Endothelin-1 Regulates Tone of Isolated Small Arteries in the Rat

Abstract

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 (nϭ16) 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 (0.98Ϯ0.09 pmol/L; PϽ.05) versus untreated sham-operated rats (0.43Ϯ0.04 pmol/L), whereas systolic arterial blood pressure increased (139Ϯ5 versus 128Ϯ4 mm Hg in untreated rats; PϽ.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 ET A receptor antagonist); bosentan (ET A/B receptor antagonist) prevented ET-1-induced contraction in both groups. After inhibition of nitric oxide synthase with N -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 (PϽ.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 (PϽ.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. (Hypertension. 1998;31:1035-1041.)

Orchidectomy enhances the expression of endothelin-1 and ET_B receptors in rat portal vein

“…Therefore, the findings of the present study support the previously proposed hypothesis that orchidectomy promotes an increment of the expression of ET-1 on the portal vein, thereby increasing the α 1 -adrenoceptor-mediated contractile effects of phenylephrine. This hypothesis is also supported by previous studies which suggest that locally produced ET-1 potentiates the vascular effects of α 1 -adrenoceptor agonists (17, 18). …”

Physical activity opposes the age‐related increase in skeletal muscle and plasma endothelin‐1 levels and normalizes plasma endothelin‐1 levels in individuals with essential hypertension

“…) and an increase in systolic blood pressure (Thorin et al . ), suggesting that the reduction in plasma ET‐1 concentrations could be important for the training‐induced lowering of blood pressure observed in the current study.…”

Structural and Functional Alteration of Blood Vessels Caused by Cigarette Smoking: An Overview of Molecular Mechanisms

“…ET is a potent mitogen [85] and can alter smooth muscle cell responses to other vasoactive agents [86]. Rabbit airway smooth muscle cell cultures exposed to cigarette smoke extract have increased proliferation via release of ET-1 and its associated autocrine mitogenic actions [87].…”