Endothelin-1 potentiation of coronary artery contraction after ischemia–reperfusion Angel Luis García-Villalón ⁎ , Yesika María Amezquita, Luis Monge, Nuria Fernández, Adely Salcedo, Godofredo Diéguez Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, 28029 Madrid, Spain Received 17 July 2007; received in revised form 11 September 2007; accepted 11 January 2008 Abstract Hearts from Sprague–Dawley rats were perfused at constant flow and then exposed to 30 min global zero-flow ischemia followed by 15 min reperfusion. After ischemia–reperfusion, coronary arteries were dissected from the heart and segments 2 mm long were prepared for isometric tension recording in organ baths. Stimulation of the arteries with 5-hydroxytryptamine (10 - 6 M) produced contraction, which was potentiated by treatment with endothelin-1 (3 × 10 - 10 ; 10 - 9 M). This potentiation was lower in the arteries from hearts after ischemia–reperfusion (for 3×10 - 10 M, 15 ± 5%; P N 0.05; for 10 - 9 M, 37 ± 7%, P b 0.01, n = 5) than after control (for 3 × 10 - 10 M, 34 ± 4%; P b 0.01; for 10 - 9 M, 50 ± 6%, P b 0.01, n = 5), and the potentiation was reduced by the inhibitor of nitric oxide synthesis L-NAME (10 - 4 M), the antagonist of endothelin ET A receptors BQ123 (10 - 6 M) and the antagonist of endothelin ET B receptors BQ788 (10 - 6 M), but not by the cyclooxygenase inhibitor meclofenamate (10 - 5 M). These results suggest that endothelin-1 at low concentrations potentiates coronary vasoconstriction, and this effect is reduced after ischemia–reperfusion, mediated by endothelin ET A and ET B receptors and dependent on nitric oxide release. © 2008 Elsevier Inc. All rights reserved. Keywords: Perfused heart; nitric oxide endothelin ETA receptors; ETB receptors; U46619; 5-hydroxytryptamine 1. Introduction There is evidence that endothelin may play a role in different pathological states, such as ischemia–reperfusion. Myocardial ischemia increases gene expression and release of endothelin (Brunner et al., 1992; Vitola et al., 1996), and plasma levels of this peptide are increased in patients with myocardial infarction (Stewart et al., 1991) or vasospastic angina pectoris (Toyo-oka et al., 1991). Also, antagonists of endothelin receptors may reduce infarct size and improve recovery of myocardial performance after myocardial ischemia (Pernow and Wang, 1997; Wang et al., 2002). The mechanisms of this deleterious effect of endothelin may in- volve coronary vasoconstriction and coronary blood flow reduction (Muramatsu et al., 1991) and/or antagonism of nitric oxide (Gonon et al., 2000; Bauersachs et al., 2000). Several studies suggest that response to endothelin-1 may be altered after ischemia–reperfu- sion, as ischemia–reperfusion can increase coronary vasoconstric- tion in response to endothelin-1 (Watts et al., 1992; Thompson et al., 1995; Wang et al., 1995), and this increase may be related to inhibition of nitric oxide release (Fernández et al., 2003). The cardiovascular physiologic role of endothelin-1 may be more complex as the concentrations of this peptide in plasma are usually low, and these low concentrations of endothelin may modulate the response to other stimuli. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and seroto- nin in coronary arteries from humans (Yang et al., 1990) or pigs (Nakayama et al., 1991). Moreover, this potentiating effect of endothelin-1 may be altered in pathological conditions. The potentiation by endothelin-1 of the sympathetic contraction in the rat tail artery is reduced during hypertension (García-Villalón et al., 2000), while the potentiation of the contraction to the calcium agonist Bay K8644 in canine renal and iliac arteries is increased after ischemia–reperfusion (Edwards et al., 1995). Therefore, the Available online at www.sciencedirect.com Vascular Pharmacology 48 (2008) 109 – 114 www.elsevier.com/locate/vph ⁎ Corresponding author. Departamento de Fisiología, Facultad de Medicina, Universidad Autonoma, Arzobispo Morcillo 2, 28029 Madrid, Spain. Tel.: +34 91 4975412; fax: +34 91 4975478. E-mail address: angeluis.villalon@uam.es (A.L. García-Villalón). 1537-1891/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2008.01.003