endothelin-1 and Hypotension

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Topics: Autonomic Nervous System; Blood Volume; Endothelin-1; Hemodynamics; Humans; Hypotension; Nitric Oxide; Renal Dialysis; Syncope, Vasovagal; Uremia

Intradialytic hypotension is a major complication during hemodialysis session, associated with increased risk of cardiovascular events and mortality. Its pathophysiology is believed to be multifactorial and remains not well elucidated. The aim of this study is to put forward new mechanisms behind the development of intradialytic hypotension. The study included sixty-five subjects on chronic hemodialysis, divided into two groups: intradialytic hypotensive (n=12) and normotensive (n=53), according to the variation of systolic blood pressure between post-dialysis and pre-dialysis measurements. Renin and angiotensin converting enzyme I plasma concentrations increased in both groups but more likely in normotensive group. Aldosterone plasma concentration is increased in the normotensive group while it decreased in the intradialytic hypotension group. Plasma endothelin concentrations showed higher values in intradialytic hypotension group. Post-dialysis asymmetric dimethylarginine and angiotensin converting enzyme 2 plasma concentrations were significantly higher in intradialytic hypotension group as compared to normotensive one. Collectrin plasma concentrations were significantly lower in intradialytic hypotension group. Finally, post-dialysis vascular endothelial growth factor C plasma concentration significantly increased in intradialytic hypotension group. In conclusion, endothelial dysfunction characterized by a lower level of vasoactive molecule seems to play a critical role in intradialytic hypotension development.

Topics: Aged; Aged, 80 and over; Aldosterone; Angiotensin-Converting Enzyme 2; Arginine; Biomarkers; Blood Pressure; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypotension; Kidney Diseases; Male; Membrane Glycoproteins; Middle Aged; Peptidyl-Dipeptidase A; Renal Dialysis; Renin; Time Factors; Vascular Endothelial Growth Factor C

Endothelin-1 (ET-1), tissue plasminogen activator (tPA), and extracellular signal-regulated kinases-mitogen activated protein kinase (ERK-MAPK) are mediators of impaired cerebral hemodynamics after fluid percussion brain injury (FPI) in piglets. Microparticles (MPs) are released into the circulation from a variety of cells during stress, are pro-thrombotic and pro-inflammatory, and may be lysed with polyethylene glycol telomere B (PEG-TB). We hypothesized that MPs released after traumatic brain injury impair hypotensive cerebrovasodilation and that PEG-TB protects the vascular response via MP lysis, and we investigated the relationship between MPs, tPA, ET-1, and ERK-MAPK in that process. FPI was induced in piglets equipped with a closed cranial window. Animals received PEG-TB or saline (vehicle) 30-minutes post-injury. Serum and cerebrospinal fluid (CSF) were sampled and pial arteries were measured pre- and post-injury. MPs were quantified by flow cytometry. CSF samples were analyzed with enzyme-linked immunosorbent assay. MP levels, vasodilatory responses, and CSF signaling assays were similar in all animals prior to injury and treatment. After injury, MP levels were elevated in the serum of vehicle but not in PEG-TB-treated animals. Pial artery dilation in response to hypotension was impaired after injury but protected in PEG-TB-treated animals. After injury, CSF levels of tPA, ET-1, and ERK-MAPK were all elevated, but not in PEG-TB-treated animals. PEG-TB-treated animals also showed reduction in neuronal injury in CA1 and CA3 hippocampus, compared with control animals. These results show that serum MP levels are elevated after FPI and lead to impaired hypotensive cerebrovasodilation via over-expression of tPA, ET-1, and ERK-MAPK. Treatment with PEG-TB after injury reduces MP levels and protects hypotensive cerebrovasodilation and limits hippocampal neuronal cell injury.

Topics: Animals; Animals, Newborn; Brain Injuries; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Cell-Derived Microparticles; Disease Models, Animal; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Female; Hypotension; Male; Swine; Tissue Plasminogen Activator; Vasodilation

Effective management of hypotension refractory to vasoconstrictors in severe sepsis is limited. A new strategy to ameliorate endotoxemic hypotension by inducing endothelium-dependent constriction of large arteries was assessed.. Endotoxemia in rats was induced by injection of LPS (10 mg·kg(-1), i.v.). Haemodynamics were measured in vivo, reactivity of isolated mesenteric arteries by myography and expression of proteins and enzyme activities by immunohistochemistry, biochemistry and molecular biology.. Six hours after LPS, the hypotension was promptly reversed following injection (i.v. or i.p.) of oroxylin-A (OroA) . In isolated LPS-treated but not normal mesenteric arteries, OroA (1-10 μM) induced endothelium-dependent, sustained constriction, blocked by endothelin-1 (ET-1) receptor antagonists. OroA further enhanced LPS-induced expression of endothelin-converting enzyme, ET-1 mRNA and proteins and ET-1 release, OroA also enhanced phosphorylation of Rho-associated protein kinase (ROCK) and reversed LPS-induced suppression of RhoA activities in smooth muscle of arteries with endothelium. Activated- phosphorylation of smooth muscle ROCK was blocked by ET-1-receptor antagonists and ROCK inhibitors. Moreover, OroA post-treatment suppressed, via inhibiting NF-κB activation, inducible NOS expression and circulating NO.. Reversal of endotoxemic hypotensive by OroA was due to release of endothelial ET-1, upregulated by LPS, from mesenteric arteries, inducing prompt and sustained vasoconstriction via activation of vascular smooth muscle RhoA/ROCK-pathway. In late endotoxemia, OroA-induced vasoconstriction was partly due to decreased circulating NO. Activation of endothelium-dependent constriction in large resistance arteries and suppression of systemic inflammation offer new strategies for acute management of endotoxemic hypotensive shock.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Endotoxemia; Flavonoids; Hypotension; Lipopolysaccharides; Male; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Shock, Septic; Vasoconstriction

Traumatic brain injury contributes to morbidity in children and boys are disproportionately represented. Autoregulation is impaired more in male compared with female piglets after traumatic brain injury through sex-dependent up-regulation of the spasmogen endothelin-1 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK), a family of three kinases: ERK, p38, and JNK). Elevation of mean arterial pressure leading to increased cerebral perfusion pressure via phenylephrine improves impairment of autoregulation after traumatic brain injury in female but not male piglets through modulation of endothelin-1 and ERK MAPK up-regulation, blocked in females, but aggravated in males. We hypothesized that pressor choice to elevate cerebral perfusion pressure is important in improving cerebral hemodynamics after traumatic brain injury and that dopamine will prevent impairment of autoregulation in both male and female piglets through blockade of endothelin-1 and ERK MAPK.. Prospective, randomized animal study.. University laboratory.. Newborn (1-5 days old) pigs.. Cerebral perfusion pressure and pial artery diameter were determined before and after lateral fluid percussion brain injury was produced in piglets equipped with a closed cranial window. Dopamine (15 µg/kg/min IV) was administered 30 mins post fluid percussion injury. Cerebrospinal fluid ERK MAPK was determined by enzyme-linked immunosorbent assay.. Dopamine increased cerebral perfusion pressure equivalently in both sexes and prevented sex-dependent reductions in pial artery diameter after fluid percussion injury. Loss of pial artery dilation during hypotension was greater in male than in female piglets after fluid percussion injury, but dopamine prevented such impairment equivalently in both sexes post injury. endothelin-1 and ERK MAPK release was greater in male compared to female piglets after fluid percussion injury, but dopamine also blocked their up-regulation equivalently in male and female piglets after fluid percussion injury.. These data indicate that dopamine is protective of autoregulation after fluid percussion injury in both sexes. These observations advocate for the consideration of development of sex based therapies for treatment of hemodynamic sequalae of pediatric traumatic brain injury.

Topics: Analysis of Variance; Animals; Blood Pressure; Brain Injuries; Cerebrovascular Circulation; Dopamine; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Female; Hypotension; Male; MAP Kinase Signaling System; Sex Factors; Swine; Sympathomimetics; Up-Regulation; Vasodilation

In recent years, several studies have demonstrated that urotensin II (UII) and urotensin II-related peptide (URP) can exhibit differential biological activity. So far, known antagonists of the urotensin II receptor (UT) are of limited usefulness for investigating the specific pathophysiological role of UII or URP. Therefore, identification of new compounds able to discriminate UII- and URP-associated biological activities is crucially needed. In the present study, we report preliminary data regarding the pharmacological properties of a novel UT ligand termed urocontrin, i.e. [Bip(4)]URP, that is able to reduce the ex vivo efficacy of hUII- but not URP-induced vasoconstriction in rat aortic rings. In vivo studies support the pharmacological profile described above. Although urocontrin exert some residual agonist activity, this compound should be useful for the rational design of potent molecules that would allow discriminating specific biological action mediated by UII or URP.

Topics: Animals; Antihypertensive Agents; Aorta; CHO Cells; Cricetinae; Endothelin-1; Hypotension; Intracellular Signaling Peptides and Proteins; Male; Molecular Structure; Peptide Hormones; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Urotensins; Vasoconstriction

Topics: Adult; Blood Pressure; Cohort Studies; Dietary Supplements; E-Selectin; Endothelin-1; Humans; Hypotension; Nitric Oxide Synthase Type III; Polymorphism, Single Nucleotide; Potassium, Dietary; Sodium Chloride, Dietary

The etiology of hemodialysis (HD)-induced hypotension and hypertension remains speculative. There is mounting evidence that endothelin-1 (ET-1) may play a vital role in these hemodynamic changes. We examined the possible role of intradialytic changes of ET-1 in the pathogenesis of hypotension and rebound hypertension during HD.. The present study included 45 patients with end-stage renal disease (ESRD) on regular HD. They were divided according to their hemodynamic status during HD into three groups (group I had stable intradialytic hemodynamics, group II had dialysis-induced hypotension, and group III had rebound hypertension during HD). In addition, 15 healthy volunteers were included as a control group. Pulse and blood pressure were monitored before, during (every half hour), and after HD session. ET-1 level was measured at the beginning, middle, and end of HD. ET-1 was measured in the control group for comparison.. Pre-dialysis levels of ET-1 were significantly higher in dialysis patients compared to the controls (P < 0.001); however, they were comparable in the three HD groups. The post-dialysis ET-1 level was not changed significantly in group I compared with predialysis values (14.49 +/- 2.04 vs. 14.33 +/- 2.23 pg/ml; P = NS), while the ET-1 concentration decreased significantly in group II and increased in group III in comparison to predialysis values (8.56 +/- 1.44 vs. 11.75 +/- 2.51; 16.39 +/- 3.12 vs. 11.93 +/- 2.11 pg/ml, respectively; P < 0.001).. Altered ET-1 levels may be involved in the pathogenesis of rebound hypertension and hypotension during HD.

Topics: Adult; Blood Pressure; Case-Control Studies; Egypt; Endothelin-1; Female; Heart Rate; Humans; Hypertension; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

The purpose of the study was to investigate whether provoked changes of cerebral perfusion pressure and arterial carbon dioxide tension are able to influence the cerebral metabolism of endothelin-1 (ET-1) in a porcine model. Brain tissue oxygen tension, regional cerebral blood flow and mean arterial blood pressure were monitored in 10 healthy pigs during induced hyperventilation (HV), hypertension (HrT) and hypotension (HoT). ET-1 was determined in the arterial and cerebrovenous blood. Microdialysis samples (lactate, glucose and pyruvate) were taken from brain and subcutaneous tissue. A significant decrease (p<0.05) of the arterial ET-1 (1.46+/-0.33 fmol/mL) compared to the baseline (2.18+/-0.36 fmol/mL) was observed after the HoT-period. We detected a positive correlation between cerebrovenous ET-1 and extracellular cerebral glucose (0.68; p<0.05) after the baseline as well as a negative correlation of -0.81 (p<0.005) between the cerebrovenous ET-1 level and the extracellular cerebral lactate after the HoT-period. These data imply that with increasingly pathological changes of the cerebral metabolism endothelin becomes progressively more important in the regulation of cerebral vascular tone.

Topics: Animals; Blood Circulation Time; Blood Glucose; Cerebrovascular Circulation; Disease Models, Animal; Endothelin-1; Extracellular Fluid; Hypertension; Hyperventilation; Hypotension; Intracranial Pressure; Lactates; Microdialysis; Regional Blood Flow; Swine; Time Factors

Coronary effects of endothelin-1 and vasopressin during acute hypotension, and the role of NO and prostanoids in these effects were examined in anesthetized goats. Left circumflex coronary artery flow was measured electromagnetically, and hypotension was induced by constriction of the caudal vena cava in animals non-treated (7 goats) or treated with the inhibitor of NO synthesis N(w)-nitro-L-arginine methyl esther (L-NAME, 5 goats), the cyclooxygenase inhibitor meclofenamate (5 goats) or both drugs (5 goats). Under normotension (22 goats), mean arterial pressure averaged 93 +/- 3 mm Hg and coronary vascular conductance (CVC) 0.37 +/- 0.025 ml/min/mm Hg. Endothelin-1 (0.01-0.3 nmol) and vasopressin (0.03-1 nmol), intracoronarily injected, dose-dependently decreased CVC by up to 56% for endothelin-1 and 40% for vasopressin. During hypotension in every condition tested, mean arterial pressure decreased to approximately 60 mm Hg, and CVC only decreased during hypotension pretreated with L-NAME (23%) or L-NAME + meclofenamate (34%). Under non-treated hypotension, the decreases in CVC by endothelin-1 were augmented approximately 1.5 fold, and those by vasopressin were not modified. This increase in CVR by endothelin-1 was not affected by L-NAME and was reversed by meclofenamate or L-NAME + meclofenamate. The coronary effects of vasopressin were not modified by any of these treatments. Therefore, acute hypotension increases the coronary vasoconstriction in response to endothelin-1 but not to vasopressin. This increased response to endothelin-1 may be related to both inhibition of NO release and release of vasoconstrictor prostanoids.

Topics: Acute Disease; Anesthesia; Animals; Blood Pressure; Coronary Circulation; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Female; Goats; Hypotension; Meclofenamic Acid; NG-Nitroarginine Methyl Ester; Nitric Oxide; Vasoconstriction; Vasopressins

To determine whether plasma endothelin-1 (ET-1) relates to clinical manifestations of sepsis in the newborn, especially with systemic hypotension, acidosis, severe hypoxemia (which may represent pulmonary hypertension) and oliguria.. Prospective study of 35 consecutive newborns with clinical sepsis: 22 with hemoculture-positive (HC+) sepsis and 13 hemoculture-negative (HC-). Plasma ET-1 concentrations were measured within 2 days of the diagnosis of sepsis. SNAP-II severity score was performed at the time of highest clinical severity.. Newborns with HC+ sepsis had higher plasma ET-1 concentrations and SNAP-II scores (especially PO 2 /FiO 2 ratio) than HC- septic children. Plasma ET-1 concentrations increased linearly with each item of the SNAP-II score, but only reached significant differences in lowest mean blood pressure (P=0.030), lowest pH (P=0.048), multiple seizures (P=0.010) and lowest urine output (P=0.013). Leukocyte count, immature/total neutrophil ratio and C-reactive protein value were not different. Each item of the SNAP-II score was independently related only to ET-1 level. Oliguria, acidosis and systemic hypotension were more correlated (R 2 >0.5).. Plasma ET-1 levels in neonatal sepsis are related to the severity of clinical manifestations, especially oliguria, acidosis and systemic hypotension.

Topics: Acidosis; Candida; Endothelin-1; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Hypotension; Infant, Newborn; Infant, Newborn, Diseases; Intensive Care Units, Neonatal; Male; Oliguria; Predictive Value of Tests; Prospective Studies; Sepsis; Severity of Illness Index; Spain

The present study was done to investigate the role of endothelin-1 (ET-1) in hypotension and bronchospasm provoked by anaphylaxis in rabbits in vivo.. Forty-five rabbits sensitized to horse serum were randomly allocated to five groups: Group 1 (n = 10) received 0.5 nmol x kg(-1) of ET-1; Group 2 (n = 10) received 0.5 nmol x kg(-1) of ET-1 and 200 nmol x kg(-1) of a selective ETA receptor antagonist, BQ 610, without anaphylaxis; Group 3 (n = 5) received 200nmol x kg(-1) of BQ 610 alone without anaphylaxis, Group 4 (n = 10) received normal saline alone before being antigen challenged to induce anaphylaxis; Group 5 (n = 10) received 200 nmol x kg(-1) of BQ 610 before antigen challenge.. Mean arterial pressure (MAP) values were significantly different between Groups 1 and 2. Heart rate (HR), central venous pressure (CVP), dynamic pulmonary compliance (C(dyn)), and pulmonary airway resistance (R(L)) did not differ significantly between Groups 1 and 2. MAP values were significantly decreased compared with baseline in both Groups 4 and 5; however, the values were not significantly different between two groups. CVP values were significantly different between Groups 4 and 5 only at the 15-min time point following antigen challenge. HR, R(L), and C(dyn) values were not significantly different between Groups 4 and 5, nor were the survival rates.. BQ 610 does not improve hypotension or survival rates in systemic aggregated anaphylactic rabbits in vivo, implying that circulating ET-1 may not play an important role in anaphylaxis, although direct proof of production of circulating ET-1 or activation of ETA receptors is lacking in this study.

Topics: Anaphylaxis; Animals; Bronchial Spasm; Endothelin-1; Female; Hemodynamics; Hypotension; Male; Oligopeptides; Rabbits; Sodium Chloride; Time Factors

In the present study, we examined cardiac and regional haemodynamic effects of endothelin-1 (ET-1), a potent vasoconstrictive factor, in a rat model of pressure-controlled irreversible haemorrhagic shock resulting in the death of all control animals within 30 min. Experiments were carried out in male ethylurethane-anaesthetised Wistar rats subjected to hypotension of 20-25 mmHg, which resulted in bradycardia, an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF). ET-1 (50, 200 pmol/kg) administered intravenously at 5 min of critical hypotension produced increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly higher than those in normotensive animals, and a 100% survival at 2 h after treatment. The effects were accompanied by a rise in CI, a decrease in TPRI, with increases in RBF and HBF and persistently lowered MBF, and an increase in circulating blood volume 20 min after treatment. The cardiovascular effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 (1 mg/kg), while the ETB receptor antagonist BQ-788 (3 mg/kg) had no effect. In conclusion, ET-1 acting via ETA receptors produces reversal of haemorrhagic hypotension in rats due to the mobilisation of blood from venous reservoirs, with the improvements in cardiac function and the perfusion of peripheral tissues.

Topics: Animals; Blood Pressure; Bradycardia; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Hemorrhage; Hindlimb; Hypotension; Injections, Intravenous; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Circulation; Shock, Hemorrhagic; Sodium Chloride; Splanchnic Circulation; Time Factors; Vascular Resistance

Etiology of dialysis induced hypotension and hypertension remains speculative. There is mounting evidence that nitric oxide (NO) and endothelin (ET-1) may play a vital role in these hemodynamic changes. We examined the intradialytic dynamic changes in NO and ET-1 levels and their role in the pathogenesis of hypotension and rebound hypertension during hemodialysis (HD).. The serum nitrate + nitrite (NT), fractional exhaled NO concentration (FENO), L-arginine (L-Arg), NGNG-dimethyl-L-arginine (ADMA) and endothelin (ET-1) profiles were studied in 27 end-stage renal disease (ESRD) patients on HD and 6 matched controls. The ESRD patients were grouped according to their hemodynamic profile; Group I patients had stable BP throughout HD, Group II had dialysis-induced hypotension, and Group III had intradialytic rebound hypertension.. Pre-dialysis FENO was significantly lower in the dialysis patients compared to controls (19.3 +/- 6.3 vs. 28.6 +/- 3.4 ppb, P < 0.002). Between the experimental groups, pre-dialysis FENO was significantly higher in Group II (24.1 +/- 6.7 ppb) compared to Group I (17.8 +/- 5.6 ppb) and Group III (16.1 +/- 4.2 ppb; P < 0.05). Post-dialysis, FENO increased significantly from the pre-dialysis values (19.3 +/- 6.3 vs. 22.6 +/- 7.9 ppb; P=0.001). Pre-dialysis NT (34.4 +/- 28.2 micromol/L/L) level was not significantly different from that of controls (30.2 +/- 12.3 micromol/L/L). Serum NT decreased from 34.4 +/- 28.2 micromol/L/L at initiation of dialysis to 10.0 +/- 7.4 micormol/L/L at end of dialysis (P < 0.001). NT concentration was comparable in all the three groups at all time points. Pre-dialysis L-Arg (105.3 +/- 25.2 vs. 93.7 +/- 6.0 micromol/L/L; P < 0.05) and ADMA levels were significantly higher in ESRD patients (4.0 +/- 1.8 vs. 0.9 +/- 0.2 micromol/L/L; P < 0.001) compared to controls. Dialysis resulted in significant reduction in L-Arg (105.3 +/- 25.2 vs. 86.8 +/- 19.8 micromol/L/L; P < 0.005) and ADMA (4.0 +/- 1.8 vs. 1.6 +/- 0.7 micromol/L/L; P < 0.001) concentrations. Pre-dialysis ET-1 levels were significantly higher in ESRD patients compared to the controls (8.0 +/- 1.9 vs. 12.7 +/- 4.1 pg/mL; P < 0.002), but were comparable in the three study groups. Post-dialysis ET-1 levels did not change significantly in Group I compared to pre-dialysis values (14.3 +/- 4.3 vs.15.0 +/- 2.4 pg/mL, P=NS). However, while the ET-1 concentration decreased significantly in Group II (12.0 +/- 4.0 vs. 8.7 +/- 1.8 pg/mL, P < 0.05), it increased in Group III from pre-dialysis levels (12.8 +/- 3.8 vs. 16.7 +/- 4.5 pg/mL, P=0.06).. Pre-dialysis FENO is elevated in patients with dialysis-induced hypotension and may be a more reliable than NT as a marker for endogenous NO activity in dialysis patients. Altered NO/ET-1 balance may be involved in the pathogenesis of rebound hypertension and hypotension during dialysis.

Topics: Adult; Aged; Arginine; Endothelin-1; Female; Humans; Hypertension, Renal; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Renal Dialysis

Altered regulation of blood pressure (BP) in hemodialysis patients is associated with increased morbidity and mortality. Regulation of BP is dependent in part on such vasoactive agents as nitric oxide (NO) and endothelin-1 (ET-1). Cytokine-mediated NO synthase activation during dialysis previously has been reported. The purpose of this study is to investigate the relationship between cytokine-mediated activation of the NO and ET-1 systems and BP regulation in hemodialysis patients.. Nine patients with chronic hypotension (predialysis systolic BP < 110 mm Hg, duration > 1 month), nine patients with hypertension (predialysis systolic BP > or = 180 mm Hg), and nine age- and sex-matched normotensive controls were enrolled.. Predialysis NO end product levels in the hypotensive group were greater than in controls (17.63 +/- 5.9 versus 11.06 +/- 2.12 microm/mL; P = 0.01), whereas the hypertensive group showed lower levels (4.76 +/- 2.33 microm/mL; P < 0.01). The hypotensive group had low postdialysis levels (3.45 +/- 1.11 microm/mL; P = 0.01). Predialysis ET-1 levels in the hypotensive and hypertensive groups were greater in comparison to the normotensive group (7.54 +/- 4.52 and 8.95 +/- 3.52 versus 4.41 +/- 0.6 pg/mL; P < 0.01). Postdialysis endothelin levels increased in both the control and hypertensive groups (P < 0.01). Interleukin-1 and tumor necrosis factor-alpha levels increased postdialysis in all groups, but not significantly.. High levels of NO end products in hypotensive patients and low levels in hypertensive patients suggest a critical influence of NO in BP control. In addition, elevated ET-1 levels in hypertensive patients may contribute to systemic vasoconstriction and may suggest vascular dysfunction in this patient population.

Topics: Adolescent; Adult; Blood Pressure; Chronic Disease; Endothelin-1; Female; Humans; Hypertension; Hypotension; Interleukin-1; Male; Middle Aged; Nitric Oxide; Renal Dialysis; Tumor Necrosis Factor-alpha

Both nitric oxide (NO) and endothelin-1 (ET-1) are important mediators in the regulation of vascular tone during pregnancy and preeclampsia. This study was designed to investigate the ET-1-induced hypotensive effect in late pregnant rats (P) and in NO-deprived hypertensive pregnant rats (TP), a model of preeclampsia. From day 13 of pregnancy Wistar rats were fed a control or an N(omega)-nitro-L-arginine-enriched diet. On gestational day 20, mean arterial pressure (MAP +/- SEM, in mm Hg) and heart rate (HR) were measured with a carotid catheter in anesthetized rats after a bolus intravenous injection of several agonists and antagonists. After 7 days of chronic NO synthase inhibition, there was a significant increase in MAP (+45 +/- 3.9, P < .01) and 24-h urinary nitrate excretion was significantly decreased (P < .05). ET-1 bolus injection (0.1 nmol/kg) was rapidly followed by a significant decrease in MAP and a slight delayed increase, with no change in HR. The magnitude of the decrease had significantly dropped off in P (-30 +/- 2.2) as compared to that in TP (-46 +/- 5.1) and in virgin rats (-51 +/- 6.3) (P < .05). In P and TP, in vivo depressor effect was also obtained with sarafotoxin S6c, a specific ETB agonist, and blocked by the specific ETB antagonist BQ-788. After inhibition of cyclooxygenase with acetylsalicylic acid, the ET-1-induced hypotension was not modified either in P or in TP. In conclusion, the present data highlight an enhanced ETB receptor mediated hypotensive effect of ET-1 in anesthetized TP as compared to P. The magnitude of the hypotensive effect of ET-1 observed in TP is of the same order as that in virgin rats and neither NO nor vasodilator prostaglandins seem to be involved in TP. The enhanced hypotensive effect of ET-1 could be a beneficial counter-balancing mechanism in this rat model of preeclamptic pathology where an increased sensitivity to vasoconstrictor agents is generally described.

Topics: Animals; Blood Pressure; Endothelin-1; Female; Hypotension; Nitric Oxide; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; Receptor, Endothelin B; Receptors, Endothelin

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

Endothelin-1 has vasoconstrictor and mitogenic properties and may contribute to the pathogenesis of hypertension by enhancing vasoconstrictor mechanisms. In this study, we investigated the ability of endothelin-1 decrease the hypotensive effects of the vasodilator bradykinin in anesthetized rats. We also studied the effects a two-week oral pre-treatment with losartan (10 mg/kg/day) or enalapril (25 mg/kg/day) on endothelin-1-induced changes in the hypotensive responses to bradykinin. Bradykinin (0.4, 1.6, 6.4, and 25 mcg/kg, i.v.) induced dose-dependent hypotensive responses which were attenuated (P<0.05) by endothelin-1 (2 mcg/kg, i.v.). This effect of endothelin-1 was abolished by the mixed endothelin receptor antagonist N-Acetyl-alpha-[10,11-Dihydro-5H-dibenzo[a, d]cycloheptadien-5-yl]-D-Gly-Leu-Asp-Ile-Ile-Trp (PD145065, 1 mg/kg, i.v.). Endothelin-1 also decreased (P<0.05) the responses to bradykinin in rats pre-treated with losartan, but had no effect in rats pre-treated with enalapril. These results suggest that endothelin-1 may contribute to the development of hypertension by decreasing the responses to bradykinin through a mechanism not involving angiotensin AT(1) receptors, although the inhibition of angiotensin converting enzyme blunted the effect of endothelin-1.

Topics: Administration, Oral; Animals; Blood Pressure; Bradykinin; Dose-Response Relationship, Drug; Enalapril; Endothelin-1; Hypotension; Injections, Intravenous; Losartan; Male; Rats; Rats, Wistar

Submandibular secretory responses to stimulation of the parasympathetic chorda-lingual nerve in anaesthetized cats have been investigated before, during, and after intracarotid infusion of endothelin-1 (ET-1), which reduced blood flow through the gland by 64+/-7%. Stimulation at different frequencies (2, 4, 8, and 16 Hz) evoked a frequency-dependent increase in the flow of submandibular saliva, sodium concentration and output, and output of both potassium and protein. The reduction in submandibular blood flow, which occurred in response to the infusion of ET-1, was associated with a decreased flow of saliva and a diminished output of both sodium and protein. The flow of saliva was linearly related to submandibular blood flow both in the presence and absence of ET-1. It is concluded that submandibular secretory responses to electrical stimulation of the parasympathetic innervation can be significantly attenuated by reducing the blood flow through the gland by ET-1 infusion, just as it is when the blood flow is reduced by hypotension.

Topics: Anesthesia; Animals; Cats; Chorda Tympani Nerve; Electric Stimulation; Endothelin-1; Hypotension; Lingual Nerve; Male; Parasympathetic Nervous System; Regional Blood Flow; Saliva; Submandibular Gland

Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative stress is endotoxic shock. Moreover, HO-1 is markedly induced in multiple organs after the administration of endotoxin (lipopolysaccharide [LPS]) to mice.. To determine the role of HO-1 in endotoxemia, we administered LPS to mice that were wild-type (+/+), heterozygous (+/-), or homozygous null (-/-) for targeted disruption of HO-1. LPS produced a similar induction of HO-1 mRNA and protein in HO-1(+/+) and HO-1(+/-) mice, whereas HO-1(-/-) mice showed no HO-1 expression. Four hours after LPS, systolic blood pressure (SBP) decreased in all the groups. However, SBP was significantly higher in HO-1(-/-) mice (121+/-5 mm Hg) after 24 hours, compared with HO-1(+/+) (96+/-7 mm Hg) and HO-1(+/-) (89+/-13 mm Hg) mice. A sustained increase in endothelin-1 contributed to this SBP response. Even though SBP was higher, mortality was increased in HO-1(-/-) mice, and they exhibited hepatic and renal dysfunction that was not present in HO-1(+/+) and HO-1(+/-) mice. The end-organ damage and death in HO-1(-/-) mice was related to increased oxidative stress.. These data suggest that the increased mortality during endotoxemia in HO-1(-/-) mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.

Topics: Animals; Endothelin-1; Endotoxemia; Female; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hypotension; Lipopolysaccharides; Lung; Membrane Proteins; Mice; Mice, Inbred BALB C; Mortality; Multiple Organ Failure; Oxidative Stress; RNA, Messenger

Endothelin-1 (ET-1), a novel vasoconstrictor, possibly plays a role in the mediation of ischemia/reperfusion (I/R) injury. Tacrolimus (FK506) and cyclosporin A (CsA) were reported to maintain tissue microcirculation of the liver subjected to I/R. This study investigated the effects of these immunosuppressants on intestinal I/R in terms of intestinal tissue microcirculation associated with ET-1.. Male S-D rats were pretreated twice with FK506 (0.2 mg/kg), CsA (10 mg/kg) or only saline solution (0.5 mL). The tissue microcirculation in the control was reduced after I/R (29% +/- 10%) accompanied by hypotension, increased tissue ET-1 expression (25.0% +/- 6.4% to 67.9% +/- 5.0% 60 minutes after reperfusion), and increased ET-1 level in the portal blood (3.4 +/- 0.9 to 23.6 +/- 6.1 pg/mL). FK506 suppressed ET-1 expression (27.3% +/- 5.2%, 4.1 +/- 2.2 pg/mL), maintained microcirculation (96% +/- 16%), and blood pressure, reduced histologic damage, and improved survival. CsA had a similar but weaker effect compared with FK506. An additional experiment was performed with BQ485Na (BQ), an ETA receptor antagonist, to evaluate the genuine role of ET-1. BQ showed almost the same effects as FK506.. FK506 and CsA, particularly the former, maintain microcirculation and protect the tissue from I/R injury by suppressing the production and release of ET-1.

Topics: Animals; Azepines; Blood Pressure; Cyclosporine; Endothelin Receptor Antagonists; Endothelin-1; Hypotension; Immunosuppressive Agents; Intestine, Small; Ischemia; Male; Microcirculation; Oligopeptides; Portal System; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Reperfusion Injury; Survival Rate; Tacrolimus; Time Factors

1. This study attempts to investigate if endogenous nitric oxide (NO) can modulate the eicosanoid-releasing properties of intravenously administered endothelin-1 (ET-1) in the pulmonary and circulatory systems in the guinea-pig. 2. The nitric oxide synthase blocker N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A2 (TxA2) stimulated by ET-1, the selective ET(B) receptor agonist IRL 1620 (Suc-[Glu9,Ala11,15]-ET-1(8-21)) or bradykinin (BK) (5, 50 and 50 nM, respectively, 3 min infusion) in guinea-pig isolated and perfused lungs. 3. In anaesthetized and ventilated guinea-pigs intravenous injection of ET-1 (0.1-1.0 nmol kg(-1)), IRL 1620 (0.2-1.6 nmol kg(-1)), BK (1.0-10.0 nmol kg(-1)) or U 46619 (0.2-5.7 nmol kg(-1)) each induced dose-dependent increases in pulmonary insufflation pressure (PIP). Pretreatment with L-NAME (5 mg kg(-1)) did not change basal PIP, but increased, in L-arginine sensitive manner, the magnitude of the PIP increases (in both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg(-1), respectively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg(-1)). 4. The increases in PIP induced by ET-1, IRL 1620 (0.25 and 0.4 nmol kg(-1), respectively) or U 46619 (0.57 nmol kg(-1)) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment with L-NAME (5 mg kg(-1); i.v. raised basal MAP persistently and, under this condition, subsequent administration of ET-1 or IRL 1620, but not of U-46619, induced hypotensive responses which were prevented by pretreatment with the cyclo-oxygenase inhibitor indomethacin. 5. Thus, endogenous NO appears to modulate ET-1-induced bronchoconstriction and pressor effects in the guinea-pig by limiting the peptide's ability to induce, possibly via ET(B) receptors, the release of TxA2 in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it would seem that these eicosanoid-dependent actions of ET-1 in the pulmonary system and on systemic arterial resistance in this species are physiologically dissociated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Bradykinin; Bronchoconstriction; Cyclooxygenase Inhibitors; Drug Synergism; Eicosanoids; Endothelin-1; Endothelins; Enzyme Inhibitors; Female; Guinea Pigs; Hypotension; In Vitro Techniques; Indomethacin; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oligopeptides; Peptide Fragments; Perfusion; Piperidines; Thromboxane A2; Vasoconstrictor Agents

Purified human cross-linked hemoglobin (alpha alpha Hb) as well as recombinant human hemoglobin is undergoing clinical trials in the setting of acute blood loss and perioperative hemodilution. We have previously demonstrated that in rabbits with circulating plasma Hb, such as alpha alpha Hb, infusion of endotoxin (LPS) impairs myocardial contractility which results in hypotension, tissue hypoperfusion and increased mortality. The untoward cardiovascular effects occurring after the combined infusion of LPS and alpha alpha Hb in this model are similar to those reported for other agents that inhibit nitric oxide (NO) availability. To determine if the deleterious effects of alpha alpha Hb and LPS were species specific, we performed similar studies in rats. Anesthetized Sprague-Dawley rats received LPS (4 mg/kg or 40 mg/kg) alone or in combination with alpha alpha Hb (0.7 g/kg). Mean arterial blood pressures (MAP) increased in the group that received alpha alpha Hb alone (105 +/- 8 to 120 +/- 7 mm Hg, p = 0.2) and a decrease was noted in the groups that received low dose LPS (4 mg/kg, p = 0.5) and high dose LPS (40 mg/kg, p = 0.016). MAP in rats treated with the LPS at either dose combined with alpha alpha Hb remained unchanged. Levels of urine nitrite, which was measured as a surrogate marker for plasma NO, were significantly decreased at 2 hr in groups that received the combination of alpha alpha Hb and LPS at 4 mg/kg (p = 0.022) and 40 mg/kg (p = 0.003). No significant decrease was observed in animals treated only with alpha alpha Hb (p = 0.21) or LPS (4 mg/kg; p = 0.78 and 40 mg/kg; p = 0.65). Survival was evaluated during 72 hr in animals that were infused with high dose LPS (40 mg/kg) alone or in combination with alpha alpha Hb and then allowed to recover. The survival of rats treated with LPS alone or the combination was 29% at the end of 24 hr and was 100% for rats receiving only alpha alpha Hb. The data suggest that the toxicity of alpha alpha Hb appears to be a species specific phenomenon.

Topics: Anesthesia; Animals; Blood Pressure; Drug Synergism; Endothelin-1; Endotoxins; Hemoglobins; Humans; Hypotension; Lipopolysaccharides; Male; Nitric Oxide; Nitrites; Rabbits; Rats; Rats, Sprague-Dawley

Endothelin-1 (ET-1) as a potent vasoconstrictor, has mitogenic and inotropic properties, stimulates the renin-angiotensin-aldosterone system and sympathetic nervous system. The results of recent studies suggest that overall hemodynamic effects of ET-1 may play a part in the control of blood pressure and the pathophysiology of hypertension. Several investigators have invoked increase level of ET-1 in human essential hypertension but the results of studies concerning hypertensive patients with normal renal function have shown that they have similar concentrations of ET-1 to those in normotensives. To establish whether ET-1 may elevate of blood pressure, the value of plasma ET-1 activity was determined in peripheral blood in 101 patients with essential hypertension. There was no significant difference between in mean level of ET-1 in patients with essential hypertension and in control group. The plasma ET 1 was significantly higher in patients with severe hypertension than that of patients with mild and moderate hypertension, and in patients with severe hypertension there was a correlation between the level of ET-1 and microalbuminuria. There was no correlation between the plasma ET-1 level and systolic blood pressure and diastolic blood pressure in the patients with essential hypertension as a whole, not was there any correlation between ET-1 and noradrenaline, aldosterone level and renin plasma activity.

Topics: Adult; Aldosterone; Endothelin-1; Female; Humans; Hypotension; Male; Middle Aged; Norepinephrine; Renin; Severity of Illness Index

This study was designed to compare the effect of fluid percussion brain injury (FPI) on the hypotensive cerebrovascular response in newborn and juvenile pigs as a function of time postinsult and to determine the role of endothelin-1 (ET-1) in any age-dependent differences in hypotensive cerebrovascular regulation after injury. Ten minutes of hypotension (10-15 ml blood/kg) decreased mean arterial blood pressure uniformly in both groups ( approximately 45%). In the newborn, hypotensive pial artery dilation (PAD) was blunted within 1 h, remained diminished for at least 72 h, but was resolved within 168 h postinjury (66 +/- 4, 69 +/- 4, 71 +/- 4, and 64 +/- 4% inhibition at 1, 4, 8, and 72 h post-FPI). During normotension, regional cerebral blood flow (rCBF) was decreased by FPI, and hypotension further reduced the already decremented rCBF for at least 72 h. Cerebrospinal fluid (CSF) ET-1 was increased from 26 +/- 4 to 206 +/- 25 pg/ml within 72 h post-FPI, whereas an ET-1 antagonist partially restored impaired hypotensive PAD and altered hypotensive rCBF. In contrast, hypotensive PAD and altered CBF were only inhibited for 4 h post-FPI in the juvenile (56 +/- 3 and 34 +/- 4% inhibition at 1 and 4 h post-FPI). CSF ET-1 was only increased from 27 +/- 4 to 67 +/- 9 pg/ml at 4 h, whereas the concentration returned to preinjury value by 8 h post-FPI. ET-1 antagonism similarly partially restored impaired hypotensive PAD and altered hypotensive rCBF. These data show that FPI disturbs cerebral autoregulation during hypotension both to a greater magnitude and for a longer duration in the newborn than in the juvenile. These data suggest that the greater FPI-induced ET-1 release in the newborn could contribute to age-dependent differences in impaired hypotensive cerebral autoregulation after FPI.

Topics: Aging; Animals; Animals, Newborn; Arteries; Blood Pressure; Brain Injuries; Cerebrovascular Circulation; Endothelin-1; Female; Homeostasis; Hypotension; Male; Pia Mater; Swine; Time Factors; Vasodilation; Wounds, Nonpenetrating

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

To investigate the possible involvement of endogenous nitric oxide (NO) in acute hypotension during maintenance hemodialysis, we measured the plasma concentration of the nitrate anion NO3-, a stable metabolite of NO, in 19 patients undergoing hemodialysis. We analyzed heart rate variability to estimate the relationship between autonomic nervous activity and NO production, low-frequency/high-frequency components (L/H) as a parameter of cardiac sympathetic activity, and high-frequency power as a parameter of cardiac vagal activity. Six patients developed severe hypotension (a change in mean blood pressure during dialysis > or = 20 mm Hg), four patients developed mild hypotension (a change in mean blood pressure < or = 19 mm Hg and > or = 1 mm Hg), and nine patients did not develop hypotension. The plasma levels of NO3- before dialysis were markedly elevated in the severely hypotensive group compared with the patients who showed no hypotension (566+/-122 micromol/L v 133+/-38 micromol/L; P < 0.01), and this difference disappeared midhemodialysis and after hemodialysis. The plasma concentration of NO3- before dialysis was significantly associated with both the change in mean blood pressure during dialysis (r= -0.735; P = 0.003) and the mean blood pressure after dialysis (r = -0.675; P = 0.0015). The L/H ratio was inhibited before or after dialysis in the severely hypotensive group compared with the nonhypotensive group, and hypotension during dialysis was correlated with the inhibited L/H ratio before (r = 0.784; P = 0.001) or after (r = 0.822; P = 0.001) dialysis. Plasma NO3- concentrations were correlated with the L/H ratio before (r = -0.553; P = .014) or after (r = -0.546; P = 0.015) dialysis. These results suggest that inhibited sympathetic activity is one of the causes of acute hypotension during dialysis, and the enhanced production of NO is involved in this inhibition of the sympathetic activity in patients having a hypotensive episode during dialysis. The plasma concentration of NO3- before dialysis may be a predictor of the risk of hypotension during dialysis in patients with end-stage renal disease.

Topics: Acute Disease; Anions; Blood Pressure; Cyclic GMP; Endothelin-1; Female; Heart Rate; Humans; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Renal Dialysis; Sympathetic Nervous System

Hypertensive pregnant rats with inhibition of NO synthase are frequently considered as model of pre-eclampsia with proteinuria, hypertension and elevated endothelin (ET-1) blood levels. We describe here the cardiovascular in vivo effects of ET-1 in this rat model since ET-1 and NO are both important vasoactive mediators in uteroplacental circulation. From day 13 of gestation 2 groups of Wistar female rats were fed control (C) or nitroarginine enriched diet (0.063%, Treated: T). On gestational day 20 mean arterial pressure (MAP, mmHg) was measured via a carotid catheter in pentobarbital (60 mg/kg) anesthetized rats. After chronic NO synthase inhibition hypertension develops; MAP on day 20: 158 +/- 2.2 in T and 113 +/- 2.2 in C, p < 0.001. ET-1 bolus injection (0.1 nmol/kg) is rapidly followed by a decrease in blood pressure significantly more important in T: -46 +/- 5.1 than in C: -30 +/- 2.2. In vivo depressor effect is blocked by the specific antagonist BQ-788. After inhibition of cycloxygenase with acetylsalicylic acid (27 mumol/kg, 30 min before) the hypotension is not modified. Since NO and PGI2 productions are not expected in our conditions, vasodepressor effect can be explained by an endothelial hyperpolarazing factor (EDHF). In conclusion in vivo ET-1 hypotensive effects in pregnant rats are mediated by ETB receptors and more pronounced in hypertensive NO-deprived animals.

Topics: Animals; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Hypotension; Nitric Oxide Synthase; Oligopeptides; Piperidines; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar

The effects of sterile meningitis on endothelin-1 (ET-1) and big ET-1 concentrations during hypotension and hypertension were studied in the cerebrospinal fluid and plasma of newborn piglets. Cerebrospinal fluid was obtained via cisterna magna puncture, and blood was obtained from the sagittal sinus vein and left subclavian artery. The study group consisted of 14 newborn piglets injected with 0.5 mL heat-killed group B streptococcus (GBS) (10(9) colony forming unit (cfu) equivalents), into the right cerebral lateral ventricle; the control group consisted of 10 newborn piglets injected with sterile normal saline, in a similar fashion. Hypotension (mean arterial blood pressure (MABP) 20-59 mmHg; 1 mmHg = 133.3 Pa) and hypertension (MABP 110-140 mmHg) were induced 1.5-2 h apart in random sequence in each animal, by inflating balloon-tipped catheters placed at the aortic root and descending aorta, respectively. Cerebral blood flow (CBF) was measured using radiolabeled microspheres, 15 min before and after injection of GBS or saline (normotension), during the hypotension and hypertension episodes, and during recovery normotension, immediately prior to cerebrospinal fluid and blood sampling. ET-1 and big ET-1 concentrations (pg/mL) were measured using radioimmunoassay kits. The combined effect of induced sterile meningitis and induced hypotension resulted in a significant rise in the concentration of cerebrospinal fluid ET-1 (control, 5.1 +/- 0.1; GBS, 9.3 +/- 0.2 pg/mL; p < 0.01), cerebrospinal fluid big ET-1 (control, 0; GBS, 18.1 +/- 2.7 pg/mL; p < 0.01), and sagittal sinus (cerebrovascular) big ET-1 (control, 15.5 +/- 4.2; GBS, 47.5 +/- 9.6 pg/mL; p < 0.01). In contrast, the combined effect of induced sterile meningitis and induced hypertension resulted in a marked elevation in cerebrovascular ET-1 concentrations (control, 9.5 +/- 0.9; GBS, 28.5 +/- 6.1 pg/mL; p < 0.01), with no significant change in cerebrospinal fluid concentrations. In addition, cerebrovascular production of ET-1 increased dramatically during hypertension in the GBS group (control, 0; GBS, 161.7 +/- 13.2 pg.min-1.100 g-1; p < 0.001), and was maintained during the recovery period (133.7 +/- 10.8 pg.min-1.100 g-1). Cerebrovascular ET-1 concentrations correlated significantly with total CBF and MABP in both groups of animals (control, r = 0.49, p < 0.002; GBS, r = 0.64, p < 0.0001), but the response was of a much greater magnitude in the GBS group. There was an inverse relationship between

Topics: Animals; Animals, Newborn; Blood Pressure; Brain Chemistry; Cerebrospinal Fluid Proteins; Cerebrovascular Circulation; Endothelin-1; Endothelins; Hypertension; Hypotension; Leukocyte Count; Meningitis, Aseptic; Protein Precursors; Streptococcus agalactiae; Swine; Vascular Resistance

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