Endothelin stimulation

Stasch, J. P., Hirth-Dietrich, C., Kazda, S., and Neuser, D., Endothelin stimulates release of atrial natriuretic peptides in vitro and in vivo. Life Sci. 45,869-875 (1989). 

Simonson MS, Wann S, Mene P, DubyakM, KesterY, NakazatoY, Sedor JR, Dunn MJ. Endothelin stimulates phospholipase C, Na/H exchange, c-fos expression and mitogenesisin rat mesangial cells. J Clin Invest 1989 83 708-712. 

Komuro I, Kurihara H, Sugiyama T, Takaku F, Yazaki Y (1988) Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS lett 238 249-252... 

Nontraditional Hormones. Novel hormones identified ia cardiovascular tissue have profound effects on maintenance of blood pressure and blood volume ia mammals. Atrial natriuretic hormone (ANH) is a polypeptide hormone secreted from the atria of the heart. When the cardiac atrium is stretched by increased blood volume, secretion of ANH is stimulated ANH ia turn increases salt and water excretion and reduces blood pressure (6). Endothelin is a polypeptide hormone secreted by endothehal cells throughout the vasculature. Although endothelin is released into the circulation, it acts locally in a paracrine fashion to constrict adjacent vascular smooth muscle and increase blood pressure (7). 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

In the interstitium, angiotensin II induces proliferation of mesangial cells and fibroblasts and the synthesis of collagen and other matrix molecules by these cells via the ATI receptor. Moreover, by the concomitant stimulation of chemoattractant cytokines, inflammation is induced. These processes are mediated by endothelin, transforming growth factor(3, and reactive oxygen species, and finally lead to interstitial fibrosis and glomerulosclerosis observed in hypertension and diabetes. 

ESP Eosinophil stimulation promoter ESR Erythrocyte sedimentation rate e.s.r. Electron spin resonance ET, ET-1 Endothelin, -1 ETYA Eicosatetraynoic acid... 

Endothelin-1, one of the most potent physiologic vasoconstrictors, is an important contributor to HF pathophysiology.9 Endothelin-1 binds to two G-protein coupled receptors, endothelin-A (ET-A) and endothelin-B (ET-B). Endothelin-A receptors mediate vasoconstriction and are prevalent in vascular smooth muscle and cardiac cells. Endothelin-B receptors are expressed on the endothelium and in vascular smooth muscle, and receptor stimulation mediates vasodilation. Levels of ET-1 correlate with HF functional class and mortality. 

Interleukin-6 (IL-6) is a small polypeptide with a molecular mass of 26 kDa (see Table 2). IL-6 can be induced in various cell types, including fibroblasts, macrophages/monocytes, epithelial cells, T cells, B cells, and diverse tumor cells (L4). TNF, IL-1, and LPS can stimulate IL-6 gene expression in macrophages/monocytes and fibroblasts. In vivo studies showed that systemic administration of TNF, LPS, and IL-1 was followed by a rapid induction of circulating IL-6 (B49, J2). Also, endothelin (ET) at concentrations observed pathophysiolog-ically may trigger production of IL-6 (Ml7). 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Constriction Angiotensin II Sympathetic stimulation Endothelin Adenosine Vasopressin Prostaglandin blockade Dilatation Angiotensin II blockade Prostaglandins Reduced GFR... 

Figure 22.4 Injury to endothelial cells can lead to vasospasm. Normal endothelial cells release nitric oxide (NO) which relaxes smooth muscle this is achieved by nitric oxide increasing the concentration of cyclic GMP within smooth muscle fibres and cyclic GMP relaxing the smooth muscle. Injured endothelial cells secrete very little nitric oxide but secrete more endothelin. The latter increases the formation of inositol trisphosphate (IP3), which binds to the sarcoplasmic reticulum (SR) where it stimulates the Ca ion channel. The Ca ion channel in the plasma membrane is also activated. Both effects result in an increase in cytosolic Ca ion concentration, which then stimulates contraction (vasospasm). This reduces the diameter of the lumen of the artery.

Normal endothelial cells produce nitric oxide, which relaxes smooth muscle, whereas damaged cells release less nitric oxide but more of a local hormone, endothelin, which stimulates contraction of smooth muscle (Figure 22.4). 

The most important stimulus to the release of ANP from the heart is atrial stretch via mechanosensitive ion channels. ANP release is also increased by volume expansion, changing from the standing to the supine position, and exercise. ANP release can also be increased by sympathetic stimulation via aiA-adrenoceptors, endothelins via the -receptor subtype (see below), glucocorticoids, and vasopressin. Plasma ANP concentration increases in various pathologic states, including heart failure, primary aldosteronism, chronic renal failure, and inappropriate ADH secretion syndrome. 

Fig. (18). Effect of kuwanon H (2) on agonist-induced increases in [Ca2+I, in Swiss 3T3 cells. Cells were stimulated by I O mol/L bombesin (BOM), 10" mol/L endothelin-l (ET) or 10" mol/L bradykinin (BK). Kuwanon H (S, 500 nmol/L at the final concentration) or dimethyl sulfoxide (V) was added I min before stimulation.

Iwasaki H, Eguchi S, Marumo F, Hirata Y. 1998. Endothelin-1 stimulates DNA synthesis of vascular smooth-muscle cells through transactivation of epidermal growth factor receptor. J Cardio-vasc Pharmacol 31 Suppl 1 S182-S184. 

Endothelial cells and the kidneys play probably an important role in the longterm homeostasis as well as in the development of AD. Endothelial cells synthesize and release vasorelaxant and vasoconstrictor substances. The vasoconstrictor mediators, endothelins, were isolated, purified, sequenced, and cloned [100], The human endothelin receptor has seven membrane helices and is apparently G-protein-coupled. Endothelin-induced smooth muscle contraction involves the following processes activation of PLC, PIP2 hydrolysis, generation of 1,4,5-IP3, accumulation of DAG, mobilization of intracellular Ca2+ with facilitation of Ca2+ influx, activation of PKC, activation of PLA2 and arachidonic acid release, activation of PLD, and stimulation of Na+-H+... 

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