endothelin-1 and Shock

To evaluate the endocrinologic response to a combined arginine vasopressin and norepinephrine (AVP/NE) infusion in advanced vasodilatory shock, and to examine the relationship between baseline plasma AVP concentrations and the hemodynamic response to AVP.. Preliminary, prospective, randomized, controlled clinical study.. Twenty-three-bed general and surgical intensive care unit.. Thirty-eight patients with advanced vasodilatory shock. Hemodynamic and laboratory data of 34 patients have already been presented in a recently published prospective, randomized, controlled study.. Continuous AVP (4 units/hr) and NE infusion in study patients; NE infusion only in control patients.. At baseline, 24 hrs, and 48 hrs after randomization, plasma concentrations of AVP, adrenocorticotropic hormone, cortisol, renin, angiotensin II, aldosterone, prolactin, endothelin I, and atrial natriuretic factor were determined. Hemodynamic variables were recorded at baseline and 1, 12, and 24 hrs after randomization. Linear mixed effects models were used to test for differences between groups. The relationship between AVP plasma concentrations and hemodynamic response to AVP was analyzed using linear regression analyses. AVP/NE patients exhibited significantly higher AVP (p <.001) and prolactin (p <.001) plasma concentrations during the study period; there were no significant differences in plasma concentrations of other hormones. No significant correlation was detected between plasma AVP concentrations and the increase in mean arterial pressure after 1 hr (Pearson's correlation coefficient =.134, p =.584) and after 24 hrs (Pearson's correlation coefficient = -.198, p =.417). There were further no correlations between AVP plasma concentrations and the 24-hr response to AVP therapy in heart rate (Pearson's correlation coefficient = -.065, p =.791), stroke volume index (Pearson's correlation coefficient = -.106, p =.687), and NE requirements (Pearson's correlation coefficient =.04, p =.869).. The preliminary results of this study indicate that a combined AVP and NE infusion increases prolactin plasma concentrations in advanced vasodilatory shock. Hemodynamic effects of AVP infusion are independent of baseline plasma AVP concentrations.

Topics: Adrenocorticotropic Hormone; Aged; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Endocrine Glands; Endothelin-1; Female; Hemodynamics; Humans; Hydrocortisone; Infusions, Intravenous; Male; Norepinephrine; Prolactin; Prospective Studies; Renin; Shock

The mechanisms underlying acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE) are not fully understood. We hypothesized that regulators of endothelial function, circulatory homeostasis, hypoxia and cell stress contribute to the pathobiology of AMS and HAPE.. We conducted a prospective case-control study of climbers developing altitude illness who were evacuated to the CIWEC clinic in Kathmandu, compared to healthy acclimatized climbers. ELISA was used to measure plasma biomarkers of the above pathways.. Of the 175 participants, there were 71 cases of HAPE, 54 cases of AMS and 50 acclimatized controls (ACs). Markers of endothelial function were associated with HAPE: circulating levels of endothelin-1 (ET-1) were significantly elevated and levels of sKDR (soluble kinase domain receptor) were significantly decreased in cases of HAPE compared to AC or AMS. ET-1 levels were associated with disease severity as indicated by oxygen saturation. Angiopoietin-like 4 (Angptl4) and resistin, a marker of cell stress, were associated with AMS and HAPE irrespective of severity. Corin and angiotensin converting enzyme, regulators of volume homeostasis, were significantly decreased in HAPE compared to AC.. Our findings indicate that regulators of endothelial function, vascular tone and cell stress are altered in altitude illness and may mechanistically contribute to the pathobiology of HAPE.

Topics: Acclimatization; Acute Disease; Adult; Altitude Sickness; Biomarkers; Case-Control Studies; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Mountaineering; Nepal; Peptidyl-Dipeptidase A; Prospective Studies; Shock; Travel

In this study, we investigated the acute hemodynamic effects of an infusion of the endothelin-1 (ET-1)-A-selective receptor antagonists BQ-610 and BQ-123 in heatstroke rats with circulatory shock and cerebral ischemia. Heatstroke was induced by putting the anesthetized adult Sprague-Dawley rats into an ambient temperature of 42 degrees C. The moment in which the mean arterial pressure dropped irreversibly from the peak for an extent of 25 mmHg was taken as the onset of heatstroke. The interval between initiation of heat exposure and heatstroke onset was found to be about 80 min for rats treated with vehicle solution. When the animals were exposed to 42 degrees C for 80 min, hyperthermia, arterial hypotension, decrement of cardiac output (due to decreased stroke volume and decreased total peripheral resistance), increment of plasma ET-1 and tumor necrosis factor-alpha, and increment of cerebral ischemia and injury markers were manifested. Prior antagonism of ET-1 A receptors with BQ-610 (0.5 mg/kg, i.v.) or BQ-123 (1 mg/kg, i.v.), but not ET-1B receptors with BQ-788 (0.5 mg/kg, i.v.), 60 min before the initiation of heat exposure, appreciably alleviated hyperthermia, arterial hypotension, decreased cardiac output, increment of tumor necrosis factor-alpha, and increment of cerebral ischemia (e.g., glutamate and lactate/pyruvate ratio) and injury (e.g., glycerol) markers exhibited during heatstroke. The data indicates that ET-1A receptor antagonism may maintain appropriate levels of mean arterial pressure and cerebral circulation during heatstroke by reducing production of tumor necrosis factor-alpha.

Topics: Animals; Brain Ischemia; Endothelin-1; Heat Stroke; Male; Oligopeptides; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Shock; Time Factors

Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. To determine the extent to which chronic AM overproduction affects circulatory physiology under normal and pathological conditions, we used a preproendothelin-1 promoter to establish transgenic mouse lines overexpressing AM in their vasculature.. Transgenic mice overexpressing AM mainly in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure (BP) and higher plasma cGMP levels than their wild-type littermates. Blockade of NO synthase with N(G)-monomethyl-L-arginine elevated BP to a greater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopolysaccharide elicited smaller declines in BP and less severe organ damage in AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survival rate after induction of lipopolysaccharide shock was significantly higher in the transgenic mice.. A chronic increase in vascular AM production reduces BP at least in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulatory collapse, organ damage, and mortality characteristic of endotoxic shock.

Topics: Adrenomedullin; Animals; Blood Pressure; Blood Vessels; Disease Susceptibility; Endothelin-1; Endothelins; Hypotension; Lipopolysaccharides; Liver; Mice; Mice, Transgenic; Peptides; Protein Precursors; Shock

In the process of developing a model of Escherichia coli endotoxin-induced acute lung injury and shock in specific pathogen-free pigs, the effects of pretreatment with metyrapone (a cortisol-synthesis inhibitor) were examined. Metyrapone was administered 1.5 h before start of endotoxin infusion at t = 0 h (MET-ETOX group, n = 6). At the end of the experiments (t = 4 h) a bronchoalveolar lavage (BAL) was performed. Control animals received only endotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The following results are presented as means +/- SEM. It was found that metyrapone successfully blocked endogenous cortisol synthesis (plasma cortisol levels were 41.0 +/- 5.9 nM in MET-ETOX vs. 339.0 +/- 37.7 nM in CON-ETOX at t = 4 h, P <0.01). At t = 4 h the MET-ETOX animals had substantially increased systemic hypotension compared to the CON-ETOX group (mean arterial pressure 26.7 +/- 4.3 vs. 77.7 +/- 12.2 mmHg, P <0.01), decreased dynamic lung compliance (10.9 +/- 0.7 vs. 13.7 +/- 0.6 ml/cmH2O, P <0.01), increased percentage of BAL neutrophils (28.4 +/- 6.5 vs. 6.6 +/-1.8, P <0.01), pulmonary edema (BAL total protein 0.82 +/- 0.21 vs. 0.42 +/- 0.09 mg/mL, P <0.05), elevated levels of interleukin-8 (1924 +/- 275 vs. 324 +/- 131 pg/mL, P <0.01) and acidosis (pH 7.11 +/- 0.03 vs. 7.23 +/- 0.06, P <0.05). The MET-ETOX group also showed an increased pulmonary hypertension between 2 and 3 h after start of endotoxin infusion and a trend toward significantly increased levels of plasma interleukin-8 (P = 0.052). Arterial pCO2, pO2/FiO2, plasma endothelin-1, plasma TNFalpha, and blood leukocytes were not markedly influenced by the plasma cortisol levels. Nitric oxide production did not seem to be altered by endotoxin infusion in this model, in contrast to other animal studies; this discrepancy could be thought to be due to endotoxin-dosage differences or species differences. It is concluded that if endogenous cortisol production is blocked by metyrapone, the reactions occurring as a result of the endotoxin-induced acute lung injury and shock are greatly enhanced and that therefore pretreatment with metyrapone might be an important addition to this model with specific pathogen-free pigs.

Topics: Acid-Base Imbalance; Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelin-1; Endotoxins; Female; Hydrocortisone; Hypotension; Interleukin-8; Leukocytes; Male; Metyrapone; Neutrophils; Nitric Oxide; Nitrites; Peroxidase; Proteins; Pulmonary Edema; Respiratory Distress Syndrome; Respiratory Function Tests; Shock; Specific Pathogen-Free Organisms; Swine; Tumor Necrosis Factor-alpha

Production of the powerful vasoconstrictor endothelin-1 (ET1) is increased in a number of pathological conditions. This study was performed 1. to assess the effects of a twofold elevation of circulating ET1 on global hemodynamics and cardiac function, and 2. to determine the ET receptor subtypes that are responsible for this action. We have used the ETA receptor-selective antagonist BQ 610, the novel ETA receptor antagonist ETR-Pl/fl peptide and the specific ETB receptor antagonist IRL 1038 to investigate the role of these receptor subtypes in mediating circulatory changes induced by ET1 in anesthetized Wistar rats. ET1 infusion produced a significant rise in mean arterial pressure (MAP), elevated total peripheral resistance (TPR), and decreased cardiac output (CO). BQ 610 and ETR-Pl/fl pretreatment significantly attenuated the ET1-induced hemodynamic changes. Pretreatment with IRL 1038 had no effect on CO, but significantly reduced MAP and TPR elevation 20 min after ET1 infusion. These results suggest that ET1 may contribute to circulatory failure in conditions with increased ET1 production via a mechanism involving ETA receptors. ETB receptors, albeit to a lesser extent than ETA receptors, are also involved in mediating ET1-induced peripheral vasoconstriction in the rat.

Topics: Animals; Blood Circulation; Blood Pressure; Cardiac Output; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart; Hemodynamics; Infusions, Intravenous; Intercellular Signaling Peptides and Proteins; Male; Oligopeptides; Peptide Fragments; Peptides; Rats; Rats, Wistar; Receptors, Endothelin; Shock; Vascular Resistance; Vasoconstrictor Agents

Topics: Animals; Cytokines; Endothelin-1; Endothelin-3; Endothelins; Humans; Hypotension; Shock; Systemic Inflammatory Response Syndrome; Vascular Resistance; Wounds and Injuries