Enhanced involvement of endothelin in the haemodynamic sequelae of endotoxaemia in conscious, hypertensive, transgenic ((mRen‐2)27) rats

The renin-angiotensin-aldosterone (RAA) system and the endothelin (ET) system entail the most potent vasopressor mechanisms identified to date. Although they were studied in depth in relation to arterial hypertension and cardiovascular diseases, limited information on their interrelationships in causing hypertension and related target organ damage exists. The identification of consensus sequences for jun in the regulatory region of the preproendothelin-1 (ppET-1) gene raised the possibility of its transcriptional regulation by angiotensin II (Ang II). This was confirmed by the finding that stimulation with Ang II of cultured vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) induced expression of the ppET-1 gene and synthesis of ET-1. Endogenously produced ET-1 was found to contribute to the hypertrophic response of cardiomyocytes to Ang II and thereby to cardiac hypertrophy. Furthermore, ET-1 exerts multifaceted effects on the RAA system, such as dose-dependent inhibition of renin synthesis, and stimulation of aldosterone secretion. The finding of abundant specific ET-1 receptors in the adrenocortical zona glomerulosa (ZG) suggested a direct secretagogue effect of ET-1. In rats, ETB receptors mediate such an effect, whilst in humans, both ETA and ETB receptor subtypes intervene in regulating the transcription of the aldosterone synthase gene. In addition, ET-1 stimulates DNA synthesis and proliferation of ZG cells via ETA receptors and, therefore, might play a role in cell turnover of the normal adrenal cortex and in the onset of adrenal tumours. Studies on the in vivo interactions between ETs and the RAA system have given conflicting results, insofar as some suggested a participation of ET-1 in the pressor and cellular effects of exogenously administered Ang II, whereas others did not in the transgenic TGR(Ren 2m)27 rats and in the two-kidney, one clip.

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Interactions between endothelin-1 and the renin–angiotensin–aldosterone system

Rossi

Sacchetto

Cesari

et al. 1999

Cardiovascular Research

167

102

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Comment on ''Interactions between endothelin-1 and the renin-angiotensin-aldosterone system''

Gardiner

Bennett

1999

Cardiovascular Research

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Influence of FR 167653, an Inhibitor of TNF-α and IL-1, on the Cardiovascular Responses to Chronic Infusion of Lipopolysaccharide in Conscious Rats

et al. 1999

Journal of Cardiovascular Pharmacology

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Conscious, male Long Evans rats (350-450 g) chronically instrumented for the measurement of regional haemodynamics, were infused with FR 167653, a dual inhibitor of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) synthesis (0.32 mg/kg/h) for 24 h, beginning 1 h before coinfusion of saline, or with saline for 24 h beginning 1 h before coinfusion of lipopolysaccharide (150 microg/kg/h), or with FR 167653 beginning 1 h before coinfusion of lipopolysaccharide. Animals infused with FR 167653 and saline showed progressive hindquarters vasoconstriction over the 24-h period, but this was not different from the change seen in animals (n = 3) infused with saline alone. However, plasma analysis at the end of the coinfusion of FR 167653 and saline showed substantial elevation in levels of creatine kinase, lactate dehydrogenase, and potassium, consistent with some tissue damage (heart, liver, or skeletal muscle, or a combination of these). Animals coinfused with saline and lipopolysaccharide showed biphasic decreases in mean arterial blood pressure accompanied by renal hyperaemic vasodilatation, and decreases followed by increases in mesenteric and hindquarters flows and vascular conductances. At the end of the infusion period, plasma analysis showed signs of renal dysfunction (elevated creatinine) and hepatic dysfunction (elevated alkaline phosphatase, gamma-glutamyl transferase, and alanine aminotransferase). In the presence of FR 167653, the hypotensive effects of lipopolysaccharide were abolished, but regional haemodynamics were unchanged, as were signs of organ dysfunction. One explanation of these observations is that FR 167653 causes a relative improvement in cardiac function during infusion of lipopolysaccharide, and this opposes the hypotensive effects of the latter, in spite of its persistent vasodilator effects.

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Enhanced involvement of endothelin in the haemodynamic sequelae of endotoxaemia in conscious, hypertensive, transgenic ((mRen‐2)27) rats

Cited by 4 publications

References 28 publications

Interactions between endothelin-1 and the renin–angiotensin–aldosterone system

Interactions between endothelin-1 and the renin–angiotensin–aldosterone system

Comment on ''Interactions between endothelin-1 and the renin-angiotensin-aldosterone system''

Influence of FR 167653, an Inhibitor of TNF-α and IL-1, on the Cardiovascular Responses to Chronic Infusion of Lipopolysaccharide in Conscious Rats

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