytopenia (HIT) in a patient with essential thrombocythemia (ET).

Immune-mediated heparin-induced thrombocytopenia (HIT) is a relatively common complication in patients receiving heparin, and represents a strong risk factor for thromboembolic disease associated with high morbidity and mortality. The condition is commonly defined as a platelet count fall of greater than 30-50% to values below 150 x 10(9)/l. Despite this, several cases with platelet count nadirs in the normal range have been reported. This report describes a patient with status post-carotid thrombendarterectomy presenting with neurological symptoms and thrombocytosis (1235 x 10(9)/l), which in due course was diagnosed to be caused by essential thrombocythemia (ET). Heparin therapy was established and symptoms resolved markedly. After 5 days of standard heparin therapy, serologically confirmed HIT with new neurological symptoms occurred. The platelet count nadir attributed to HIT was far above normal (633 x 10(9)/l), which nevertheless represented a substantial relative platelet count fall (49%). This is the first reported case of serologically confirmed HIT in a patient with ET. Furthermore, it represents the first published case of HIT being present in thrombocytosis. Clinicians should be aware that atypical HIT can even be present in thrombocytosis and, because of nomenclature, HIT with normal and elevated platelet count nadirs is likely to be largely underdiagnosed.     

Renal endothelin ET(A)/ET(B) receptor imbalance differentiates salt-sensitive from salt-resistant spontaneous hypertension

It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250+/-6 versus 172+/-5 mm Hg, P:<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (P:<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (U(Na(+))) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P:<0.005, respectively). SHR animals showed a similar increase in both renal ET(A) and ET(B) receptor densities after NX-NaCl (2.2-fold, P:<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ET(A) compared with ET(B) binding (4.7-fold versus 2.4-fold, P:<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ET(A)/ET(B) receptor ratio only in the SHRSP-NX-NaCl (P:<0.05). Thus, activation of the renal ET system together with an increased ET(A)/ET(B) receptor ratio may contribute to the development and progression of SS-SH.     

Effects of ET(A) - and ET(B)-receptor antagonists on regional kidney blood flow, and responses to intravenous endothelin-1, in anaesthetized rabbits

OBJECTIVE : To determine the roles of endothelin (ET)-receptor subtypes in the effects of exogenous and endogenous ETs on regional kidney blood flow in anaesthetized rabbits. DESIGN AND METHODS : The effects on regional kidney blood flow of the ET(A) antagonist BQ610, and the ET(B) antagonist BQ788, were tested. We also examined the effects of intravenous and renal arterial bolus doses of ET-1, and how these responses are modified by pretreatment with BQ610 and BQ788. RESULTS : BQ610 reduced mean arterial pressure (MAP, 3%), and increased total renal blood flow (RBF, 10%), cortical perfusion (CBF, 11%) and medullary perfusion (MBF, 16%). BQ788 increased MAP (6%) and reduced RBF (16%) and CBF (13%) but not MBF. The effects of BQ788 were abolished by pretreatment with BQ610. Intravenous ET-1 (300 ng/kg) reduced RBF and CBF, but increased MBF. BQ788 potentiated ET-1 mediated reductions in CBF, and abolished increases in MBF. BQ610 blunted reductions in RBF and CBF produced by ET-1, but did not significantly affect MBF responses. The renal vascular effects of intravenous ET-1 were mimicked by lower doses (1-30 ng/kg) administered into the renal artery. CONCLUSIONS : Endogenous ETs act at ET(A)-receptors to reduce MBF and CBF, but ET(B)-receptors have little direct role in physiological control of renal haemodynamics. Bolus doses of ET-1 act at ET(B)-receptors in the kidney to increase MBF. The effects of bolus ET-1 on the cortical vasculature appear to result from the competing influences of ET(A)-mediated vasoconstriction and ET(B)-mediated vasodilatation.     

Comparison of selective ET(A) and ET(B) receptor antagonists in patients with chronic heart failure

BACKGROUND: The vasoconstrictor action of endothelin-1 (ET-1) is mediated through ET(A) and ET(B) receptor subtypes on vascular smooth muscle. ET(B) receptors are also present on the vascular endothelium where they mediate vasodilation. Animal studies suggest that the ET(B) receptor also acts as a clearance receptor for endothelin. AIMS: To investigate the effects of a selective ET(A) and a selective ET(B) receptor antagonist alone and in combination on haemodynamics and circulating concentrations of ET-1 in patients with chronic heart failure. RESULTS: Infusion of BQ-123 (n=10), a selective ET(A) receptor antagonist, led to systemic vasodilation and did not change plasma ET-1 concentrations (1.38+/-0.82 to 1.38+/-0.91 fmol/ml, ns). Infusion of BQ-788 (n=8) led to systemic vasoconstriction with a rise in plasma ET-1 (1.84+/-1.06 to 2.73+/-0.99 fmol/ml, p<0.01). The addition of BQ-123 to BQ-788 led to systemic and pulmonary vasodilation with no further increase in plasma ET-1 concentrations (2.80+/-1.14 to 2.90+/-1.20 fmol/ml, ns). CONCLUSION: The rise in plasma ET-1 concentrations in response to selective blockade of ET(B) receptors and the associated adverse haemodynamic effects suggest that ET(B) receptors have a role in the clearance of ET-1 in man and that their blockade may not be advantageous for patients with heart failure.     

ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells

We determined the distribution of ET(A) and ET(B) receptors in pulmonary arteries from pulmonary hypertensive patients and control subjects, using in vitro autoradiography, and investigated their role in mediating the proliferative effects of endothelin-1 (ET-1) on distal human pulmonary artery smooth muscle cells (PASMCs). Distal arteries possessed more medial [(125)I]-ET-1 binding sites (105 +/- 10 versus 45 +/- 6 amol/mm(2); p < 0.001) and a greater proportion of ET(B) receptors than proximal arteries (36 +/- 3% versus 3 +/- 1%; p < 0.001). Receptor density in distal arteries and lung parenchyma was twofold greater (p < 0.05) in pulmonary hypertensive patients than in control subjects. ET-1 (10(-9)-10(-7) mol/L) stimulated DNA synthesis (147 +/- 10% of control subjects; p < 0.05) and attenuated the antiproliferative action of cicaprost and forskolin on PASMCs, these effects being mediated via ET(A) and ET(B) receptors. Serum-stimulated proliferation was attenuated by inhibiting either endogenous ET-1 release with phosphoramidon (10(-5) mol/L) or its action with PD145065 (10(-5) mol/L). Cicaprost (10(-10)-10(-7) mol/L) inhibited ET-1 release from PASMCs (49 +/- 16% of control after 24 h; p < 0.001) and increased intracellular cAMP levels, whereas ET(B) receptor stimulation selectively reduced cAMP levels. In conclusion, ET(A) and ET(B) receptors are differentially distributed in human pulmonary arteries. Both receptors promote the proliferation of PASMCs in vitro and may contribute to vascular remodeling in pulmonary hypertension.     

一氧化氮、内皮素及其比值与糖尿病肾病的相关研究

目的探讨2型糖尿病(DM)患者一氧化氮(NO)、内皮素(ET)及其比值的变化规律和在糖尿病肾病(DN)发病中的作用.方法测定76例2型DM患者与40例正常入血中NO、ET水平,计算NO/ET比值;采用Student-t检验,单因素直线相关分析及多因素分析.结果①NO/ET值在正常白蛋白尿组(NA)显著升高(P＜0.01),微量白蛋白尿组(mA)和大量白蛋白尿组(MA)明显降低(P＜0.05).②NO/ET与病程、UAER(自然对数值)呈负相关(P＜0.01);ET与病程、UAER呈正相关(P＜0.01).③NO/ET、NO及体重指数(BMI)、吸烟、舒张压(DBP)、文化程度为DN发病的主要危险因素.结论 2型糖尿病患者血NO/ET比值是DN发生发展的主要危险因素之一.     

Effects of capsaicin (C) and dihydrocapsaicin (DC) on serum ethanol (ET) concentration of ET treated CF-1 mice

In this study adult male CF-1 mice were treated on a daily basis as follows: Group A - controls, Group B - ethanol (ET) treated (1.25 g ET/kg body weight (b.wt.], Group C - ET plus 4 mg Capsaicin (C)/kg b.wt., and Group D - ET plus 4 mg dihydrocapsaicin (DC)/kg b.wt. At the end of the sixth week experimental period the animals were anesthetized, exsanguinated and hepatectomized. Our study suggests that ET administered at the rate of 1.25 g ET/kg b.wt. reaches a mean serum value of 43 + 14 mg/dL within 15 minutes. In addition, chronic ET ingestion significantly decreases mean hepatic glycogen content and mean serum triglyceride concentration of the animals. Conjoint administration of ET plus C decreases significantly mean body weight and mean ET and the triglyceride concentration of the serum. Prolonged ET ingestion plus DC administration decreases mean wet liver weight and lowers significantly the mean serum ET, cholesterol and triglyceride concentrations of CF-1 mice.     

Discrepant distribution of big endothelin (ET)-1 and ET receptors in the pulmonary artery.

Since pulmonary vasculature is complex in terms of regional difference in structure and function, it is important to understand the site of endothelin (ET) synthesis and the distribution of the ET system along the axial pathways of pulmonary artery. The expression of big ET-1, ET converting enzyme (ECE) and ET(A) receptors were examined in rat pulmonary arteries under normal and hypoxic conditions using an immunohistochemical method and Northern blot analysis. In normal conditions, big ET-1 was expressed in the intima and media of pulmonary arteries with a predominant distribution in the distal segments and a preferential localization in the media, while ETA receptors were dominantly expressed in the proximal segments. ECE was constitutively expressed in the intima and media. Following exposure to hypoxia, messenger ribonucleic acid (mRNA) expression of ET-1 and ET(A) receptors were up-regulated by two-fold and immunoreactivities for big ET-1, ECE, and ET(A) receptors significantly increased by two to five-fold in the distal segments. Smooth muscle cells are an important source of endothelin-1 in the pulmonary artery. The distribution of big endothelin-1 and endothelin A receptors in pulmonary arteries was discrepant in normal conditions while their expression concomitantly increased in the distal segments in hypoxic conditions. This heterogeneity may play an important role in the regulation of pulmonary vascular tone.     

Anagrelide in the treatment of thrombocythemia essential (ET)

Essential thrombocythaemia (ET), the most often occurring myeloproliferative disorder is a clonal malignant disorder arising from stem cell. The course of the disease is complicated by some severe thrombotic events and far less commonly by haemorrhagic phenomena. Treatment of ET consist of antiplatelet drugs (e.g. aspirin) and lowering platelet count (hydroxyurea or interferon alpha). Anagrelide (anagrelide hydrochloride) is an imidazoquinazoline derivative which lowers platelet count probably by inhibiting thrombopoiesis and reduces platelet aggregation. The aim of the study was to evaluate the efficacy and side effects of anagrelide in patients with ET refractory to prior treatment with hydroxyurea. Anagrelide (Agrylin or Thromboreductin) was used in 40 patients with ET from Jan. 1999 to June. 2003. Out of 40 patients, there were 29 females and 11 males, (median age 52.0 +/- 14.25 years; range, 21-72). Median follow up was 23 months (range, 8 to 54 months). Anagrelide in the average dose of 2,0 mg (range, 1,0-3,5 mg) reduced platelet count in all patients. Median time of response was 3-4 weeks. Complete remission (platelet count < or =450 G/l) achieved 22 persons (55%) and partial remission 17 persons, and only one patient had platelet count slightly above 600 G/l (627 G/l). There was a significant (p < 0.05) reduction in platelet count from a mean of 1136.05 +/- 295.09 G/l to 480.98 +/- 72.26 G/l (56%) Despite platelet count reduction <500 G/l in 3 patients reappeared symptoms of low extremities deep venous thrombosis and in one transient ischaemic cerebral stroke was found. Hemoglobin level in a single case was lower than 12 g/dL (10.8 g/dL), and neither leukopenia nor disturbances of hepatic or renal function were observed. During the first two months of treatment with anagrelide some mild and transient side effects were noticed, eg. headache in 10 (25%), fluid retention in 8 (20%), palpitations in 4 (10%), and diarrhoea in 2 (5%) patients, but all of them continued therapy. Achieved platelet count reduction allowed in 2 ET patients safe performance of planned surgery (cholecystectomy, partial thyroidectomy) and in 1 balloon coronary angioplasty. Anagrelide proved to be an effective drug for of ET patients refractory to hydroxyurea.     

Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension

BACKGROUND: Both nonselective ET(A/B) receptor and selective ET(A) receptor antagonists can reduce pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) in various animal models. Depending on their net effects after blockade of endothelial and smooth muscle ET(B) receptors, nonselective ET(A/B) antagonists could be more or less effective than selective ET(A) antagonists. METHODS AND RESULTS: Two weeks after injection of saline or 60 mg/kg monocrotaline (MCT), rats received 50 mg x kg(-1) x d(-1) of a selective (LU135252) or nonselective (BSF420627) antagonist for 3 weeks. This resulted in 4 groups: control (n=15), MCT (n=60), MCT+ET(A) (n=39), and MCT+ET(A/B) (n=40). Five-week survival was 35% in the MCT group; this was increased to 56% in the MCT+ET(A) group (P:=0.10) and to 67% in the MCT+ET(A/B) group (P:=0.0015). Drug administration was stopped 48 hours before hemodynamic measurements to evaluate the chronic effects of therapy: PH in the MCT group (RV systolic pressure 87+/-1 mm Hg) was improved similarly in both MCT+ET(A) and MCT+ET(A/B) groups (72+/-3 and 70+/-3 mm Hg, respectively, P:<0.05). Severe RVH in the MCT group (RV/left ventricle+septum weight ratio 73+/-1%) was not affected by the selective antagonist (70+/-2%) but was reduced to 54+/-2% in the MCT+ET(A/B) group (P:<0.01). Pulmonary resistive properties, assessed from isolated lung pressure-flow relationships, were improved similarly in survivors from both treated groups. CONCLUSIONS: Both the nonselective ET(A/B) antagonist BSF420627 and the selective ET(A) antagonist LU135252 are effective in this model of PH. Similar direct comparative studies in other models of PH and with various dosage regimens are warranted to define the optimal pharmacological approach of PH when ET receptor antagonists are used.     

Synergistic effects of AT(1) and ET(A) receptor blockade in a transgenic, angiotensin II-dependent, rat model

Angiotensin II and endothelin may participate in increasing blood pressure and inducing end-organ damage, but the evidence is conflicting. We tested the hypothesis that endothelin(A) receptor blockade would ameliorate blood pressure and end-organ damage in a rat model of human renin-dependent hypertension. We studied rats that were transgenic for both the human renin and angiotensinogen genes. Experimental groups (n=12 each) of untreated transgenic rats, transgenic rats receiving subdepressor doses of losartan (10 mg/kg), transgenic rats receiving LU 135252 (30 mg/kg), transgenic rats receiving both drugs, and nontransgenic rats were studied between 6 to 10 weeks of age. Blood pressure was measured with tail-cuff sphygmomanometry. Gene expression for atrial natriuretic peptide, collagen III, and ACE was measured. The mortality rate in untreated transgenic rats was 42%, which is consistent with previous observations in this line. Single losartan or LU 135252 treatment reduced mortality incidence to 1 rat per group (8%), without significantly lowering blood pressure. In the combination group, blood pressure was normalized and all rats survived. The drug combination also decreased elevated water intake in transgenic rats to normal levels and significantly reduced cardiac hypertrophy. Furthermore, the combination of drugs decreased cardiac atrial natriuretic peptide, ACE gene, and renal collagen III gene expression. We suggest that endothelin participates in this model of angiotensin II-induced hypertension and end-organ damage. Our findings may have clinical implications and provide a rationale for combining angiotensin II type 1 receptor and endothelin(A) receptor blockade to obtain a synergistic effect.     

原发性高血压患者血浆内皮素、一氧化氮和D-二聚体的检测及临床意义分析

目的检测原发性高血压（essentialhypertension，EH）患者血浆内皮素（ET-1）、一氧化氮（NO）和D-二聚体（DD）的水平变化及分析其临床意义。方法选取94例原发性高血压患者作为研究对象，以62例健康人作为正常对照。分别采用放射免疫法测定血浆内皮素水平，硝酸还原酶法测定血浆一氧化氮水平和散射免疫比浊法测定D-二聚体水平，并进行统计学分析。结果与正常对照相比较，原发性高血压患者血浆ET-1和DD水平明显升高（P〈0．01），而NO水平则降低（P〈0．01）；经过治疗之后患者血浆ET-1和DD水平降低（P〈0．01），而NO水平升高（P〈0．01）。结论血浆ET-1、NO和DD联合检测，能够较好地反映原发性高血压患者的病情及进展，为其早期治疗和预测发展趋势提供重要依据。     

Effect of an ET(B)-selective and a mixed ET(A/B) endothelin receptor antagonist on venomotor tone in deoxycorticosterone-salt hypertension

OBJECTIVES: Because the ET(B) receptor is important in venoconstriction, we examined the effects of a selective ET(B) receptor antagonist (A-1 92621) and a mixed ET(A/B) receptor antagonist (A-182086) on endogenous endothelin-1 (ET-1) contributions to elevated venomotor tone in deoxycorticosterone acetate-salt (DOCA-salt) hypertension. METHODS: Changes in venomotor tone were assessed using repeated measurements of mean circulatory filling pressure (MCFP) in awake, uninephrectomized, DOCA-salt-treated rats and uninephrectomized sham rats following intravenous (i.v.) injections of the ET(B) antagonist (12 mg/kg i.v.) or the ET(A/B) antagonist (12 mg/kg i.v.) alone, or 1 h before ganglion blockade with hexamethonium (30 mg/kg i.v.). RESULTS: DOCA-salt rats were hypertensive and exhibited higher MCFP than sham normotensive rats. The ET(A/B) receptor antagonist lowered mean arterial blood pressure (MABP) in DOCA-salt and sham rats, but MCFP fell in DOCA-salt rats only. The ET(B) antagonist produced no changes in MCFP while MABP increased in both groups. Pre-treatment of DOCA-salt rats, but not sham rats, with either antagonist produced greater declines in MCFP following hexamethonium than after hexamethonium alone. CONCLUSIONS: The present study confirms previous findings of elevated MCFP in DOCA-salt hypertensive rats compared to normotensive rats, but is the first to show that venomotor tone is affected by the actions of endogenous ET-1 acting at ET(B) receptors to modulate sympathetic input to the veins, as well as direct actions of ET-1 on vascular smooth muscle (VSM) ET(A) receptors. We also showed that mixed ET(A/B) receptor antagonism was effective in lowering MCFP and MABP in DOCA-salt hypertensive rats.     

Essential Thrombocythemia (ET): Moving from Palliation to Cure

Essential thrombocythemia (ET) is a clonal hematopoietic stem cell myeloproliferative disorder characterized by megakaryocytic hyperplasia and persistent thrombocytosis. The clinical presentation and evolution of ET are heterogeneous. This review highlights the current treatment options in the management of ET, including hydroxyurea, anagrelide and both regular and pegylated interferons. Anagrelide, while very effective at controlling counts and symptoms in most patients, may not consistently reduce the bone marrow megakaryocyte mass. Interferon is very effective and not associated with leukemogenesis, but has not been proven to restore polyclonal hematopoiesis and has significant dose-related adverse events. Pegylated interferon represents a significant improvement over the unmodified interferon preparations. Novel therapeutic options directed towards eradication of the malignant ET clone are required.     

Essential thrombocythemia (ET): moving from palliation to cure

Essential thrombocythemia (ET) is a clonal hematopoietic stem cell myeloproliferative disorder characterized by megakaryocytic hyperplasia and persistent thrombocytosis. The clinical presentation and evolution of ET are heterogeneous. This review highlights the current treatment options in the management of ET, including hydroxyurea, anagrelide and both regular and pegylated interferons. Anagrelide, while very effective at controlling counts and symptoms in most patients, may not consistently reduce the bone marrow megakaryocyte mass. Interferon is very effective and not associated with leukemogenesis, but has not been proven to restore polyclonal hematopoiesis and has significant dose-related adverse events. Pegylated interferon represents a significant improvement over the unmodified interferon preparations. Novel therapeutic options directed towards eradication of the malignant ET clone are required.     

Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators

OBJECTIVES

To investigate the hemodynamic effects of the selective endothelin (ET)_A receptor antagonist LU135252 in patients with congestive heart failure (CHF).

BACKGROUND

Nonselective ET_A/B receptor antagonists improve hemodynamics in patients with CHF. Since ET_B receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET_A antagonists are of special interest.

METHODS

The hemodynamic effects of a single oral dose of the selective ET_A receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II–III) with an ejection fraction ≤35%.

RESULTS

Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37–0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = −0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03–0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035–< 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant.

CONCLUSIONS

In patients with CHF, a single oral dose of the selective ET_A receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.