(Hypertension. 1995;26:1041-1045.)
© 1995 American Heart Association, Inc.
Articles |
Endothelin Subtype B Receptor–Mediated Calcium and Contractile Responses in Small Arteries of Hypertensive Rats
From the MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
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Abstract |
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Abstract Endothelin-1 elicits vasoconstrictor responses through endothelin subtype A receptors, which are located on vascular smooth muscle cells, and vasodilator responses through endothelin subtype B receptors, which occur predominantly on endothelial cells. Endothelin subtype B receptors also may be present on vascular smooth muscle cells, in which they may mediate vasoconstriction. The aims of this study were to determine the presence of vascular smooth muscle vasoconstrictor endothelin subtype B receptors in mesenteric resistance arteries and to assess whether endothelin subtype B receptor–mediated responses differ between spontaneously hypertensive rats and Wistar-Kyoto rats. Contractile responses to the endothelin subtype B receptor agonist sarafotoxin S6c and endothelin-1 were measured simultaneously with [Ca2+]i in endothelium-denuded mesenteric resistance arteries from adult spontaneously hypertensive rats and Wistar-Kyoto rats. To simulate in vivo conditions matched as closely as possible to in vitro conditions, vessels were mounted in a vessel flow chamber in which intraluminal pressure was maintained at 60 mm Hg. Contraction was determined by video imaging to record lumen diameter, and [Ca2+]i was measured by the fura 2 method. Basal [Ca2+]i was significantly higher (P<.01) in hypertensive (170±4 nmol/L) compared with normotensive rats (134±3 nmol/L). The endothelin subtype B receptor agonist sarafotoxin S6c increased [Ca2+]i in a concentration-dependent manner. Sarafotoxin S6c–induced [Ca2+]i and contractile responses were significantly lower in hypertensive compared with normotensive rats. These data demonstrate that endothelin subtype B receptors are present in vascular smooth muscle of small arteries and that endothelin subtype B receptor–mediated vasoconstriction occurs through intracellular calcium signaling pathways. Although the contribution of endothelin subtype B receptor–induced contraction is small, responses mediated by this receptor subtype in spontaneously hypertensive rats are attenuated compared with age-matched Wistar-Kyoto rats.
Key Words: vasoconstriction • signaling, intracellular • arteries • rats, inbred SHR • muscle, smooth, vascular
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Endothelin-1 is a potent vasoconstrictor peptide of 21 amino acids. The endothelin family may play an important role in the regulation of vascular smooth muscle.1 Endothelin-1 binds to G protein–coupled receptors of which two subtypes, ETA and ETB, have been characterized.2 3 ETA receptors are present on vascular smooth muscle cells and mediate endothelin-induced vasoconstriction through intracellular calcium signaling pathways.4 5 ETB receptors occur predominantly on endothelial cells and mediate vasodilation by generation of prostacyclin and endothelium-derived nitric oxide.6 7 Recent evidence suggests that ETB receptors may also mediate vasoconstriction.8 Functional ETB receptors have been identified on vascular smooth muscle cells of large vessels9 and recently on vascular smooth muscle cells from small resistance arteries.10 In addition ETB-mediated vasoconstriction has been demonstrated in large vessels such as in human internal mammary vessels,11 rat renal and pulmonary vessels,12 13 and porcine coronary arteries14 as well as in human and rat resistance arteries.15 16 17 The intracellular signaling pathway through which ETB receptor–linked vasoconstriction is mediated is unclear but probably involves phospholipase C activation and intracellular calcium mobilization. This is supported by studies in cultured vascular smooth muscle cells in which ETB agonists IRL-1620 and sarafotoxin S6c induced significant elevations in [Ca2+]i.10
The role of vascular ETB receptors and ETB receptor–mediated vasoconstriction in hypertension is not known. Although endothelin-1–induced vasoconstriction through ETB receptors is small relative to that mediated through ETA receptors,15 the ETB component may contribute to changes in endothelin-1 effects that have been described in hypertension. In SHR, vascular responses to endothelin-1 have been reported to be enhanced,18 reduced,19 or normal.20 We have demonstrated repeatedly in intact mesenteric resistance arteries and primary cultured mesenteric vascular smooth muscle cells that endothelin-1 responses are normal or blunted in SHR compared with normotensive WKY and Wistar rats.10 21 22 23 In addition, we recently demonstrated that ETB-mediated [Ca2+]i responses in cultured vascular smooth muscle cells from SHR are reduced and that this may be due to decreased vascular ETB receptor density.24 Whether ETB vasoconstrictor effects are mediated through calcium-linked pathways in intact vessels and whether ETB vascular responses are altered in SHR are unknown.
The aims of this study were to determine pharmacologically the presence of vasoconstrictor ETB receptors in mesenteric resistance arteries, to assess whether ETB-induced vasoconstriction occurs through [Ca2+]i signaling pathways, and to assess whether vascular ETB responses are altered in hypertension. Contractile and [Ca2+]i effects of the highly selective ETB receptor agonist sarafotoxin S6c25 were studied in endothelium-denuded resistance vessels from adult SHR and WKY. Unlike in previous investigations, in the present study vessels were mounted in a perfusion myograph, which facilitates assessment of vessels in conditions that approximate in vivo conditions.
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Methods |
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Materials
All reagents were of the highest grade available. The ETB agonist sarafotoxin S6c was from Bachem California, and human endothelin-1 and BQ-123 were from Peninsula Laboratories. Fura 2-AM and pluronic F-127 were from Molecular Probes. All other chemicals were obtained from Sigma Chemical Co, Fisher Scientific Co, and BDH Inc.
Experimental Animals
The study was approved by the Animal Ethics Committee of the
Clinical Research Institute of Montreal, Canada. Male SHR and WKY 16
weeks of age were acquired from Taconic Farms, Inc, Germantown, NY. The
rats were housed under standardized conditions with controlled
temperature (22°C) and humidity level (60%) and exposure to a
12-hour light/dark cycle. Indirect systolic blood pressure was
measured by the tail-cuff method in conscious, restrained animals.
Rats were killed by decapitation at 18 weeks of age.
Experimental Setup
The mesentery was removed and the mesenteric vascular bed
dissected. An arterial segment 
2 mm long of a second- or
third-order branch (intraluminal diameter 200 to 250 µm) was
transferred to a vessel flow chamber (Living Systems Instrumentation
Inc) filled with warmed (37°C), oxygenated (95%
O2/5% CO2)
physiological salt solution, which contained (in
mmol/L): NaCl 120, NaHCO3 25, KCl 4.7,
KH2PO4 1.18, MgSO4 1.18,
CaCl2 2.5, EDTA 0.026, and glucose 5.5. The chamber
contained two glass microcannulas. The proximal and distal ends of the
artery were mounted onto the proximal and distal ends of the cannulas,
respectively. Both ends of the artery were secured to the microcannulas
with a surgical nylon suture. The axial length of the
arterial segment was adjusted by carefully moving the
cannula until the vascular walls were parallel, without any warping.
Intraluminal flow was initiated with a peristaltic pump, and warmed
physiological salt solution was passed at a
constant flow of 75 µL/min. The vessels were pressurized to 60 mm Hg
and maintained at this constant pressure without further intraluminal
perfusion. The superfusate solution to which the agonists
were applied circulated at a flow rate of 2 mL/min. Before the vessels
were pressurized, the endothelium was removed by
intraluminal passage of air, and absence of the
endothelium was verified by the absence of dilation of
norepinephrine-preconstricted vessels in response to
the endothelium-dependent vasodilator acetylcholine
(10-5 mol/L).
Measurement of [Ca2+]i in
Pressurized Vessels
Vessel [Ca2+]i was measured by
fluorescence digital imaging with the use of the
fluorescent dye fura 2-AM. The mounted,
endothelium-denuded vessel was loaded with 10
µmol fura 2-AM dissolved in 0.5% dimethyl sulfoxide, 0.02% pluronic
F-127, and 0.1% cremophor EL. To load the tissue fura 2-AM was applied
intraluminally and extraluminally and incubated in the dark for 3.5
hours. Thereafter, extraneous dye was washed out by intraluminal and
extraluminal perfusion of prewarmed physiological
salt solution. The flow chamber was placed on the stage of an inverted
microscope (Axiovert 135, Zeiss) equipped for dual excitation
wavelength (343 and 380 nm) and single-emission wavelength (520 nm)
fluorescence. Vessel [Ca2+]i
was measured by fluorescence digital imaging (Attofluor,
Ratiovision, Digital Fluorescence System, Zeiss) on the basis
of previously described methods.26 27 The
Kd for the fura 2–Ca2+
complex was assumed to be 342 nmol/L according to previously described
calibration techniques for whole vessels.27 Images were
stored on computer for determination of lumen diameter, which was
considered to be a measurement of contractile response.
Protocols
To determine whether vasoconstrictor ETB receptors
are present on vascular smooth muscle cells in mesenteric vessels,
concentration-response curves to the ETB agonist
sarafotoxin S6c (10-11 to
10-6 mol/L) were obtained. Cumulative
dose responses could not be obtained because repetitive stimulations
resulted in failure of vessels to respond to the agonists. For this
reason, single vessels were used for single experiments. In some
experiments, vessels were exposed to the ETA receptor
antagonist BQ-12328
10-6 mol/L for 5 minutes before addition
of sarafotoxin S6c 10-6 mol/L.
Dose-response curves to endothelin-1
(10-12 to
10-5 mol/L) were also obtained. All
agents were perfused extraluminally in the
superfusate at a constant perfusion flow rate. Vessels were
exposed to the agonist for 5 minutes, and the response was taken to be
the maximal contraction and [Ca2+]i
response elicited for each concentration.
Lumen diameter was measured with the artery in the resting and agonist-stimulated states. Measurements were made at six points along the length of the vessel segment, and the mean was calculated. Contractions were determined to be the percentage change in lumen diameter induced by the agonist relative to the lumen diameter with the vessel in the unstimulated state (taken to be 100%).
Statistical Analysis
Data are expressed as mean±SEM. Differences between groups were
evaluated by Student's t test. Concentration-response
curves were fitted by nonlinear regression, the concentration of the
agonists (in moles per liter) causing half-maximal response
(EC50) was determined, and the pD2 value was
calculated as -log EC50.
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Results |
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Blood Pressure, Weight, and Morphological Characteristics of Vessels
SHR weighed significantly less (P<.01) than 17-week-old age-matched WKY (326±10 versus 470±17 g). The mean systolic blood pressure of SHR (200±10 mm Hg) was significantly higher (P<.01) than that of age-matched control WKY (108±16 mm Hg). The lumen diameter and the media external diameter were significantly smaller, whereas the media thickness and the ratio of media to lumen were significantly greater in SHR than WKY vessels (Table).
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Intracellular Cytosolic Free Calcium in Mesenteric
Arteries
Basal [Ca2+]i in vessels of SHR
(170±4 nmol/L) was significantly higher than in vessels of WKY (134±3
nmol/L). Sarafotoxin S6c increased
[Ca2+]i in a dose-dependent manner
(Fig 1). Preexposure of vessels to the ETA
receptor antagonist BQ-123 had no effect on sarafotoxin
S6c–induced responses. The pD2 value in SHR was
8.8±0.9, which was not significantly different from that of WKY rats
(8.4±0.3). Maximal [Ca2+]i responses
induced by sarafotoxin S6c at concentrations of
10-11 to
10-9 mol/L were significantly greater
(P<.01) in SHR than in WKY (Fig 1). When
[Ca2+]i transients were compared as
relative changes induced by sarafotoxin S6c (calculated as the
difference between agonist-induced
[Ca2+]i and basal
[Ca2+]i), however, responses were
significantly lower in SHR (Fig 1). Endothelin-1 also induced
concentration-dependent increases in
[Ca2+]i. The pD2 values
for endothelin-1 stimulation of
[Ca2+]i were 8.7±0.5 for SHR and
8.1±0.6 for WKY. Endothelin-1 and sarafotoxin S6c at concentrations
that elicit maximal responses (10-5 mol
endothelin-1 and 10-6 mol/L sarafotoxin
S6c) induced significantly smaller
[Ca2+]i responses in SHR than WKY
cells (Figs 2 and 3).
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Effects of Sarafotoxin S6c and Endothelin-1 on Vascular
Contraction
Sarafotoxin S6c at low concentrations induced small changes
(<10% decrease in lumen diameter) in vessel lumen size. At
concentrations <10-8 mol/L, there were
no significant differences in sarafotoxin S6c–induced contractile
responses between SHR and WKY vessels. Sarafotoxin S6c at a maximal
dose of 10-6 mol/L induced a 28±3%
reduction in lumen diameter in WKY vessels and a significantly smaller
(P<.05) reduction (17±2%) in SHR vessels (Fig 3). These
changes followed the same pattern as sarafotoxin S6c–induced
[Ca2+]i responses (Fig 3).
Endothelin-1 produced concentration-dependent contractions in WKY
and SHR vessels (pD2=9.3±0.15 for WKY, 9.6±0.42 for SHR).
The change in lumen diameter induced by
10-5 mol/L endothelin-1 was less in SHR
vessels compared with WKY vessels, but the difference did not
reach significance (Fig 2).
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Discussion |
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This study demonstrates that mesenteric vessels possess vasoconstrictor ETB receptors that are linked to Ca2+ signaling pathways. In SHR, ETB receptor-mediated vasoconstriction is reduced, and this may be due to attenuated [Ca2+]i responsiveness. In agreement with other reports, the present study demonstrates that resistance vessels from SHR have smaller lumen diameter, smaller external media diameter, and thicker media than those from WKY.21 23 These morphological differences may contribute to alterations in vascular function in SHR. In our study, contractile responses to both sarafotoxin S6c and endothelin-1 were reduced in SHR. Since contraction was determined to be the net agonist-induced change in lumen diameter relative to the lumen diameter in the basal unstimulated state, differences observed were true contractile differences and not simply due to SHR vessels having smaller basal lumen diameters.
Sarafotoxin S6c has a much higher affinity for ETB than ETA receptors and can be used as an ETB-selective agonist.25 The facts that sarafotoxin S6c elicited [Ca2+]i and contractile responses in endothelium-denuded vessels (ie, removal of endothelial ETB receptors) and that these responses were unaffected in the presence of ETA receptor blockade confirm the existence of ETB receptors on vascular smooth muscle cells in mesenteric vessels. However, the relative contribution of vascular ETB receptors to endothelin-1 vasoconstriction is unclear. In the present study, endothelin-1–stimulated effects (through ETA and ETB receptors) were significantly greater than that of sarafotoxin S6c, suggesting that vascular ETB responses may be quantitatively small in mesenteric vessels. Nevertheless, although the relative importance of vascular ETB receptors compared with ETA receptors is minimal, the ETB component may contribute to the maintenance of vascular tone.15 This seems to be especially important in large arteries and veins29 30 and in endothelin-1–induced contraction in old rats.12
ETA receptor–linked, endothelin-1–induced vasoconstriction is mediated through two distinct intracellular signaling transduction systems, phospholipase C activation and intracellular calcium release, and through opening of Ca2+ channels. Endothelin-1 increases vascular smooth muscle [Ca2+]i, which is a vital determinant of vascular contraction.4 5 31 Underlying mechanisms for ETB-mediated constriction are unknown. In cultured, passaged aortic cells and primary unpassaged mesenteric vascular smooth muscle cells, ETB agonists significantly elevate [Ca2+]i, suggesting that vascular ETB receptors may also mediate their contractile effects through phospholipase C activation inducing calcium release and possibly through Ca2+ channels. We demonstrate in the present study for the first time that the ETB agonist sarafotoxin S6c increases [Ca2+]i in intact, pressurized vessels in a concentration-dependent manner and that elevations in [Ca2+]i are related to vascular contraction. These results confirm that ETB receptors are linked to intracellular Ca2+ signaling pathways.
Although ET-1 plays an important physiological role in maintaining vascular tone, its role in hypertension is unclear. In severe and malignant hypertension, endothelin-1 probably increases blood pressure through its vasoconstrictor and mitogenic effects in resistance vessels, but in spontaneous and essential hypertension endothelin-1 appears to be less important.32 Some studies have demonstrated enhanced responses to endothelin-1, whereas we and others have consistently found that endothelin-1–induced responses are unchanged or reduced in SHR.21 22 23 In the present study, we present the novel finding that ETB-mediated constriction is also reduced in SHR. The underlying mechanisms for this are not clear, but it has been suggested that ETB receptors are downregulated much more easily and more rapidly than ETA receptors.33 We have also shown that in SHR mesenteric vessels, ETB receptor density is significantly reduced.24 The significance of attenuated ETB vasoconstriction in SHR awaits clarification.
In conclusion, the presence of ETB receptors is demonstrated in rat mesenteric small arteries. Vasoconstrictor responses elicited by ETB receptors are mediated through elevations in [Ca2+]i, suggesting that ETB receptors are associated with cytosolic Ca2+ signaling pathways. Although ETB receptor–mediated constriction is quantitatively small, these receptors may contribute to maintenance of vascular tone. In SHR, reduced ETB-elicited effects may be a manifestation of overall blunting of the endothelin system in this model of hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from the Medical Research Council of Canada (MRCC) to the Multidisciplinary Research Group on Hypertension. R.M. Touyz is a fellow of the MRCC. We thank Angie Poliseno for secretarial help.
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Footnotes |
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Reprint requests to Ernesto L. Schiffrin, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec H2W 1R7, Canada.
Received June 19, 1995; first decision September 21, 1995; accepted October 6, 1995.
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