endothelin-1 and Substance-Withdrawal-Syndrome

Although angiotensin receptor antagonists and 3-hydroxy-3-methylgultaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to attenuate proteinuria individually, it remains unclear whether proteinuria may be additionally improved by statin therapy in well-controlled hypertensive patients treated with angiotensin receptor antagonists-based regimen and whether withdrawal of chronic statin treatment may abrogate this beneficial effect in normolipidemic patients.. A total of consecutive 82 proteinuric patients treated with antihypertensive agents, including losartan, were randomized 10 mg of pravastatin or placebo with a 6-month treatment. After completing 6 months of drug treatment, the pravastatin-treated patients were randomly assigned to continue (N= 19) or withdraw (N= 17) pravastatin for a further 6 months.. Subjects treated with pravastatin had significant further improvement of proteinuria at 6 months compared with placebo group (559 +/- 251 mg/24 hours vs. 1262 +/- 557 mg/24 hours) (P < 0.0001). Of 17 patients assigned to withdraw pravastatin, proteinuria returned to the pretreatment levels and was significantly higher than those who continued treatment. Multivariate analysis revealed that proteinuric improvement was significantly correlated with the continuous statin use. Urinary excretion of endothelin-1 (ET-1) is decreased in pravastatin-treated patients, but withdrawal of statin resulted in 27% up-regulation. The linear regression models in the initial statin-treated group showed that changes in urinary ET-1 correlated with urinary protein excretion (r= 0.83, P < 0.0001).. We conclude that pravastatin administration is associated with improved proteinuria probably by inhibiting urine ET-1 levels in patients with losartan-based treatment. However, statin withdrawal abrogates this beneficial effect in patients initially responsive to this therapy.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Drug Interactions; Drug Resistance; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Renal; Lipids; Losartan; Male; Middle Aged; Pravastatin; Proteinuria; Substance Withdrawal Syndrome

Cocaine use has been related with the development of accelerated atherosclerosis and with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood, although thrombus formation and altered vascular function are prominent findings.. Our aim was to evaluate markers of endothelial dysfunction in chronic cocaine consumers before and after drug withdrawal.. We determined circulating endothelial cells (CECs) and plasma levels of stromal cell-derived factor-1 (SDF-1), monocyte chemotactic protein-1(MCP-1), soluble intracellular adhesion molecule (sICAM), high-sensitivity C reactive protein (hsCRP) and endothelin-1(ET-1), in DSM-IV cocaine addicts at baseline and after one month of cocaine abstinence.. Cocaine users showed a strikingly higher numbers of CEC (62.35 ± 18.4 vs 8.25 ± 13.8 CEC/mL) and significantly elevated plasma levels for all the markers evaluated as compared to the control group. After cocaine withdrawal, patients improved SDF-1, ET-1, hsCRP and sICAM levels. However, CEC number and MCP-1 plasma levels remained significantly elevated. All the results were adjusted for blood levels of cholesterol and triglycerides and for smoking habit.. Our results demonstrated that chronic cocaine consumption alters several functions of the endothelium towards a pro-thrombotic condition and that some of those functions remain abnormal even after short-term drug withdrawal. These observations support the notion that endothelial dysfunction may play a key role in the pathogenesis of ischemic vascular disease observed in cocaine abusers.

Topics: Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Cell Count; Chemokine CXCL12; Chile; Chronic Disease; Cocaine-Related Disorders; Endothelial Cells; Endothelin-1; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Substance Withdrawal Syndrome; Time Factors; Up-Regulation; Young Adult

Inhaled nitric oxide (iNO) is front-line therapy for pulmonary hypertension after repair of congenital heart disease. However, little clinical data exists regarding the effects of iNO on regulators of pulmonary vascular resistance. An imbalance between primary vasodilators, such as NO, and vasoconstrictors, such as endothelin-1 (ET-1), has been implicated in rebound pulmonary hypertension upon iNO withdrawal. The objective of this study was to determine whether iNO therapy alters plasma ET-1 levels.. This is a prospective study involving pediatric and adult patients at risk for pulmonary hypertension.. Pediatric patients were in the cardiac intensive care unit and adult patients were in a tertiary-care hospital.. Group 1 included children with congenital heart disease requiring iNO for treatment of pulmonary hypertension after cardiopulmonary bypass (n = 15), group 2 was adults receiving iNO (n = 10), and group 3 included children at risk for pulmonary hypertension after bypass that did not require iNO (n = 8).. Dosages of iNO were 2-60 ppm. The duration of therapy ranged from 23 to 188 hrs in group 1 and 29 to 108 hrs in group 2.. Arterial blood was obtained for the measurement of ET-1 levels before and during iNO therapy and 24 hrs after iNO withdrawal. Group 1 mean ET-1 levels increased to 127% of baseline by 12 hrs of iNO, remained elevated at 48 hrs (p < .05), then decreased to 71% of iNO levels 24 hrs after withdrawal (p < .01). Group 2 ET-1 levels increased to 147%, and 137% of baseline at 12 and 24 hrs of iNO therapy, then fell to 68% of baseline within 24 hrs of discontinuing iNO. ET-1 levels in group 3 decreased after surgery (p < .05).. These data suggest that iNO increased plasma ET-1 levels, which subsequently decreased when iNO was discontinued. Increased circulating ET-1 levels might contribute to rebound pulmonary hypertension upon iNO withdrawal.

Topics: Administration, Inhalation; Adult; Aged; Endothelin-1; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Middle Aged; Nitric Oxide; Substance Withdrawal Syndrome; Vasodilator Agents

Clinically significant increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO). Endothelin (ET)-1 is a vasoactive peptide produced by the vascular endothelium that may participate in the pathophysiology of pulmonary hypertension. The objectives of this study were to determine the effects of inhaled NO on endogenous ET-1 production in vivo in the intact lamb and to determine the potential role of ET-1 in the rebound pulmonary hypertension associated with the withdrawal of inhaled NO. Seven 1-mo-old vehicle-treated control lambs and six PD-156707 (an ET(A) receptor antagonist)-treated lambs were mechanically ventilated. Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn. After 24 h of inhaled NO, plasma ET-1 levels increased by 119.5 +/- 42.2% (P < 0.05). Western blot analysis revealed that protein levels of preproET-1, endothelin-converting enzyme-1alpha, and ET(A) and ET(B) receptors were unchanged. On acute withdrawal of NO, pulmonary vascular resistance (PVR) increased by 77.8% (P < 0.05) in control lambs but was unchanged (-5.5%) in PD-156707-treated lambs. Inhaled NO increased plasma ET-1 concentrations but not gene expression in the intact lamb, and ET(A) receptor blockade prevented the increase in PVR after NO withdrawal. These data suggest a role for ET-1 in the rebound pulmonary hypertension noted on acute withdrawal of inhaled NO.

Topics: Administration, Inhalation; Animals; Animals, Newborn; Blotting, Western; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Hypertension, Pulmonary; Lung; Metalloendopeptidases; Nitric Oxide; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Respiration, Artificial; Sheep; Substance Withdrawal Syndrome; Vascular Resistance