Endothelin in renal disease: role of endothelin antagonists.
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Acute Kidney Injury↗
Biomedical subjects
R R Wenzel
Publications and source records attributed to R R Wenzel.
[Acute hemolysis with subsequent life-threatening pancreatitis in hemodialysis. A complication which is not preventable with current dialysis equipment].
A retrospective study was undertaken of 14 patients (eleven men, three women; mean age 52 [33-68] years in whom haemolysis had occurred during chronic haemodialysis (n = 12) or haemofiltration (n = 2). The haemolysis was of mechanical cause in eight patients, by an osmotic mechanism in one, and of unknown cause in five. Cardinal symptoms were nausea in 14 patients, abdominal pain in nine, vomiting in eight and raised blood pressure in ten. The plasma was discoloured in all patients and there was also an increase in free haemoglobin (110-2400 mg/dl) and (or) lactate dehydrogenase (311-7403 U/l). In all of eleven patients in whom it was measured the activity of serum amylase and (or) lipase was more than doubled (to 73-2400 U/l and 473-16,740 U/l, respectively). All patients were treated symptomatically, three had a blood exchange, two others plasma separation. Eight patients recovered within a few days, but necrotizing pancreatitis developed in six, three of whom died while two had permanent sequelae. This series shows that dialysis-induced acute haemolysis can cause life-threatening pancreatitis. Narrowings within the extracorporeal circuit, not always recognized in current dialysis equipment, are the most frequent cause of the mechanical haemolysis.
Acute Disease↗
Endothelin receptor antagonists inhibit endothelin in human skin microcirculation.
Endothelin is a potent vasoconstrictor peptide produced by endothelial cells, but its role in physiology and disease is uncertain. We investigated the influence of the endothelin-A-selective receptor antagonist PD 147953 and the nonselective endothelin receptor antagonist PD 145065 on the effects of endothelin-1 and endothelin-3 in the skin microcirculation of healthy volunteers, using laser Doppler flowmetry. A double injection model was developed, allowing simultaneous injection of two substances, ie, agonist and antagonist or saline. The injection of saline led to a well-defined vasodilation at the injection site (maximum increase, from 19 +/- 2 to 97 +/- 15 perfusion units at 6 minutes; P < .001; n = 10). Endothelin-1 (10(-12) mol) decreased blood flow (difference from saline control, -79 +/- 14 perfusion units; P < .001; n = 11) within the injection wheal (diameter, 4 to 5 mm), while endothelin-3 had no effect. In the surrounding area (at 8 mm from the injection site), both endothelin-1 (+116 +/- 32 perfusion units; P < .001; n = 11) and endothelin-3 (+59 +/- 16 perfusion units; P < .001; n = 11) markedly increased blood flow. Both endothelin receptor antagonists slightly increased blood flow (maximum difference from control, +56 +/- 18 [PD 147953] and +31 +/- 10 [PD 145065] perfusion units; P < .05; n = 8) and inhibited endothelin-1-induced (P < .01) vasoconstriction. The vasoconstriction to norepinephrine was not affected by the endothelin antagonist PD 147953. Endothelin-1- and endothelin-3-induced vasodilation in the surrounding area were also inhibited by both endothelin antagonists or by lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Endothelin and endothelin antagonists: potential role in cardiovascular and renal disease.
Endothelin-1 is a recently discovered peptide mainly released from endothelial cells. Hypoxia and ischemia as well as numerous factors such as angiotensin 11, thrombin and transforming growth factor beta 1 stimulate the formation of the peptide. On the other hand the synthesis of endothelin is inhibited by nitric oxide and atrial natriuretic peptide via the formation of cyclic guanosine monophosphate. Released from endothelial cells endothelin-1 mediates transient vasodilation followed by a profound and longlasting vasoconstriction. Endothelin is also a mitogen for smooth muscle proliferation. Endothelins exert their biological effects via activation of specific receptors. Two different receptors have been cloned from mammalian tissues (ET(A) and ET(B) receptors). On vascular smooth muscle cells both receptors mediate contractions. Endothelial cells only express ET(B) receptors linked to the formation of nitric oxide and/or prostacyclin formation. Increased plasma concentrations of endothelin-1 have been described in a variety of diseases such as pulmonary hypertension, arteriosclerosis, renal failure, acute coronary syndromes, heart failure, migraine and vascular diseases. Recently an increasing number of endothelin receptor antagonists have been synthetized, which have been shown to inhibit endothelin-mediated vasoconstriction. Clinical studies are now ongoing to elucidate the pathophysiologic role of endothelin and the potential benefit of the blockade of the system in different disease states.
Animals↗
Endothelin in cardiovascular control: the role of endothelin antagonists.
Endothelin (ET) is a potent vasoconstrictor associated with various cardiovascular diseases. ET mediates its effects through ET receptors on vascular smooth muscle cells as well as on the vascular endothelium. Furthermore, a neurotransmitter role for ET has been suggested on the basis of experimental and human in vivo studies. ET antagonists are potent tools for studying the effects of ET and its receptors. They have been widely used in vitro and in experimental models of cardiovascular disease, where ET levels are elevated and reactivity to ET is altered. Promising clinical trials in hypertension, coronary artery disease, and congestive heart failure are discussed in this review. Different forms of renal failure are associated with markedly increased ET levels, and ET antagonists experimentally improve renal function in these models. Extrapolating from experimental and first clinical experience, ET antagonists could be useful in the treatment of hypertension, coronary artery disease, congestive heart failure, and renal failure, especially in combination with other drugs, ie, angiotensin converting enzyme inhibitors. The inhibition of ET-induced stimulation of nociception allows for speculation that ET antagonists might even have analgesic properties.
Animals↗