(Circulation. 1999;100:1680-1683.)
© 1999 American Heart Association, Inc.
Brief Rapid Communication |
Vasoconstriction to Endogenous Endothelin-1 Is Increased in the Peripheral Circulation of Patients With Essential Hypertension
From the Department of Internal Medicine, University of Pisa (S.T., A.V., L.G., I.S., A.S.), Pisa, Italy, and TAKEDA Italia Farmaceutici SpA (M.N.), Rome, Italy.
Correspondence to Stefano Taddei, MD, Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. E-mail s.taddei{at}int.med.unipi.it
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Abstract |
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Background—In humans, endothelin (ET)-1 could be implicated in the pathophysiology of several cardiovascular diseases, including essential hypertension. We therefore evaluated the role of ET-1 in control of vascular tone in essential hypertension.
Methods and Results—We used strain-gauge venous plethysmography to test changes in forearm blood flow induced by intrabrachial infusion of TAK-044 (10, 30, and 100 µg · 100 mL-1 · min-1), an ETA/ETB receptor antagonist, or sodium nitroprusside (1 and 2 µg · 100 mL-1 · min-1), a vasodilator that acts on smooth muscle cells, in hypertensive patients and healthy controls (n=10 in each group). The NO pathway was also evaluated by infusion of NG-monomethyl-L-arginine, (L-NMMA; 10, 30, and 100 µg · 100 mL-1 · min-1), an NO synthase inhibitor, and norepinephrine (3, 9, and 30 ng · 100 mL-1 · min-1) as control. Immunoreactive plasma ET-1 was measured by radioimmunoassay. In hypertensive patients, TAK-044 caused a vasodilation that was significantly (P<0.01) increased compared with normotensive subjects. Moreover, vasoconstriction to L-NMMA was significantly (P<0.01) decreased in hypertensive patients compared with controls. In contrast, the vascular responses to sodium nitroprusside and norepinephrine, as well as levels of immunoreactive plasma ET-1, were similar in hypertensive patients and controls. In the study population, vasodilation to TAK-044 and vasoconstriction to L-NMMA showed an inverse correlation (r=-0.56, P<0.05).
Conclusions—These results indicate that TAK-044 caused a greater degree of vasodilation in the forearm vessels of essential hypertensive patients compared with normotensive subjects, an alteration associated with decreased tonic NO release.
Key Words: vasodilation • hypertension • nitric oxide • endothelin
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Introduction |
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Endothelin-1 (ET-1), a 21-amino-acid isopeptide generated by the vascular endothelium and characterized by sustained and potent vasoconstrictor action,1 acts through specific receptors termed ETA and ETB.2 ETA receptors are represented only on smooth muscle cells and mediate contractions and promote growth.2 In contrast, ETB receptors are located both on smooth muscle cells to evoke contractions3 and on endothelial cells to induce relaxation by production of nitric oxide (NO).4
In humans, ET-1 could be implicated in the pathophysiology of several cardiovascular diseases, including essential hypertension.5 Bosentan, a mixed ETA/ETB receptor antagonist, significantly lowered blood pressure values in patients with essential hypertension, which suggests a role for this peptide in the pathogenesis of hypertension.6 However, a clear demonstration of a disturbance in ET-1–mediated vascular control is still lacking in essential hypertension.
In the present study, we compared forearm vasodilation to TAK-044, a combined ETA/ETB receptor antagonist,7 in healthy control subjects and patients with essential hypertension to indirectly assess the contribution of endogenous ET-1 to vascular tone in both conditions. Moreover, the activity of the L-arginine–NO pathway was also evaluated.
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Methods |
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The study population included 10 normotensive control subjects (age 51.2±6.4 years; blood pressure 121.4±4.3/78.2±3.2 mm Hg) and 10 matched never-treated patients with essential hypertension (age 50.6±6.8 years; blood pressure 160.2±6.2/101.6±2.8 mm Hg) characterized by no history of smoking or drinking and by similar values of plasma glucose, total and LDL cholesterol, and creatinine clearance (all within normal ranges). The protocol was approved by the ethics committee of the University of Pisa, and all patients gave written consent to participate in the study.
Briefly, the brachial artery was cannulated for drug infusion at systemically ineffective rates and for monitoring of intra-arterial blood pressure and heart rate. Forearm blood flow (FBF) was measured in both forearms by strain-gauge venous plethysmography. Circulation to the hand was excluded 1 minute before FBF measurement by inflation of a pediatric cuff around the wrist at suprasystolic blood pressure. Forearm volume was measured according to the water-displacement method. Details concerning this method have been published previously.8
To assess ET-1 contribution to vascular tone, TAK-044 (Takeda
Chemical Industries Ltd), a specific inhibitor of
ETA/ETB
receptors,7 9 10 was infused into the brachial artery of
normotensive subjects and patients with essential hypertension (10, 30,
and 100 µg per 100 mL of forearm tissue/min; 10 minutes for each
dose).11 The IC50 for TAK-044 is 3.8
and 130 nmol/L for ETA and
ETB receptors, respectively, in vitro and is
similar in vivo.7 9 Moreover, the integrity of the NO
pathway was evaluated by administration of intrabrachial
NG-monomethyl-L-arginine
(L-NMMA; Clinalfa AG), a specific antagonist for
NO synthase12 (10, 30, and 100 µg per 100 mL of
forearm tissue/min; 5 minutes for each dose). As a control for
nonspecific vascular responses, vasodilation to sodium nitroprusside
(SNP; Malesci), a direct smooth muscle cell relaxant compound (1 and 2
µg · 100 mL forearm tissue-1 ·
min-1; 5 minutes for each dose), and
vasoconstriction to norepinephrine (NE; Jacopo Monaco), a
preferential 
-adrenoceptor agonist, (3, 9, and 30 ng · 100 mL
forearm tissue-1 ·
min-1; 5 minutes for each dose) were also
evaluated. The infusion sequence was randomized, and a 60-minute
washout period was allowed between each dose-response curve. However,
TAK-044 was always administrated as the last infusion. In each subject,
a venous blood sample was obtained for assay of plasma immunoreactive
ET concentrations (by radioimmunoassay).13
Data were analyzed in terms of forearm vascular resistances (FVRs) (calculated as the ratio between intraarterial mean pressure and FBF and expressed as standard units). Clinical characteristics of study subjects were compared by the paired Student t test. Dose-response curves were analyzed by ANOVA for repeated measures, and Scheffé's test was applied for multiple comparison testing. Results are expressed as mean±SD.
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Results |
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The Table
describes mean
blood pressure, heart rate, and experimental and contralateral FVR
behavior during each infusion.
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In healthy subjects, TAK-044 caused a modest increase in FBF (Figure 1) and a decrease in FVR
(-12.3±17.2%), whereas in patients with essential hypertension, the
FBF increase (Figure 1) and FVR decrease (- 47.2±12.1%) were
significantly (P<0.01) greater than for normotensive
controls. L-NMMA caused a decrease in FBF (Figure 1), which was
significantly (P<0.01) reduced in essential hypertensive
patients (FVR increase 41.4±14%) compared with normotensive subjects
(FVR increase 95.3±41%). Vasodilation to SNP and vasoconstriction to
NE were similar in normotensive subjects and hypertensive patients.
Contralateral FVR did not significantly change throughout the study
(Table
).
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With regard to the entire study population, vasodilation to TAK-044 was
negatively (r=-0.56, P<0.05) correlated with
vasoconstriction to L-NMMA (Figure 2).
Plasma immunoreactive ET was similar in normotensive subjects (4.9+0.1
pg/mL) and hypertensive patients (4.3+0.1 pg/mL).
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Discussion |
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The present results show that TAK-044, a combined ETA/ETB receptor antagonist,7 caused a greater degree of vasodilation in the forearm vasculature of patients with essential hypertension than in normotensive control subjects, whereas the response to SNP, a direct relaxant compound, was similar in the 2 study subgroups. These findings indicate that in patients with essential hypertension, endogenous ET-1 shows greater vasoconstrictor activity.
The possibility that this increased effect of TAK-044 in hypertensive
patients might be caused merely by an increase in ET-1
production is not supported by measurement of plasma ET-1
levels. In line with previous evidence,14 plasma ET-1
concentrations were found to be similar in normotensive controls and
essential hypertensives with normal renal function. However, because
only 
20% of generated ET is secreted luminally, whereas the greater
portion of the peptide is secreted toward the adjacent smooth
muscle,15 plasma ET measurement is not a sensitive marker
for tissue production of the peptide.
An alternative explanation may be related to impaired ET-1–mediated NO
production in essential hypertensives. As previously
demonstrated,9 intrabrachial TAK-044 only slightly
increased FBF in normotensive subjects (20%), indicating that in
healthy conditions, endothelial
ETB receptor–mediated NO-dependent vasodilation
almost completely counterbalances smooth muscle
ETA and ETB
receptor–mediated vasoconstriction.16 In essential
hypertension, ET-1–mediated endothelial
ETB receptor stimulation leads to modest NO
activation because of the presence of impaired NO
availability,8 17 thereby unmasking the vasoconstrictor
effect of the peptide. In line with this possibility and in agreement
with previous evidence,17 our hypertensive study
population was characterized by an impairment in the NO system, because
the vasoconstrictor effect of L-NMMA but not that of the unrelated
vasoconstrictor NE was decreased compared with healthy controls.
Moreover, the existence of a negative and significant correlation
between the vasodilating and vasoconstricting responses to TAK-044 and
L-NMMA, respectively, seems to indicate an association between
increased vasoconstriction to endogenous ET-1 and
diminished NO production. Finally, recent evidence indicates
that intrabrachial infusion of BQ-788, a selective
ETB receptor antagonist, causes
vasodilation and vasoconstriction in essential hypertensives and
normotensive controls, respectively,18 further supporting
the existence of a differential vascular activity for
ETB receptors in healthy conditions and in
patients with essential hypertension.
In conclusion, in essential hypertension, the vasoconstrictor activity of endogenous ET-1 is increased compared with healthy conditions, which suggests a possible role for ET-1 in the pathogenesis of hypertension and/or its complications.
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Footnotes |
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Guest Editor for this article was Kathryn G. Lamping, PhD, VA Medical Center, Iowa City, Iowa.
Received February 11, 1999; revision received August 16, 1999; accepted August 24, 1999.
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References |
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