Endothelin 1 mediates ex vivo coronary vasoconstriction caused by exogenous and endogenous cytokines.

Abstract

Treatment of rats with cytokines has been associated with an increase in the circulating levels of endothelin 1 (ET-1). Here we show that administration of tumor necrosis factor a (TNF-a; 4 ,ugkg-1) to anesthetized rats caused within 15 min a strong elevation in the circulating levels of ET-1. This was associated with a striking coronary vasoconstriction in hearts from these animals when they were removed and perfused in vitro by the Langendorff technique. This vasoconstriction was largely overcome by treatment with either the endothelin type A (ETA) receptor antagonist FR 139317 or antibody against ET-1. Furthermore, it was mimicked by in vivo exposure to exogenous ET-1. Endogenously produced TNF-a may also cause such a coronary vasoconstriction, for treatment with interleukin 2 (600 ,.g-kg-1) produced an increase in coronary perfusion pressure that correlated with the increases in circulating TNF-a. This coronary vasoconstriction was substantially reversed by treatment either with antibody against TNF-a or with FR 139317. We suggest, therefore, that cytokine-driven changes in the production of ET-1 are key events in the development of vascular pathologies.Exogenously applied endothelin 1 (ET-1) acts via specific type A and B (ETA and ETB) receptors within the vasculature to produce potent and profound changes in vessel diameter, vessel permeability, and, in the longer term, vessel structure (see refs. 1 and 2). The importance of endogenously produced ET-1 in the regulation of blood vessel activity under physiological conditions is, however, not clear, although it may, for instance, regulate basal blood flow in humans (3). Nevertheless, there is much evidence implicating an increase in ET-1 release as a causative factor in numerous pathological states (see refs. 1 and 2), including myocardial dysfunctions in both animals and humans (4-7). However, the precise regulation of ET-1 biosynthesis and release, particularly in vivo, has yet to be fully elucidated, although it is generally believed to be a slowly responding system mediating chronic vasoconstrictor responses and/or resistance changes (1, 2, 8). Cytokines enhance the release of ET-1 both from endothelial cells (9) and within the circulation (10) and, interestingly, many of the pathological conditions in which there are elevations in the circulating levels of ET-1 are associated with increased production of cytokines. Here we show that there is a direct association between the endogenous production of cytokines and the release of ET-1 and that this rapidly leads to sustained vasoconstriction. MATERIALS AND METHODSBlood Pressure. Male Wistar rats (230-260 g; Glaxo) were anesthetized with sodium thiopentone (Intraval; 120 mg-kg-', i.p.). The trachea was cannulated to facilitate respiration and body temperature was maintained at 37°C by means of a rectal probe connected to a homeothermic blanket (Biosciences, Sheerness, Kent, U.K.). The right carotid artery was cannulated and connected to a pressure transducer (Elcomatic type 750) for measurement of a...

Vasopressin Induces Vascular Superoxide Via Endothelin-1 in Mineralocorticoid Hypertension

“…29,30 Alternatively, the cellular source for new ET-1 synthesis could be smooth muscle cells instead of endothelial cells, because agonists such as cytokines have been shown to stimulate ET-1 release quite rapidly from endothelial cells. 31 However, it is important to point out that although we observed that arterial vasopressin levels are Ϸ3-fold higher in DOCA-salt rats than in sham rats (7.1Ϯ1.4 versus 1.9Ϯ04 pg/mg protein), previously published studies showed that the normal plasma vasopressin levels (1 to 30 pmol/L) are generally elevated by 3-to 5-fold in the benign phase of hypertension in this model. 32,33 In addition, although ABT627 reversed the effect of vasopressin on vascular O 2 Ϫ levels, vasopressin treatment of carotid arteries of normal rats for 24 hours in vitro only elevated arterial ET-1 levels to a small extent compared with the increase in vasopressin levels observed in the vessels of DOCA-salt rats.…”

TNF-α enhances contraction and inhibits endothelial NO-cGMP relaxation in systemic vessels of pregnant rats

“…Second, although the present data suggest that the enhanced vascular contraction in the TNF-␣-treated vessels of pregnant rats is likely due to inhibition of an endothelium-dependent vascular relaxation pathway, we cannot rule out the possibility that TNF-␣ may increase the release or the sensitivity of vascular smooth muscle to endothelium-derived contracting factors. This is supported by reports that TNF-␣ stimulates the production of endothelium-derived contracting factors such as endothelin-1 (37,42). Third, TNF-␣ may also enhance the vascular contraction by an additional endothelium-independent mechanism.…”

Cutaneous endothelin-A receptors elevate post-incisional pain

“…Inhibition of ECE-1 predictably suppresses ET-1 levels, whereas both ECE-1 transcripts and ECE-1α protein secretion are increased by U.V.-inducible IL-1α (Hachiya et al, 2002). A five-fold increase in endogenous ET-1 is caused by TNF-α, the most rapid inducer of ET-1 (Klemm et al, 1995). IL-1β and IL-1α are known to increase sensory nerve fiber excitability and produce hyperalgesia (Ferreira et al, 1988;Meyer et al, 2006), and these changes may be linked by ET-1 (Khodorova et al, 2002).…”

“…Human polymorphonuclear neutrophils (PMNs) also synthesize ET-1, providing an additional source to accompany inflammatory cytokine release in the early stages of inflammation. Intravenous cytokine administration also increases plasma levels of ET-1 in rats (Battistini et al, 1996;Klemm et al, 1995;Miyamori et al, 1991;Vemulapalli et al, 1994;Vemulapalli et al, 1991). IL-1α transcriptionally and translationally elevates the activity of endothelin-converting-enzymes-1α (ECE-1α) in human keratinocytes, an enzyme whose action yields biologically active ET-1 by cleavage of its inert precursor.…”