(Hypertension. 2000;35:925.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Shear Stress–Induced Release of Prostaglandin H2 in Arterioles of Hypertensive Rats
From the Department of Physiology, New York Medical College, Valhalla.
Correspondence to Akos Koller, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Koller{at}nymc.edu
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Abstract—The nitric oxide–mediated portion of shear stress–induced dilation of rat gracilis muscle arterioles was shown to be impaired in spontaneously hypertensive rats (SHR). Because shear stress–induced dilation is primarily mediated by endothelium-derived prostaglandins in rat cremasteric arterioles, we hypothesized that in the cremasteric vascular bed the mediation of shear stress–induced dilation by prostaglandins is altered in hypertension. At a constant intraluminal pressure of 80 mm Hg, the active diameters of isolated rat cremasteric arterioles of normotensive 30-week-old Wistar-Kyoto rats (WKY) and SHR were 58.0±3.1 and 51.7±3.6 µm, respectively, whereas their passive diameters were 109.4±4.4 and 101.9±6.7 µm, respectively. Dilations to increases in shear stress elicited by increases in intraluminal flow (from 0 to 25 µL/min) were significantly less (P<0.05) in cremasteric arterioles isolated from SHR than from WKY. Arachidonic acid (10-5 mol/L) elicited constrictions in SHR arterioles but dilations in WKY arterioles. The prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor antagonist SQ 29,548 (10-6 mol/L) significantly increased basal diameter by 11% and normalized the attenuated shear stress–induced dilation in SHR, whereas it did not affect basal diameter and arteriolar responses of WKY. Furegrelate, a specific inhibitor of TxA2 synthase, did not affect the response in SHR. Also, SQ 29,548 reversed the arachidonic acid–induced constriction to dilation in SHR arterioles, whereas it did not affect the dilator response in WKY arterioles. Constrictions of arterioles of WKY and SHR to U46,619 (a PGH2/TxA2 receptor agonist) were not different. These results demonstrate that in cremasteric arterioles of hypertensive rats, shear stress elicits an enhanced release of PGH2, resulting in a reduced shear stress–dependent dilation. Thus, augmented hemodynamic forces can alter the shear stress–induced synthesis of prostaglandins, which may contribute to the elevated vascular resistance in hypertension.
Key Words: hypertension, genetic • microcirculation • muscle, cremasteric • prostaglandins
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Introduction |
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In vivo studies of the skeletal muscle microcirculation suggest that a reduction in the caliber and number of vessels1 2 3 4 contributes to the increased peripheral resistance in hypertension. However, it is likely that functional changes occur before an alteration in the structure of microvessels. Previous studies have indicated that the endothelium plays a pivotal role in the regulation of arteriolar diameter via the production and release of dilator factors5 to a variety of agonists. In vivo, the primary stimulus for the release of endothelial factors is a change in wall shear stress (WSS), which accompanies changes in flow velocity or viscosity of the blood.6 It has been shown that in response to increases in flow/WSS, both nitric oxide (NO) and prostaglandins are produced in the endothelium of rat gracilis muscle arterioles7 ; thus, they are importantly involved in the modulation of arteriolar resistance.
Previously, it has been found that the shear stress–dependent dilation of gracilis skeletal muscle arterioles is significantly reduced in spontaneously hypertensive rats (SHR) compared with normotensive rats.8 9 This is primarily due to the absence of the NO-mediated portion of the response.8 We have also shown that in isolated gracilis arterioles, an acute increase of intraluminal pressure impairs the NO-mediated portion of shear stress–induced dilation because of an increased superoxide production.10
These findings suggest that high pressure may interfere specifically with the shear stress–induced release/synthesis of NO, most likely via an increased release of reactive oxygen species.11 Yet, there are studies showing that hypertension elicits an enhanced production of prostaglandin H2 (PGH2) in large vessels.12 13 14 15 16 Recent studies in microvessels suggest that an alteration in the production and/or release of endothelium-derived constrictor factors, such as PGH2/thromboxane A2 (TxA2), could, in addition to the lack of NO, also account for the increased vascular resistance in various forms of hypertension.17 18 19
Previously, we have found that shear stress–dependent dilation in arterioles of rat cremaster muscle of normotensive rats is mediated solely by endothelium-derived dilator prostaglandins,20 21 a condition that allows us to test the idea whether this prostaglandin-dependent response is compromised in genetically hypertensive rats. In this context, we previously found an enhanced release of PGH2 to pressure and vasoactive substances in these vessels.17 18 On the basis of the aforementioned studies, we hypothesized that shear stress–induced dilation is reduced because of the altered metabolism of prostaglandins. To test this hypothesis, we investigated the changes in diameter of isolated cremasteric arterioles of normotensive and SHR as a function of WSS (with constant intravascular pressure in the vessels) in the absence and presence of a PGH2/TxA2 receptor antagonist or a TxA2 synthase inhibitor.
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Methods |
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The studies were conducted on isolated arterioles (
55
µm in diameter) of cremaster muscle of 30-week-old male normotensive
Wistar-Kyoto rats (WKY) and SHR. All experimental protocols were
performed in accordance with institutional guidelines. Systolic
blood pressure of conscious rats 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 cremaster muscle arterioles has been described
previously.21 Briefly, the cremaster muscle of rats was
exposed by an incision of the skin. The muscle then was cut out and
placed on a Petri dish containing cold (0°C to 4°C) salt solution
(pH 7.4), which was composed of (mmol/L) NaCl 145, KCl 5.0,
CaCl2 2.0, MgSO4 1.0,
NaH2PO4 1.0, dextrose 5.0,
pyruvate 2.0, EDTA 0.02, and MOPS 3.0. Rats were euthanized by an
overdose of Nembutal.
A segment (1 mm in length) of an arteriole, branching off from
the main arteriole supplying the muscle, was isolated from the
cremaster muscle and surrounding tissue and transferred to the vessel
chamber. The physiological salt (PS) solution used
for suffusion and perfusion of the vessels contained (mmol/L) NaCl
110.0, KCl 5.0, CaCl2 2.5,
MgSO4 1.0, dextrose 10.0,
NaHCO3 24.0, and EDTA 0.02 and was equilibrated
with a gas mixture of 21%
O2+5%CO2, balanced with
N2, at pH 7.4 (34°C). From a reservoir (60 mL),
the vessel chamber (15 mL) was continuously supplied with PS solution
at a rate of 40 mL/min. After the vessel was mounted on the proximal
pipette, the perfusion pressure was raised to 20 mm Hg to clear
the debris from the lumen. Then, the other end of the vessel was
mounted on the distal pipette. As described previously,21
both proximal (inflow) and distal (outflow) micropipettes (with similar
dimensions) were connected with silicone tubing to a
pressure-servosyringe system (Living Systems Inc). To flush the vessel
and cannulas, the system was perfused for several minutes. Then, the
perfusion pressure was slowly increased to 80 mm Hg. The
temperature was set to 34°C (YSI temperature controller), and the
vessels were allowed to equilibrate for 1 hour.
Experimental Procedure
Vessels were allowed to develop spontaneous tone in response to
intraluminal pressure in the absence of vasoactive agents. After the
equilibration period, the vessels were exposed to increases in
perfusate flow from 0 to 25 µL/min in 5-µL/min steps. Flow
was established at a constant intravascular pressure (80 mm Hg)
by changing proximal and distal pressures to an equal degree, but in
opposite directions, to keep midpoint luminal pressure constant.
Responses to vasoactive agents were tested at 80 mm Hg perfusion
pressure in no-flow conditions. All drugs were added to the reservoir
connected to the vessel chamber, and final concentrations are reported.
After responses to each drug subsided, the vessel chamber was flushed
with PS solution. At the conclusion of each experiment, the suffusion
solution was changed to a Ca2+-free PS solution
that contained EGTA (1.0 mmol/L) to assess the level of active
tone generated by the arterioles in response to intravascular pressure.
The vessels were incubated for 10 minutes, and then the passive
diameter of arterioles at 80 mm Hg perfusion pressure was
obtained.
The role of constrictor prostaglandins in shear
stress–induced dilation of cremaster muscle arterioles was studied in
the following manner: After obtaining control responses, the
PGH2/TxA2 receptor
antagonist SQ 29,548 (10-6 mol/L)
was added to the suffusion solution.22 In arterioles of
SHR, the effect of furegrelate (5x10-6 mol/L),
a TxA2 synthase
inhibitor,23 on shear stress–induced dilation
was tested. After an incubation period (30 minutes), the shear
stress–diameter relations were again assessed. Also, arteriolar
responses to arachidonic acid (AA,
10-5 mol/L), prostaglandin
E2 (PGE2,
10-8 mol/L), and U46,619
(10-8 mol/L), a stable
PGH2/TxA2 receptor agonist,
were obtained before and after the vessels were exposed to SQ
29,548.
All salts and chemicals were obtained from Sigma Chemical Co or Cayman
Chemical Co. SQ 29,548, furegrelate, AA, PGE2,
and U46,619 were dissolved in ethanol as stock solutions and were
diluted with PS solution. The diameters of vessels and peak responses
were measured with an image-shearing monitor (model 907, IPM) and
recorded with an X-Y recorder (model MC6625, Multicorder). The
flow was measured by a ball flowmeter (Omega Engineering Inc), which
was calibrated by a perfusion pump (Harvard Apparatus Co,
Inc) in which flow rate was accurate in the range of 0 to 100
µL/min.21 WSS was calculated from diameter (2r) and flow
data according to the following equation:
WSS=4
Q/
r3, where is viscosity of the
perfusate (0.007 poise at 37°C), Q is perfusate flow,
and r is vessel radius. Relations between shear stress and diameter
were obtained for arterioles of both strains of rats in control
conditions and during the use of SQ 29,548 or furegrelate. Changes in
diameter in response to vasoactive agents were normalized to the
corresponding passive diameter and expressed as percent changes. Data
are mean±SEM; n refers to the number of rats. Statistical
analyses were performed by ANOVA, followed by Tukey post hoc
test, regression analysis, and paired and grouped Student
t tests, as appropriate. A value of P<0.05 was
considered significant.
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Results |
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The systolic blood pressure of the SHR (212.0±8.2 mm Hg, n=7) was significantly (P<0.05) higher than that of the WKY rats (127.1±4.9 mm Hg, n=7). The active diameters of arterioles of WKY and SHR (obtained in the presence of constant intravascular pressure of 80 mm Hg and static flow conditions) were significantly different at 58.0±3.1 and 51.7±3.6 µm, respectively, whereas their corresponding passive diameters were 109.4±4 and 101.9±9 µm. Normalizing the active diameter to their corresponding passive diameter indicates no significant difference in basal tone of arterioles (
50%).
The data related to diameter changes of arterioles of WKY and SHR as a
function of WSS under control conditions are summarized in the top
panel of Figure 1. The nearly vertical
increase of the shear stress–diameter curve at 35
dyne/cm2 demonstrates the marked sensitivity of
normotensive arterioles to increases in shear stress, to which they
respond with substantial dilation. In contrast, the diameters of
hypertensive arterioles did not increase at all in this range of shear
stress, and only at >80 dyne/cm2 did
diameters increase significantly. The significant difference in the
slopes of the shear stress–diameter curves indicates that arterioles
from SHR dilate to a lesser degree in response to increases in shear
stress. Also, as shown in the top panel of Figure 1, the maximal
increase in diameter was significantly less in arterioles of SHR
(17.4±2.2 µm) than in arterioles of WKY (27.3±4.1 µm).
The bottom panel of Figure 1 shows that for a given
intra-arteriolar flow, WSS is significantly higher in vessels of SHR
compared with WKY.
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To examine whether constrictor prostaglandins are involved in the shear stress–induced response, we used 10-6 mol/L SQ 29,548, a PGH2/TxA2 receptor blocker, after obtaining control responses. In normotensive rats, SQ 29,548 did not significantly affect shear stress–induced arteriolar dilation (Figure 2, top) and basal arteriolar tone. In contrast, in cremasteric arterioles of SHR, SQ 29,548 significantly increased basal diameter (to 57.3±3.5 µm) and augmented the arteriolar dilation in response to increases in shear stress (Figure 2, middle). In separate experiments, we found that furegrelate (5x10-6 mol/L) did not affect shear stress–induced responses of arterioles from SHR (Figure 2, bottom). Comparison of shear stress–normalized diameter curves of arterioles of WKY in control conditions and SHR in the presence of SQ 29,548 revealed no significant difference between the slopes of the curves (Figure 3).
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AA (10-5 mol/L), the precursor of prostaglandins, elicited dilation of arterioles of WKY, whereas it constricted arterioles of SHR. Also, responses to PGE2 (10-8 mol/L) were significantly attenuated in SHR compared with WKY (Figure 4), whereas constrictor responses to the PGH2/TxA2 receptor agonist U46,619 were not different in arterioles of the 2 strains of rats (Figure 4). Incubation of arterioles with SQ 29,548 completely abolished constrictions to U46,619 and reversed the AA-induced constriction to dilation in SHR, whereas it did not affect the responses of WKY arterioles. Also, in the presence of SQ 29,548, dilations of WKY and SHR arterioles to PGE2 were similar.
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Discussion |
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The salient finding of the present study is that shear stress–induced dilation of cremasteric arterioles of SHR is significantly reduced compared to that of vessels of normotensive rats and that this reduced arteriolar response is primarily due to the enhanced synthesis of PGH2.
Previous investigations of the microcirculation of hypertensive animals has revealed morphological changes in the vascular wall as well as changes in the structure of the arteriolar network.1 2 3 4 Recent studies have suggested that an altered function of arteriolar endothelial cells is also involved in the development and/or maintenance of increased arteriolar resistance in hypertension. Studies of ring preparations of aorta12 16 and mesenteric arteries24 of hypertensive rats and studies in hypertensive humans25 have indicated that the endothelial synthesis of NO and perhaps other endothelial mechanisms of peripheral vessels could be impaired. In vivo6 and in vitro21 studies have demonstrated that the endothelium contributes to circulatory homeostasis by a shear stress–dependent regulation of vascular resistance that is important primarily in microvessels. Increases in WSS can take place during increases in blood flow velocity, a condition that is likely to be present in hypertension, because a higher blood pressure drop and reduced vessel diameters are present concurrently. Previous studies have revealed that the flow/shear stress–sensitive dilation of arterioles in certain tissues and organs is reduced in SHR8 9 and Dahl salt-sensitive rats26 and that the dysfunction of this mechanism relates primarily to the lack of NO mediation. Interestingly, in a recent study, Izzard and Heagerty27 showed a reduced flow-dependent dilation in small mesenteric arteries of SHR and suggested that an impairment in the NO pathway cannot account for this observation. The alterations in the arteriolar synthesis/release of prostaglandins in response to changes in WSS in hypertension is less known. In the present study, we have used cremasteric arterioles because they release only prostaglandins in response to increases in shear stress, thus allowing us to test the hypothesis that high hemodynamic forces interfere with the synthesis and release of prostaglandins as well.
Attenuation of Shear Stress–Induced Dilation in
Hypertension
In response to increases in shear stress, isolated cremasteric
arterioles exhibited a greatly reduced dilation in hypertensive rats
compared with normotensive rats, as indicated by the significant right
shift in the slope of the shear stress–diameter curve of arterioles of
SHR compared with WKY (Figure 1, top). The importance of this
finding is further underscored by the fact that for a given flow,
significantly higher shear stress develops in vessels of SHR (Figure 1, bottom). This indicates the significant impact of increased
resistance to blood flow that results in a greater power dissipation in
hypertension28 29 30 31 and may also be partly responsible for
functional rarefaction and remodeling of the vascular wall observed in
cremaster muscle microcirculation in hypertension.1 2 3 4
Previous studies have shown that shear stress–dependent dilation of
cremaster muscle arterioles is mediated primarily by
endothelium-derived prostaglandins,
inasmuch as indomethacin completely eliminated flow-
and viscosity-induced dilation both in vivo20 and in
vitro.21 Thus, we hypothesized that alterations in the
mediation of the response by prostaglandins might be
responsible for the observed reduction in shear stress–induced
dilation in this vascular bed.
Possible Role of Constriction Prostaglandins
In normotensive rats, inhibition of
PGH2/TxA2 receptors did not
significantly affect the cremasteric arteriolar dilation to increases
in WSS, suggesting no role for
PGH2/TxA2 in the mediation
of shear stress–induced arteriolar responses in normotension. In
contrast, shear stress–induced dilation in cremasteric arterioles from
hypertensive rats is markedly enhanced in the presence of SQ 29,548
(Figure 2). Also, in the presence of SQ 29,548, shear stress–induced
dilations of arterioles from WKY and SHR were not different (Figure 3).
These findings suggest that increases in shear stress elicit an
enhanced release of
PGH2/TxA2 in cremasteric
arterioles of SHR that counteracts the dilation. The nature of the
constrictor prostaglandin was further investigated by use
of furegrelate, a specific blocker of TxA2
synthase. Because furegrelate did not affect the shear stress–diameter
relation, it is likely that increased synthesis and/or accumulation of
PGH2 is responsible for the reduced dilator
response to shear stress in SHR.
In the present study, it was also shown that AA elicits dilation of WKY arterioles but constriction of SHR arterioles. The finding indicates that the metabolism of AA is altered in SHR arterioles. The reversal of AA-induced constriction to dilation by SQ 29,548 in SHR (Figure 4) unmasked the release of dilator, in addition to constrictor, prostaglandins in hypertensive arterioles. Constrictions to U46,619, a PGH2/TxA2 agonist, were not different in the 2 strains, arguing against the possibility that an enhanced density of PGH2/TxA2 receptors is responsible for the alteration in flow-dependent response in hypertension.
Our previous study revealed that at an early age, flow-dependent dilation is still present in arterioles of SHR, suggesting that the prevailing hemodynamic conditions (eg, increased flow velocity and/or pressure) to which these arterioles are exposed as hypertension develops are causing the impairment in endothelial function.29 One reason for this change in hypertension could be an alteration in the "rheoreceptors" or the endothelial signaling pathway that links the increase in shear stress to the release of AA from the plasma membrane when the endothelium is chronically exposed to high intraluminal hemodynamic forces, such as pressure and/or shear stress. The increased level of AA then is converted by cyclooxygenase-1 and/or -2 to PGH2. There are studies suggesting that in hypertension there is an increased release of NO that, however, is accompanied by an increased release of superoxide.32 33 These 2 substances can form peroxynitrite, a free radical, which has been shown to inhibit prostaglandin I2 synthase.34 35 Moreover, PGH synthase can generate superoxide,36 and PGH2 can interact with NO.37 These interactions may be responsible for the inability of endothelium to metabolize PGH2, produced in response to increases in shear stress, which results in an excess amount of PGH2. The idea that the unmetabolized PGH2 is responsible for the impaired shear stress–dependent dilation is further supported by our previous findings that enhanced myogenic constriction in hypertension could be inhibited by SQ 29,548, but not by TxA2 synthase, blockade.16 17 Previously, we found that in addition to PGH2, endothelin also contributes to the enhanced myogenic response of arterioles in hypertension.38 Release of constrictor factors to shear stress is not unique to cremasteric arterioles. In skeletal muscle venules after blocking the synthesis of NO and prostaglandins, flow elicits an endothelin-dependent constriction.39 In small mesenteric arteries of hypertensive rats, endothelin is released in response to flow, and if SHR are treated with an endothelium receptor blocker, then dilation to flow is augmented.40 The pathophysiological role of PGH2 in this process is underscored by studies of Iwama et al41 showing that the production of PGH2 correlates well with the level of blood pressure in SHR. The inability of the inhibition of PGH2/TxA2 receptors to elicit marked reduction in blood pressure in hypertension indicates that other endothelial and nonendothelial mechanisms may be altered as well.
In conclusion, the present study demonstrates a reduced shear stress–induced dilation of cremasteric arterioles of genetically hypertensive rats. The impaired dilation is due to an enhanced synthesis and/or accumulation of PGH2 in response to shear stress. Thus, the present findings suggest an important role for the enhanced synthesis of constrictor prostanoids in the regulation of vascular resistance by shear stress in hypertension.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (HL-46813 and P01 HL-43023). We thank Miriam Nunez for her excellent secretarial assistance.
Received August 27, 1999; first decision September 15, 1999; accepted December 7, 1999.
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