Disease relevance of EDN1

• This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels [1].
• Administration of selective endothelin receptor type A antagonist Ro 61-1790 does not improve outcome in focal cerebral ischemia in cat [2].
• The long-lasting nature of endothelin-induced constriction of the cerebral arteries in vivo suggests that the peptide might be involved in the pathogenesis of cerebral vasospasm [3].
• Since it is widely held that spreading depression, or a very similar mechanism, underlies the aura phase of migraine, it may be suggested from these studies that endothelin antagonists are unlikely to be useful in migraine [4].
• Pertussis toxin inhibited both endothelin-1 and mastoparan stimulation of p38 MAP kinase activity and arachidonic acid release [5].

High impact information on EDN1

• Stimulation of myocardial Na(+)-independent Cl(-)-HCO(3)(-) exchanger by angiotensin II is mediated by endogenous endothelin [6].
• This effect was canceled by previous exposure to either 50 nmol/L PD 142,893 (nonselective endothelin receptor blocker) or 300 nmol/L BQ 123 (selective blocker of ET(A) receptors) [6].
• Exposure to ET-1 (10 nmol/L) raised pH(i) by 0.13+/-0.03 U (P<0.05) in papillary muscles superfused with nominally HCO(3)(-)-free solution, whereas no significant change was detected under CO(2)/HCO(3)(-)-buffered medium [6].
• The rate of pH(i) recovery from trimethylamine hydrochloride-induced intracellular alkaline load was enhanced so that net HCO(3) efflux increased about three times in the presence of ET-1 (2.74+/-0.25 versus 9.66+/-1.29 mmol. L(-1). min(-1) at pH(i) 7.55, P<0.05) [6].
• The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1 [1].

Chemical compound and disease context of EDN1

• 1. The effects of intravenous administration of endothelin (ET) receptor antagonists SB-209670 (0.001-10.0 mg kg(-1)), SB-217242, SB-234551 (0.01-10.0 mg kg(-1)) and BQ-788 (0.001-1.0 mg kg(-1)) were investigated on trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the carotid vasculature of the anaesthetized cat [7].
• Using a perfused CB preparation, we studied the effects of exogenous ET-1 and bosentan, a non-selective endothelin receptor type A and B antagonist, on the frequency of chemosensory discharges (f(x)) during normoxia, mild and severe hypoxia [8].
• The present data suggest that SK&F 96148 has selective thromboxane receptor blocking activity in the airways of the cat, and that bronchoconstrictor responses to endothelin-1, arachidonic acid, PAF, and E. coli endotoxin are mediated in part by the formation of TXA2 [9].
• Bronchoconstrictor responses to arachidonic acid, platelet-activating factor (PAF), endothelin-1, and E. coli endotoxin were blocked by SK&F 96148 [9].
• Inhibition of cyclic AMP accumulation by endothelin is pertussis toxin sensitive and calcium independent in isolated adult feline cardiac myocytes [10].

Biological context of EDN1

• Vasoconstrictions induced by endothelin were extremely prolonged, persisting for approximately 90 min after a single microapplication [11].
• Low doses of ET-1 (0.01 and 0.1 nmol) elicited mild but significant reductions in CBV without changes in the systemic arterial blood pressure (SABP) [12].
• The effects of intracarotidly injected endothelin (ET)-1 (0.01-3 nmol) on the local cerebral blood volume (CBV) in the parietotemporal cortex were examined by the photoelectric method in 17 anesthetized cats [12].
• The perivascular co-application of PD156707 and ET-1 (10 nM) effected a dose-dependent attenuation of the ET-1 vasoconstrictive response (IC50 = 0.1 microM) [13].
• In this study, we have examined basic mechanisms underlying the contractile response of cerebral vessels to endothelin using in vitro pharmacology and electrophysiology [14].

Anatomical context of EDN1

• The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro [1].
• Endothelin-mediated positive inotropic effect induced by reactive oxygen species in isolated cardiac muscle [15].
• In FIRE-1 expressing ventricular myocytes endothelin-1, phenylephrine, and angiotensin II all produced rapid and spatially resolved increases in [InsP3] using confocal microscopy (with free [InsP3] rising to approximately 30 nm) [16].
• There was no change in sensitivity of the cerebral artery to endothelin [14].
• In contrast, infusion of up to 3,000 pmol endothelin into the vertebral artery had no appreciable effect on basilar artery caliber [3].

Associations of EDN1 with chemical compounds

• Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence [1].
• Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2alpha, vasopressin, BAY K8644; biphasic responses to endothelin-1; or on vasodilator responses to acetylcholine, albuterol, or levcromakalim [17].
• The duration of the inhibitory actions of candesartan were dependent on dose, and the AT1 receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1, alpha,beta-methylene ATP, adenosine, acetylcholine, and bradykinin [18].
• The actions of Bosentan and PD155080, nonpeptide endothelin receptor antagonists, were examined in feline pial arterioles in situ following middle cerebral artery (MCA) occlusion to gain insight into the cerebrovascular influence of endogenous endothelins in focal cerebral ischaemia [19].
• Our observations suggest that endothelin acts in cerebral vessels from the adventitial side, not from the luminal side, possibly due to the presence of the blood-arterial wall barrier [3].

Other interactions of EDN1

• In addition to not altering responses to PGF2 alpha, PGD2 alpha, or serotonin, SQ 30741 (2 mg/kg iv) was without significant effect on pulmonary vasoconstrictor responses to the PGD2 metabolite 9 alpha, 11 beta-PGF2, norepinephrine, angiotensin II, BAY K 8644, endothelin 1, or endothelin 2 [20].
• The systemic vasodilator response to porcine endothelin was not affected by beta 2-adrenoceptor blockade [21].

Analytical, diagnostic and therapeutic context of EDN1

• Constriction/dilatation of the cerebral microvessels by intravascular endothelin-1 in cats [12].
• Endothelin receptor antagonist increases cerebral perfusion and reduces ischaemic damage in feline focal cerebral ischaemia [13].
• RIA of corresponding nonradiolabeled HPLC elution demonstrated a significantly increased release of PGE2, PGF2 alpha, and 12-HETE as well as 5-HETE in response to ET-1 stimulation [22].
• 5-HETE release from ET-1-stimulated cells was further identified by gas chromatography/mass spectrometry (GC/MS) [22].
• Real-time RT-PCR measurements of prepro-ET-1, -ET-2, and -ET-3 were performed before and 5, 15, and 30 min after stretch [23].

References