Page 23 - 82_01

catecholamines, grow factors, hypoxia, insulin,
lipoproteins, thrombin; contrarily, factors that inhibit its
secretion are NO, atrial natriuretic peptide, prostaglandin
E, PGI2 (67, 68). The concentration of ET-1 in plasma
may increase in some cardiovascular diseases such as
myocardial infarction, ischemia-reperfusion syndrome,
and heart failure (78, 80).
The biological effects, including vascular effects of
ET-1 may be mediated by two types of receptors, i. e.,
endothelin ETA and endothelin ETB; endothelin ETB
receptors are subdivided in ETB1 and ETB2. ETA
receptors are located in smooth muscle cells and coupled
to protein G, and its activation leads to increment of
cytoplasmic Ca, and then vasoconstriction (67, 68). The
debate in literature exists whether or not ETA and ETB
receptors should be blocked to provide most clinical
benefit (67, 76, 81); this feature may be of clinical
relevance, for example in treatment of myocardial
reperfusion injury. The ETA receptor has been
considered as the bad one, while the ETB receptor has
been considered as the good one; this distinction is based
on the role of ETB1 in the clearance of circulating ET-1
and on the finding that activation of this particular
receptor produces vasodilation by releasing NO. Whereas
the role of ETA receptors in vascular function is
relatively well known, the role of ETB receptors is less
known. Both ETB1 and ETB2 receptors are also a G-
protein coupled receptor and have been identified in
numerous types of blood vessels, including coronary
arteries. ETB1 receptors, situated in the endothelium,
mediate the release of relaxant factors (NO, PGI2,
EDHF), and they may play a role in ET-1 clearance, and
ETB2receptors, situated in vascular smooth muscle cells,
mediate the increase of concentrations of intracellular Ca,
protein kinase C, mitogen-activated protein kinase and
other pathways of vascular smooth cells contraction and
cell growth (67, 68).
In spite of many data demonstrating that ET-1 is a
powerful vasoconstrictor, there are also data suggesting
that under healthy conditions, ET-1 can also induce in
vivo vasodilatation. In any case, the overall effects of
ET-1 on vascular tone in vivo maybe the result of the
balance between the effects mediated by ETA and ETB2
receptors located in smooth muscle cells, and the effects
mediated by ETB1 receptors located in endothelial cells
(82, 83), and this could dependent on whether blood
vessels are healthy or unhealthy. Aging and pathological
conditions (e. g., cardiovascular diseases) facilitate the
predominance of the vasoconstrictor effects of ET-1.
Another cardiovascular function that may be of
relevance is that ET-1 may be a regulator of cardiac
physiology and pathology. Produced locally within the
myocardium in response to diverse mechanical and
neurohormonal stimuli, ET-1 seems to modulate cardiac
contractility. During pathological cardiovascular
22 @Real Academia Nacional de Farmacia. Spain
Godofredo Diéguez Castrillo
conditions such as ischemia, left ventricular hypertrophy
and heart failure, myocyte expression and activity of the
ET-1 system is enhanced, allowing the peptide to both
initiate and maintain maladaptive cellular responses.
Both the myocardial acute and chronic effects of ET-1
are dependent on the activation of intracellular signaling
pathways, regulated by the inositol-trisphosphate and
diacylglycerol produced upon activation of the ETA
receptor. Subsequent stimulation of protein kinases C and
D, calmodulin-dependent kinase II, calcineurin, and
mitogen-activated protein kinases modifies the systolic
calcium transient, myofibril function and the activity of
transcription factors that coordinate cellular remodeling
(67, 68).
Due to its potent effect on the coronary circulation,
the interest for the role of ET-1 in the physiology and
pathology of this particular vasculature increased rapidly.
In the first publication where ET-1 was identified, also it
was indicated that this peptide provokes a pronounced
constriction of isolated coronary arteries (70, 71), and
since this observation most of data show that ET-1
produces pronounced coronary vasoconstriction in vivo
(84, 85) and in vitro (70, 71, 86, 87).
In our laboratory we found that ET-1 evokes marked
coronary vasoconstriction in vivo and in vitro. In
anesthetized goats, i. v. injections of ET-1 increased
systemic arterial pressure, did not change resting blood
flow in the left anterior descending or left circumflex
coronary (LCx) arteries, and in the middle cerebral artery
(MCA) arteries, but it increased coronary and cerebral
vascular resistance, and this increment was higher in the
coronary circulation than in the cerebral circulation. In
other group of anesthetized goats, intra-arterial injections
of ET-1 decreased the LCx flow more than MCA flow. In
isolated segments from large coronary and cerebral
arteries from goats, ET-1 caused contraction, and the
concentration causing 50% of the maximal effect and the
maximal contraction were higher in coronary arteries
than in cerebral arteries. The in vitro reactivity of these
two types of arteries was unaffected by endothelium
removal or by indomethacin. Therefore, ET-1 may
produce coronary and cerebral vasoconstriction in vivo
and in vitro, probably by acting directly on vascular
musculature. The results from this study suggest that the
sensitivity to this peptide is higher in isolated cerebral
arteries than in isolated coronary arteries, but the
reactivity in vivo could be higher in the coronary
circulation than in the cerebral circulation (88). The
coronary vasoconstrictor effect of ET-1 was also
observed in isolated, perfused hearts from rats (89), and
in isolated coronary arteries from pigs (90). Figure 5
shows actual recordings of the coronary effects of ET-1
in one anesthetized goat and in one isolated, perfused rat
heart.