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Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review

Figure 4. Actual recordings of coronary blood flow (CBF, electromagnetically measured), systemic arterial pressure (SAP) and heart rate
(HR) obtained in anesthetized goats: A) during i. v. administration of the inhibitor of NO synthesis L-NAME; B) during intracoronary (i.
c) administration of this substance; and C) showing the effects of intracoronary injections of acetylcholine (Ach) on coronary blood flow
before (control) and after L-NAME injected by i. v. route; D) Summary of the effects of intracoronary injections of acetylcholine (Ach)
and sodium nitroprusiate (SNP) on coronary blood flow in anesthetized goats under control conditions and after i. v. administration of L-
NAME.

2.4. Endothelin-1 (ET-1) primarily as a paracrine regulator of vascular tone (75-
78). In addition to endothelial cells, ET-1 is also
Endothelin-1 is a member of the group of endothelins, produced by vascular smooth muscle cells,
which are a family of 21- amino-acid peptides, and they cardiomyocytes, leukocytes, macrophages, some types of
include endothelin-1 (ET-1), endothelin-2 (ET-2) and neurons, and other types of cells (67, 77, 78). ET-1, at
endothelin-3 (ET-3); they share structure homology with elevated concentrations, also induces inflammatory
the snake venom sarafotoxin b and c (S6b and S6c) (67, effects and promotes proliferation of vascular smooth
68). muscle cells (67, 68, 79).

The presence of an endothelium-derived constricting ET-1, ET-2 and ET-3 are encoded by different genes,
factor (EDCF) was perceived 1 year after the revelation on chromosomes 6, 1 and 2, respectively (67, 68). In
of the endothelium-derived relaxant properties of the endothelial cells, the product of the ET-1 gene is
endothelium (69). However, it was 8 years later that processed from a large precursor peptide of
Yanisagawa et al. identified an EDCF, ET-1 (70, 71). approximately 200 amino acid residues (preproET-1) to
Two years later, two types of receptors for ET-1 were 39-amino-acid prohormone (big ET-1), which has about
identified (72, 73), and shortly after the discovery of 1% of the activity of ET-1. This prohormone is then
ETA y ETB receptors, M. Clozel et al. presented in 1993 cleaved to form ET-1 by the action of two endothelin-
the first orally active ET-1 receptor antagonist, Ro 46- converting enzymes (ECE-1 and ECE-2) (67, 68). Small
2005 (74). amounts of big endothelin and ET-1 are secreted into
circulating blood and into interstitial space of the blood
ET-1 is one of the most potent endogenous vessel wall (67, 68). In normal human adults, plasma
vasoconstrictor identified so far (67, 68). This peptide levels of ET-1 are relatively low (0. 7-6 pg/mL (75, 76).
induces a long-lasting contraction of arteries of different ET-1 is cleared from the circulating plasma, and the
regions, including coronary arteries, and it contributes to majority is retained by the lungs and cleared from the
cardiovascular homeostasis through several pathways circulation by binding to endothelin ETB receptors (67,
that impact on the regulation of basal vascular tone (75). 68). ET-1 is not stored in secretory granules, and factors
It is released continuously, mostly from endothelial cells, that active its secretion may be angiotensin II,
by a constitutive and regulated pathway (76), and acts

@Real Academia Nacional de Farmacia. Spain 21