From the Institut de Cardiologie de Montréal, Centre de Recherche
(E.T., J.D.), and the Royal Victoria Hospital, Division of Clinical
Biochemistry (P.C.), Montréal, Canada.
Correspondence to Eric Thorin, PhD, Institut de Cardiologie de Montréal, Centre de Recherche, 5000 rue Bélanger Est, Montréal (Qc) H1T 1C8, Canada. E-mail thorin{at}icm.umontreal.ca
Abstract—Chronic elevation of plasma
endothelin-1 (ET-1) levels has been reported in several pathological
conditions. To investigate the consequences of increased circulating
ET-1 on vascular responsiveness, Sprague-Dawley rats (n=16) were
chronically instrumented with a minipump delivering ET-1 at a constant
dose for 7 days. Plasma ET-1 levels were more than doubled in treated
(0.98±0.09 pmol/L; P<.05) versus untreated
sham-operated rats (0.43±0.04 pmol/L), whereas systolic
arterial blood pressure increased (139±5 versus
128±4 mm Hg in untreated rats; P<.05). After
rats were killed, segments of middle cerebral (MCA) and mesenteric
(MES) arteries were mounted on an isometric myograph. ET-induced
contraction was shifted to the right in ET-1–treated animals and not
modified by BQ123 (an ETA receptor antagonist);
bosentan (ETA/B receptor antagonist) prevented
ET-1–induced contraction in both groups. After inhibition of nitric
oxide synthase with
N
© 1998 American Heart Association, Inc.
Scientific Contributions
Endothelin-1 Regulates Tone of Isolated Small Arteries in the Rat
Effect of Hyperendothelinemia
-nitro-L-arginine (L-NNA),
both phenylephrine and oxymetazoline (an
2-adrenoceptor agonist) induced MCA contraction. The
sensitivity to phenylephrine was decreased in ET-1–treated
compared with control rats (P<.05). Sensitivity to
phenylephrine-induced contraction was decreased by
BQ123 in control rats only. In contrast, L-NNA revealed greater
oxymetazoline-induced contractions in treated compared with control MCA
rings (P<.05); this potentiation was blunted by
bosentan but unaffected by BQ123. Removal of the
endothelium revealed a direct constrictor effect of
oxymetazoline that was insensitive to L-NNA alone or combined with
bosentan; however, oxymetazoline induced significantly lower
constriction in treated rat MCA segments. Responses to oxymetazoline
were also blunted in treated compared with untreated denuded MES
arteries. In conclusion, chronic elevated plasmatic ET-1 decreases
smooth muscle cell sensitivity to contractile agonists both in MCA and
MES rings. In cerebral vessels, endothelial
2-adrenoceptor–dependent stimulation induced greater
contractile responses in treated rats which were sensitive to bosentan,
suggesting that oxymetazoline stimulates ET-1 release from the
endothelium. This may represent a compensatory
mechanism for the loss of smooth muscle sensitivity.
Key Words: mesenteric arteries • cerebral arteries • adrenergic antagonists • endothelin • rats
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