(Hypertension. 1997;30:1210-1215.)
© 1997 American Heart Association, Inc.
Articles |
Endothelin and Prostaglandin H2 Enhance Arteriolar Myogenic Tone in Hypertension
From the Department of Physiology, New York Medical College, Valhalla, NY.
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Abstract |
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Abstract We hypothesized that endothelin in addition to prostaglandin (PG)H2 may also contribute to the enhanced myogenic tone of skeletal muscle arterioles of spontaneously hypertensive (SH) rats. Changes in the diameter of isolated, cannulated arterioles (
60 µm) from cremaster muscles of 30-week-old
normotensive Wistar Kyoto (WKY) and SH rats were measured as a function
of perfusion pressure (20 to 140 mm Hg). Pressure-induced
constrictions were significantly enhanced between 60 to 140 mm Hg
in arterioles of SH rats compared with those of WKY rats; at 80 and
140 mm Hg the normalized diameter of arterioles (expressed as a
percentage of corresponding passive diameter) of SH rats was 11.0% and
15.4% less (P<.05) than that of WKY rats. After inhibition
of thromboxane A2–PGH2 receptors
by SQ 29,548 (10-6 mol/L), the still enhanced
myogenic response of SH arterioles was eliminated by the removal of
endothelium or the administration of BQ-123
(10-7 mol/L), an endothelin A (ET-A) receptor
blocker, which also inhibited constrictions to exogenous ET-1
(10-11 to 5x10-10
mol/L). ET-1 elicited comparable responses in arterioles of SH and WKY
rats. Thus, in SH rats the enhanced arteriolar constriction to
increases in intravascular pressure seems to be due to the
production of endothelium-derived constrictor
factors PGH2 and endothelin.
Key Words: hypertension, genetic • myogenic tone • arterioles • intraluminal pressure • endothelium
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Introduction |
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The underlying mechanisms for maintaining an increased peripheral vascular resistance in hypertension are still not elucidated, but it is thought that the increased tone of skeletal muscle arteries and arterioles, due to the changes in their structure, contributes significantly to the elevated peripheral resistance.1 2 3
In vitro studies of arteries of various sizes demonstrated a thickening of the vascular wall in hypertension and suggested that this change is an adaptation to the elevated pressure resulting in the normalization of wall stress. It was also implied that the thickening of the smooth muscle layer3 is associated with an increased contractile capacity of the vessels. One of the primary local factors that contributes to the development of basal tone of arterioles is the myogenic mechanism4 that is especially prominent in the arterioles of skeletal muscle.5 Because this mechanism is activated by changes in transmural pressure, it was logical to assume that it is altered in the presence of an increased intravascular pressure in hypertension. Indeed, an augmented constriction of cerebral vessels,6 renal interlobular arteries,7 and arterioles of skeletal muscle8 9 and mesentery10 in response to changes in intravascular pressure has already been documented in various models of experimental hypertension. In addition, Henriksen et al found an augmented constrictor response to changes in transmural pressure in patients with essential hypertension.11
The myogenic response is intrinsic to vascular smooth muscle. Its magnitude in normotensive animals is modulated by the release of endothelium-derived dilator factors.5 In contrast, the altered function of endothelium results in an enhancement of pressure-induced arteriolar tone in hypertension. In earlier studies8 we have found that in SHR, PGH2 is one of the factors that is responsible for the enhanced myogenic tone, whereas the nature of the other endothelial factor or factors remained obscure.
Because previous studies have demonstrated an elevated level of endothelin in hypertension,12 13 and because endothelin-specific antibodies, intravenous infusion of endothelin receptor antagonists, or intravenous infusion of endothelin-converting enzyme inhibitors reduce blood pressure in genetic forms of hypertension,14 15 16 we hypothesized that endothelin is the other factor contributing to the enhancement of myogenic tone of arterioles of hypertensive rats.
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Methods |
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Experiments were conducted on isolated arterioles (
60
µm) of cremaster muscle of 30-week-old male normotensive WKY and SHR.
The procedures and protocols were in accordance with our institutional
guidelines. Systolic arterial blood pressure was
measured by the tail-cuff method. Rats were anesthetized with
intraperitoneal injections of sodium pentobarbital
(Nembutal sodium, 50 mg/kg). The isolation procedure of
cremasteric arterioles has been described previously.8
Briefly, the cremaster muscle of rats was exposed by a median incision
of the scrotal sac, cleared of adhering fascia, and separated from the
scrotal sac. The muscle then was cut out and placed on a Petri dish
containing cold (0 to 4°C) salt solution (pH 7.4) that was composed
of (in mmol/L) 145 NaCl, 5.0 KCl, 2.0 CaCl2,
1.0 MgSO4, 1.0 NaH2PO4, 5.0
dextrose, 2.0 pyruvate, 0.02 EDTA, and 3.0
3-N-morpholino-propane sulfonic acid. The muscle was
pinned to the silicone bottom of the dish and allowed to equilibrate
for approximately 15 minutes. After the muscle was dissected, the rats
were killed by an overdose of sodium pentobarbital. With the use of microsurgery instruments and an operating microscope (Olympus), a 1- to 2-mm length segment of a second-order arteriole branching off from the main (first-order) arteriole that supplied the muscle was isolated and then transferred to the vessel chamber. The chamber contained a pair of glass micropipettes filled with PSS (see below) at room temperature.
The inflow micropipette was connected to a silicone rubber tube linked to a pressure-servo syringe system (Living Systems Inc). The distal (outflow) pipette was equipped with a three-way stopcock. The PSS used for suffusion and perfusion of the vessels contained (in mmol/L) 118.0 NaCl, 5.0 KCl, 2.5 CaCl2, 1.0 MgSO4, 10.0 dextrose, 24.0 NaHCO3, 1.0 KH2PO4, and 0.02 EDTA; and it was equilibrated with a gas mixture of 21% O2/5% CO2, balanced with N2, at PH 7.4 (33°C). From a reservoir, the vessel chamber (15 mL) was continuously supplied with PSS at a rate of 40 mL/min.
After the vessel was mounted on the proximal pipette and secured with a
suture, the PP was raised to 20 mm Hg to clear the clotted blood
from the lumen. Then the other end of the vessel was mounted on the
distal pipette. To flush the vessel and cannulas the system was
perfused for several minutes, then the outflow cannula was closed and
the PP was slowly (1 minute) increased to 80 mm Hg. At this
time, the pressure-servo system was placed in the manual mode (ie, no
automatic maintenance of PP) in order to ascertain that there
were no leaks in the system. If no leaks were detected (ie, PP remained
constant), the pressure-servo system was set in the automatic mode. The
temperature was set to 33°C (YSI temperature controller), and the
vessel was allowed to equilibrate for about 1 hour.
In all protocols, the changes in diameter of arterioles in response to increases in PP under no-flow conditions were measured with an image shearing monitor and recorded with a strip-chart recorder. Only those vessels that developed substantial spontaneous constriction to pressure (80 mm Hg) were used, because no vasoactive agent was added to the PSS. After the equilibration period PP was decreased to 20 mm Hg, and then increased, in 20 mm Hg steps, to 140 mm Hg. Each pressure step was maintained for 5 to 10 minutes to allow the vessels to reach a stable condition before the diameter of the arterioles was measured. After obtaining the pressure-diameter relationship, the pressure was lowered to 80 mm Hg, then after approximately 20 minutes, responses of arterioles to vasoactive agents were tested.
In the first protocol after control responses, the
endothelium of the arterioles was removed by perfusion
of the vessels with air, as previously described in
detail.8 The arteriole was untied from the proximal
pipette, and through the distal pipette air (1 mL) was injected into
the lumen for 1 minute. Then the arteriole was remounted to the
proximal pipette. The arteriole was then perfused with PSS for 20
minutes at a pressure of 20 mm Hg to clear the debris. The
outflow stopcock was then closed and PP raised to 80 mm Hg for 30
minutes to establish a stable tone. At this pressure the efficacy of
endothelial denudation was ascertained by testing the
arteriolar responses to acetylcholine (5x10-8
mol/L) and sodium nitroprusside (10-7
mol/L), endothelium-dependent and -independent
vasodilators, respectively, before and after the administration of the
air bolus. As in previous studies,8 we found that infusion
of air resulted in a loss of function of the
endothelium, as indicated by the absence of dilation to
acetylcholine, whereas dilation to sodium nitroprusside remained
intact. After removal of the endothelium, changes in
diameter in response to step increases in PP were reassessed.
In the second series of experiments, after obtaining control pressure-diameter curves, the vessels were subjected to SQ 29,548 (10-6 mol/L), a TXA2-PGH2 receptor antagonist.8 16 The efficacy of this antagonist was tested by arteriolar responses to U46619 (10-8 mol/L), a TXA2-PGH2 receptor agonist, before and after the vessels were exposed to SQ 29,548. Then changes in diameter in response to step increases in PP were reassessed.
In the third group of experiments, the pressure-diameter relationship was investigated in control conditions and in the presence of BQ-123 (10-7 mol/L), a specific inhibitor of ET-A receptors.15 Then, the effect of combined administration of BQ-123 and SQ 29,548 on the pressure-diameter curve was obtained. In one group of vessels, arteriolar constrictions to ET-1 (10-11 to 5x10-10 mol/L) were assessed, while in another group of vessels from the same rat these responses were obtained in the presence of BQ-123.
All drugs were added to the reservoir connected to the vessel chamber and final concentrations are given. Responses to vasoactive agents were tested at 80 mm Hg PP. At the conclusion of each experiment, the suffusion solution was changed to a Ca2+-free PSS that contained sodium nitroprusside (10-4 mol/L) and EGTA (1.0 mmol/L). The vessels were incubated for 10 minutes, then the step increases in pressure were repeated and the passive diameter of arterioles at each pressure step was obtained.
All salts and chemicals were obtained from Sigma Chemical Co or Aldrich Co and were prepared on the day of the experiment. Changes in diameter in response to vasoactive agents or pressure were normalized to the corresponding passive diameter and expressed as percent changes. Results are presented as mean±SEM. Only one vessel was used from each rat; n refers to the number of vessels or rats.
Statistical analyses were done by ANOVA, followed by Tukey's post hoc test and Student's t test (paired and grouped t tests were used for data of drug responses within and between groups, respectively) as appropriate. A value of P<.05 was considered significant.
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Results |
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The systolic blood pressures of WKY and SHR were 127.1±4.9 (n=7) and 212.0.±8.2 mm Hg (n=7), respectively, showing a significant increase in blood pressure in SHR compared with WKY.
In the first series of experiments, the diameter of arterioles of WKY
and SHR, as a function of PP, was obtained in the presence of
endothelium. In order to assess the magnitude of the
pressure-induced active change in diameter (ie, active tone generated
by the arteriole), after the conclusion of experiments the
pressure-passive arteriolar diameter (in Ca2+-free
solution, see "Methods") relationship (Fig 1
, upper panel) was also obtained in each
vessel. Then, the changes in diameter of active arterioles to increases
in PP were normalized to the corresponding passive diameter at each
pressure step. We have found that except at 20 and 40 mm Hg PPs,
the passive diameters of arterioles from SHR and WKY were not
significantly different from each other (Fig 1, upper panel). In
contrast, the pressure-diameter curve of active arterioles
(Ca2+ present) of SHR started to deviate significantly
(P<.05) from that of WKY at 60 mm Hg pressure and
upward. That is, arterioles of SHR exhibited an enhanced constriction
in response to increases in PP, compared with arterioles of WKY (Fig 1, lower panel).
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In order to confirm our previous findings,8 first the
effect of SQ 29,548, a TXA2-PGH2 receptor
blocker, on the pressure-induced behavior of arterioles was examined.
SQ 29,548 did not affect pressure-diameter relationships of arterioles
of WKY (Fig 2, upper panel) but reduced
significantly the pressure-induced enhanced arteriolar constrictions in
arterioles of SHR (Fig 2, lower panel). In these experiments, after
removal of the endothelium, the pressure-diameter curve
of WKY shifted significantly downward; that is, the constriction of the
arterioles in response to pressure became significantly enhanced (Fig 2, upper panel). In contrast, in SHR after removal of the
endothelium, the pressure-diameter curve of arterioles
shifted significantly upward, namely the constriction of vessels to
increases in PP became significantly reduced (Fig 2, lower panel).
These findings demonstrate that in SHR arterioles PGH2 is
at least in part responsible for the enhanced constriction to pressure,
as suggested by previous studies,8 and that in arterioles
of WKY endothelium-derived dilator factors temper
myogenic constriction.
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Next, we investigated the possible contribution of ET to the
pressure-induced responses of arterioles by using BQ-123, a known ET-A
receptor blocker.15 18 In normotensive rats BQ-123 did not
affect the pressure-induced arteriolar tone (Fig 3, upper panel). In contrast, in
arterioles of SHR, BQ-123 significantly reduced the arteriolar
constrictions in response to step increases in PP (Fig 3, lower panel).
The administration of additional SQ 29,548 did not elicit significant
changes in the pressure-induced tone in arterioles from WKY, whereas it
further reduced significantly the myogenic tone of vessels from SHR
(Fig 3, upper and lower panels, respectively).
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To further assess the effect of ET on basal diameter of arterioles, as
a function of pressure, we expressed the changes in diameter of
arterioles isolated from SHR as percent of control diameter in the
presence of BQ-123 (Fig 4).
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In arterioles of both strains of rats SQ 29,548 eliminated the
constrictions to U46619, known to be a specific agonist of
PGH2-TXA2 receptors (Fig 5, upper panel). Administration of ET-1
elicited dose-dependent constrictions of arterioles that were not
significantly different in the two strains of rats. The efficacy of
BQ-123 to block ET receptors is indicated by the finding that even
responses to the highest concentration of ET-1 were completely
eliminated by BQ-123 (Fig 5, lower panel).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The salient findings of this study are that isolated skeletal muscle arterioles of SHR exhibit a significantly greater constriction to increases in intraluminal pressure than those of normotensive rats and that this enhanced myogenic response is due to the presence of endothelium-derived PGH2 and ET.
Previous studies demonstrated changes in the structure of the vascular wall of large vessels in hypertension.1 2 3 The observed thickening of the vascular wall was suggested to be responsible for the reduced diameter and enhanced contractility of smooth muscle.3 Because the large conduit vessels are responsible for only a fraction of the total peripheral resistance, in order to explain the increase in peripheral resistance in hypertension similar changes in the structure and/or function of arterioles had to be surmised.
It was logical to investigate first the myogenic mechanism of arterioles in hypertension, because it is specifically sensitive to changes in intraluminal pressure that elicit changes in the diameter of arterioles. As in the present study, many previous studies have been in cremasteric arterioles, because micropressure measurements in in vivo preparations showed an elevated intravascular pressure in these vessels in hypertensive rats compared with normotensive rats.19 20 Also, in these arterioles, both in vivo9 and in vitro,8 9 an enhanced constriction of arterioles in response to increases in intravascular pressure was found. Similar findings were reported in cerebral,6 renal,7 and mesenteric10 arteries from SHR, as well.
In cremasteric arterioles Falcone et al9 found that the
augmented pressure-induced response was neither structural in origin
nor mediated by 
-receptors. We have also observed in the current and
previous8 studies that the passive diameter of WKY and SHR
arterioles (in Ca2+-free solution) was not significantly
different in the in vivo pressure range, suggesting that structural
differences in the arteriolar wall are not sufficient to explain the
differences in their contractile activity. Thus, we hypothesized that
alterations in the function of arteriolar endothelium
are responsible for the observed changes. We found, indeed, that after
removal of the endothelium, arterioles of hypertensive
rats no longer exhibited enhanced constriction to pressure. These
findings suggested that the contractile activity of vascular smooth
muscle arterioles of hypertensive rats is greater than that of
normotensive rats only because of the presence of
endothelium-derived constrictor factors.
One of these factors that we could identify previously is
PGH2. This finding was confirmed by the present study,
which showed that the PGH2 receptor blocker SQ 29,654
significantly reduced (but did not eliminate) the enhanced response of
hypertensive arterioles to pressure (Fig 2
, lower panel). These and
previous findings21 22 together suggest that hypertension
elicits an alteration in arachidonic acid
metabolism, resulting in an enhanced synthesis of
PGH2 in arteriolar endothelium.
In vivo, in gracilis muscle of normotensive cats, Ekelund at
al18 found no role for ET in the basal tone or the
mediation of the myogenic response of arterioles. The current study
confirms their findings. In a genetic model of
hypertension,14 however, ET-specific antibodies or
intravenous infusion of ET-A and ET-B receptor
antagonists reduced blood pressure, suggesting a role for
ET in the maintenance of high blood pressure. In addition, in
borderline hypertension in humans an increased basal concentration of
plasma ET was reported.12 13 On the basis of these studies
and because in SHR removal of the endothelium resulted in a
greater attenuation of the myogenic tone than the administration of SQ
29,548 alone (Fig 2, lower panel), we surmised that ET may also
contribute to the enhanced pressure-induced constriction of
arterioles.
The ET-A receptor antagonist BQ-123 significantly reduced
pressure-induced constrictions of arterioles of hypertensive rats, ie,
it elicited dilations of 5% to 30%, which seemed to be in parallel
with increases in pressure (Fig 4), whereas it did not significantly
affect diameters of vessels of normotensive rats. Also, dose-dependent
constrictor responses to ET-1 were similar (and completely blocked by
BQ-123) in arterioles of both groups of rats (Fig 5). Thus, we
concluded that ET, produced in the endothelium,
augments the myogenic mechanism of arterioles in hypertension, whereas
synthesis of this constrictor factor is negligible in normotensive
rats. These findings correspond to the recent demonstration of
expression of ET-1 in small arteries from humans with essential
hypertension23 and an elevated level of immunoreactive
ET-1 in the plasma of hypertensive humans. Interestingly, ET-1 was also
significantly higher in hypertensive black females and males, which
have been shown to have a greater prevalence for hypertension than
white persons.24
Combined application of ET-A and PGH2 receptor
antagonists eliminated completely the enhanced
pressure-induced constrictions in hypertensive rats (Fig 3), suggesting
that PGH2 and ET together are responsible for the
enhancement of the myogenic response.
The reasons for alterations in the function of endothelium in hypertension that lead to an enhanced release of PGH2 and ET are at present uncertain. A role for oxygen-derived free radicals that could be produced in hypertension has been suggested as the possible cause of the enhanced production of PGH2,25 26 27 which may also be linked to the diminished synthesis of endothelium-derived nitric oxide, also observed in arterioles of spontaneously hypertensive rats.22 All these alterations favor vasoconstriction, which could lead to chronic increases in wall shear stress.28 Furthermore, increases in shear stress may stimulate ET release, as suggested by previous studies,29 30 which then could further enhance the myogenic mechanism. Thus, a vicious cycle can develop, leading to further increases in peripheral resistance and systemic blood pressure.
It is of interest also that in the absence of endothelium the myogenic tone of WKY arterioles became significantly enhanced, suggesting an important role for endothelium-derived vasodilator factors in reducing the pressure-induced tone of these arterioles. One of these factors is likely to be nitric oxide, since previous studies showed that inhibition of nitric oxide synthesis elicits significant increases in basal arteriolar tone but only in arterioles of normotensive rats.28 Thus, the balance of endothelium-derived dilator and constrictor factors seems to be an important determinant of arteriolar tone.
In conclusion, we found an endothelium-dependent augmentation of the pressure-induced constriction of arterioles of genetically hypertensive rats. This enhanced myogenic response of hypertensive arterioles is due to the enhanced synthesis of PGH2 and ET, which seems to be negligible in normotensive arterioles. It seems, therefore, that an altered endothelial mechanotransduction in skeletal muscle arterioles could be an important factor in the development of increased peripheral resistance in hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health HL-46813, PO1 HL 43023, and OTKA T-023863. We wish to thank Miriam Nunez for her excellent secretarial assistance.
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Footnotes |
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Reprint requests to Akos Koller, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595.
Received January 17, 1997; first decision February 13, 1997; accepted May 20, 1997.
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 E. C. Eringa, C. D.A. Stehouwer, T. Merlijn, N. Westerhof, and P. Sipkema Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles Cardiovasc Res, December 1, 2002; 56(3): 464 - 471. [Abstract] [Full Text] [PDF]
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 T Ozaki, H Nishina, M A Hanson, and L Poston Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring J. Physiol., January 1, 2001; 530(1): 141 - 152. [Abstract] [Full Text] [PDF]
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 Z. Ungvari and A. Koller Endothelin and Prostaglandin H2/Thromboxane A2 Enhance Myogenic Constriction in Hypertension by Increasing Ca2+ Sensitivity of Arteriolar Smooth Muscle Hypertension, November 1, 2000; 36(5): 856 - 861. [Abstract] [Full Text] [PDF]
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A. Huang, D. Sun, and A. Koller Shear Stress-Induced Release of Prostaglandin H2 in Arterioles of Hypertensive Rats Hypertension, April 1, 2000; 35(4): 925 - 930. [Abstract] [Full Text] [PDF]
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T.-D. Nguyen, P. Vequaud, and E. Thorin Effects of endothelin receptor antagonists and nitric oxide on myogenic tone and {alpha}-adrenergic-dependent contractions of rabbit resistance arteries Cardiovasc Res, August 15, 1999; 43(3): 755 - 761. [Abstract] [Full Text] [PDF]
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A. Huang, D. Sun, G. Kaley, and A. Koller Estrogen Preserves Regulation of Shear Stress by Nitric Oxide in Arterioles of Female Hypertensive Rats Hypertension, January 1, 1998; 31(1): 309 - 314. [Abstract] [Full Text] [PDF]
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