Endothelin is a recently isolated 21 amino acid peptide with vasoconstrictor activity. It seems to be part of the "hormonal" production by the vascular endothelium and might play a key role in the regulation of vasomotricity. The principal property of endothelin is that it induces an intense and prolonged arterial and venous contraction. Endothelin is secreted by endothelial cells under the influence of various stimuli (thrombin, adrenaline, shearing stress, hypoxia, etc.), then binds to specific membrane receptors thereby increasing the intracellular free calcium concentration. Endothelin has many other vascular and extravascular properties: it has positive inotropic and chronotropic effects, increases renal vascular resistances and reduces the glomerular filtration rate, contracts bronchial and gastrointestinal smooth muscle, induces proliferation of the vascular smooth muscle cells as well as that of fibroblasts and glomerular mesangial cells. Compared with experimental data in animals, human data are still scantly. Plasma endothelin concentration rises in acute renal failure and in chronic renal failure treated by dialysis, diabetes mellitus, essential arterial hypertension, pre-eclampsia and asthma. The development of specific antagonists and endothelin in synthesis inhibitors should soon enable us to specify the modes of regulation of endothelin production before considering applications to therapy.

Animals↗

PubMed1993

Variations in plasma endothelin concentrations during coronary spasm.

A provocation test using methylergometrine was carried out in patients with a normal coronary angiogram. Patients exhibiting spasm (Group 1, n = 6) were compared with non-spasm patients (Group II, n = 6). The endothelin concentration was determined in all cases at 0800, 1100, 1400, 1600, 1900, 2100, 2300 and 0100 h. The provocation test was carried out at 1700 h and an additional determination was made during spasm if the test was positive. The two groups had similar clinical characteristics and did not differ in terms of risk factors. Apart from the value recorded during spasm, the endothelin plasma level was significantly higher in Group I. A time x measurement interaction was noted in both groups, with a higher endothelin level in the morning. The endothelin level increased significantly during spasm in Group I patients. The plasma concentration of endothelin appeared to be higher in the basal state and during spasm in patients exhibiting spastic angina.

Adult↗

PubMed1993

Glomerular atrial natriuretic factor receptors in experimental congestive heart failure.

Heart failure is usually characterized by a relative insensitivity to atrial natriuretic factor (ANF). Downregulation of ANF receptors has been reported but remains controversial. Renal response to ANF infusion, glomerular ANF receptors, and guanosine 3',5'-cyclic monophosphate (cGMP) production have been studied in rabbits with congestive heart failure (CHF) after traumatic aortic regurgitation and abdominal aortic stenosis. Diuresis and natriuresis induced by ANF infusions were significantly decreased in CHF animals. Plasma cGMP was higher in CHF rabbits before ANF administration than in controls (37.6 +/- 7.2 vs. 17.1 +/- 3.9 pmol/ml, P < 0.02) and increased to a same level after ANF in both groups (48.8 +/- 4.2 vs. 52.5 +/- 2.8 pmol/ml, NS). No difference was found in glomerular ANF receptor density (436 +/- 54 vs. 425 +/- 57 fmol/mg protein, NS) nor in affinity between the two groups (dissociation constant; 240 +/- 24 vs. 347 +/- 49 pM, NS). Moreover, in vitro glomerular cGMP production in response to exogenous ANF was preserved. In conclusion, despite a blunted renal response to ANF in vivo, glomerular ANF receptors were unchanged in this model, and no defect in cGMP production in response to ANF was found. This suggests the existence of an intracellular defect beyond the second messenger.

Animals↗

PubMed1993

Mechanisms of isoproterenol-induced atrial natriuretic peptide release from superfused rabbit atria.

The mechanisms for isoproterenol-induced atrial natriuretic peptide (ANP) release were studied in superfused rabbit sliced right atria. Addition of 1 microM norepinephrine to this preparation induced a significant monophasic twofold rise in ANP release. This effect was abolished by 1 microM propranolol and mimicked by 1 microM isoproterenol. Furthermore, addition of 200 microM 3-isobutyl-1-methylxanthine (IBMX) to the superfusing medium potentiated isoproterenol effect 31%. In addition, superfusion of slices with 0.5 mM N6,2-O-dibutyryladenosine 3',5'-cyclic monophosphate [(Bu)-2cAMP] enhanced ANP release in the same manner as the beta-agonist. After isoproterenol stimulation, adenosine 3',5'-cyclic monophosphate (cAMP) concentration in effluents increased significantly. ANP secretory response to isoproterenol was unaffected by extracellular calcium concentration or 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). Finally, 10 microM indomethacin significantly reduced isoproterenol-stimulated ANP release. It is concluded that 1) norepinephrine-induced ANP release is mediated by its beta-agonist activity, 2) isoproterenol-stimulated release appears to be mediated by cAMP, 3) isoproterenol effect does not require extracellular calcium, and 4) prostaglandins may be involved in this beta-adrenergic effect.

Animals↗

PubMed1993

[Changes in plasma endothelin during coronary spasm].

The role of endothelin, a powerful vasoconstrictor, was studied in coronary spasm. A methylergonovine stress test was performed in patients with normal coronary angiography. Patients who developed spasm (Group I, n = 6) were compared with those who did not (Group II, n = 6). Plasma endothelin was measured at 8, 11 a.m., 2 p.m., 4, 7, 9, 11 p.m. and 1 a.m. The stress test was carried out at 17 hours and an additional endothelin measurement was performed during spasm in positive cases. The clinical characteristics of the two groups were comparable especially with regards to cardiovascular risk factors. Except for the value recorded during coronary spasm, the plasma endothelin levels were significantly higher in the group with coronary spasm. A time-dependent variation was observed in both groups with higher endothelin levels in the morning. In group I the plasma endothelin levels were higher under basal conditions and during spasm in patients with spastic angina.

Adult↗

PubMed1993

Endothelin-1 secretion by human gallbladder epithelial cells in primary culture.

BACKGROUND: The three isoforms of endothelin (ET), ET-1, ET-2, and ET-3 are potent contractile agonists for smooth muscle in a wide variety of tissues including the gallbladder. There is increasing evidence that endothelin acts in a paracrine fashion, however, its cell source in the gallbladder is unclear. EXPERIMENTAL DESIGN: To examine the production of ET by gallbladder and bile duct epithelium. RESULTS: We show that human gallbladder epithelial cells in primary culture secrete endothelin. ET release was time-dependent, and intracellular ET was negligible, indicating de novo synthesis. Secretion was increased by physiologic concentrations of cholecystokinin. Epithelial cells lining hepatic cysts in primary culture also released ET, suggesting that the intrahepatic, as well as the extrahepatic biliary epithelium is a source of this cytokine. High performance liquid chromatography separation of the conditioned medium from both cell types showed a single peak corresponding to that of ET-1. In vivo, ET-1 was present in hepatic cyst fluid, but was not detectable in gallbladder or choledochal bile. On tissue sections, both intrahepatic and extrahepatic bile duct epithelial cells were labeled with an anti-"big" ET-1 polyclonal antibody. CONCLUSIONS: These results suggest that ET-1 is locally produced in the biliary tract and by a paracrine route, could play a role in choledochal motility and gallbladder contraction.

Bile Ducts↗

PubMed1993

[Neurohormonal profile in aortic valve stenosis].

The authors studied the responses of the main systems of sympathetic and hormonal regulation in valvular aortic stenosis, a special model of dissociation between arterial pressure and left ventricular function. The series comprised 14 patients with an average age of 70 +/- 9 years without diuretic therapy presenting with pure calcific aortic stenosis without other valvular or coronary disease. All were in sinus rhythm; 5 were taking an angiotensin converting enzyme inhibitor. Plasma concentrations of endothelin 1, atrial natriuretic factor (ANF), arginine vasopressin (AVP), catecholamines, plasma renin activity (PRA), angiotensin II and aldosterone were measured in resting, fasting patients, by blood samplings from a peripheral vein immediately before cardiac catheterisation. The results were compared with the severity of the aortic stenosis (aortic valve area greater or less than 0.7 cm2), the ratio of left ventricular work/myocardial mass (greater or less than 0.6) and treatment (with or without ACE inhibitors). Catecholamine levels were much higher in severe aortic stenosis (noradrenaline: 579 +/- 66 pg/ml when valve surface area > 0.7 cm2 versus 900 +/- 92 pg/ml when valve surface area < 0.7 cm2; p < 0.01). Endothelin -1 and AVP concentrations were normal. Whereas PRA was normal, aldosterone levels were increased in patients without treatment by ACE inhibitors. This treatment did not, however, normalise the noradrenaline levels. The increase in ANF concentration was large when left ventricular work decreased with respect to myocardial mass (190.8 +/- 42.3 pg/ml if W/M was decreased versus 82.7 +/- 15.4 pg/ml when W/M was normal): this could be related to the degree of left ventricular hypertrophy.

Aged↗

PubMed1993

[Microalbuminuria before and one month after extracorporeal lithotripsy. First results].

Extracorporeal shock wave lithotripsy represents extraordinary progress for the treatment of urinary calculi. The apparent aggressivity of this technique leads to investigating whether it may have an impact on the renal parenchyma, as was suggested by many works, especially with radionuclide explorations. Microalbumin assays before and about one month after lithotripsy show an iatrogenic pathological increase in levels in some cases, especially after long, intensive sessions of treatment, whether the lithotripter used was of the shock-wave or piezoelectric-wave type. When lithotripty was performed with a piezoelectric-wave device, the increase in microalbumin is related to the "cumulative" factor, which is in turn related to the power, frequency (per second) and length of shots. More extensive investigations and, most importantly, investigations over a longer period are necessary to confirm or invalidate the results of this first study, to establish the frequency of cases where this abnormality appears, whether it can last long, and how far it can be predictive of the parenchymal lesions and of their long-term impact.

Albuminuria↗

PubMed1992

Thromboxane and prostacyclin metabolites in pulmonary hypertension.

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Endothelins↗

PubMed1992

[Atrial natriuretic factor in heart insufficiency].

The atrial natriuretic factor is a peptide with vasodilator and natriuretic properties which is synthesized and released by atrial myocytes. In patients with chronic heart failure the ventricles contribute to the synthesis of this peptide, so that its plasma concentration rises in proportion to the heart filling pressure. The atrial natriuretic factor, therefore, seems to be a good biological marker of functional and haemodynamic severity of heart failure. However, the weight of this factor in the neuro-hormonal balance has not yet been fully evaluated, owing to the usual attenuation of its biological effects. This, and the necessity of continuous parenteral administration limits, for the moment, its therapeutic applications. Inhibitors of the enzyme involved in its metabolism are being tested, but only preliminary results are available in humans.

Atrial Natriuretic Factor↗

PubMed1992

Atrial natriuretic peptide during water deprivation or hemorrhage in rats. Relationship with arginine vasopressin and osmolarity.

The concentrations of atrial natriuretic peptide (ANP) in atria, hypothalami and plasma were investigated in relation to the variations of the plasma endogenous immunoreactive arginine vasopressin (Ir-AVP) during water deprivation or hemorrhage in normal conscious Wistar rats. Furthermore, the in vitro and in vivo effect of extracellular hyperosmolarity on ANP release from right atrium and hypothalamus was examined. Water deprivation elevated circulating immunoreactive ANP (Ir-ANP: pg/ml) to 153 +/- 7 (24 h); 174 +/- 1 (48 h) from the control level (109.6 +/- 7.8). This increase in Ir-ANP concentration which correlated with atrial (r = -0.93) or hypothalamic (r = -0.87) Ir-ANP content decrease, was associated with significantly enhanced levels of plasma Ir-AVP, plasma sodium, osmolarity and hematocrit. An acute volume depletion by hemorrhage significantly reduced plasma Ir-ANP (67 +/- 8.4 pg/ml) from the sham operated level (140 +/- 18 pg/ml). Plasma Ir-AVP was elevated dramatically (207.4 +/- 53.4 pg/ml) compared with the sham operated level (8.8 +/- 2.6 pg/ml). These results, indicating the lack of correlation between plasma Ir-ANP and Ir-AVP in vivo, suggest that the ANP secretion, which is regulated mainly by plasma volume, may be modulated by a change in plasma osmolarity. Extracellular hyperosmolarity stimulated the ANP release from superfused sliced normal rat atria and hypothalami.

Animals↗