(Hypertension. 1995;25:758-763.)
© 1995 American Heart Association, Inc.
Articles |
Shear Stress–Induced Dilation Is Attenuated in Skeletal Muscle Arterioles of Hypertensive Rats
From the Department of Physiology, New York Medical College, Valhalla.
Correspondence to Akos Koller, MD, Department of Physiology, New York Medical College, Valhalla, NY 10595.
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Abstract |
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Abstract Hypertension is thought to alter many of the functions of the vascular endothelium. The present study examines whether shear stress–induced endothelium-dependent skeletal muscle arteriolar dilation is compromised in genetically hypertensive rats. Changes in the diameter of isolated, perfused arterioles (approximately 60 µm) from gracilis muscles of 12-week-old normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR) were investigated. At a constant perfusion pressure (80 mm Hg), the active diameter of NWR and SHR arterioles was 57.1±2.0 and 50.9±3.5 µm, respectively (mean±SEM), while the passive diameter (in Ca2+-free solution) was 113.2±3.1 and 100.6±2.9 µm, respectively. Increases in wall shear stress (from 0 to 100 dyne/cm2) elicited by increases in perfusate flow (from 0 to 25 µL/min) resulted in marked increases in the diameter of NWR arterioles, but such increases produced substantially smaller dilations in SHR arterioles (43.0 versus 18.9 µm). The prostaglandin synthesis inhibitor indomethacin (10-5 mol/L) significantly attenuated the shear stress–induced dilations in both strains of rats. In contrast, the nitric oxide synthase inhibitor N
-nitro-L-arginine
(10-4 mol/L) significantly shifted the shear
stress–diameter curve to the right in vessels from NWR (by 50
dyne/cm2) but not in those from SHR. Thus, in gracilis
muscle arterioles of SHR, the reduced dilation to increases in shear
stress seems to be due to the lack of nitric oxide synthesis and/or
release in response to shear stress. The absence of this mechanism
could result in elevated shear stress and power dissipation in the
peripheral circulation and may promote further pathological changes in
the endothelium in hypertension.
Key Words: hypertension, genetic • nitric oxide • prostaglandins • arterioles • muscle, skeletal
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Introduction |
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In vivo studies of the skeletal muscle microcirculation have demonstrated that changes in vessel caliber and vessel number may contribute to increased peripheral vascular resistance in hypertension.1 2 3 4 Previous studies indicated that the vascular endothelium plays an important role in the physiological regulation of the microcirculation through the production and release of dilator factors in response to a variety of agonists.5 We have also shown that both nitric oxide (NO) and prostaglandins are produced in the endothelium of rat skeletal muscle arterioles in response to increases in flow (wall shear stress [WSS])6 and that they are importantly involved in the development of arteriolar resistance. Recent in vitro7 8 9 10 and in vivo,11 12 including human,13 14 studies suggest that an alteration in the production and/or release of endothelium-derived relaxing factors, such as NO, could also account for the increased vascular resistance in various forms of hypertension.
We hypothesized that in hypertension the shear stress–sensitive vasodilator mechanisms of skeletal muscle arterioles are altered and that this dysfunction contributes to enhanced arteriolar resistance. To test our hypothesis, we investigated the changes in arteriolar diameter as a function of WSS and the changes in WSS as a function of perfusate flow (in the presence of a constant intravascular pressure) in isolated gracilis arterioles of normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). In addition, the role of endothelial factors in the shear stress–induced dilation of NWR and SHR arterioles was assessed by the use of pharmacological agents affecting the synthesis of endothelium-derived relaxing factor/NO and prostaglandins.15 16
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Methods |
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The studies were conducted on isolated arterioles (approximately 60 µm in diameter) of gracilis muscle of 12-week-old male NWR and SHR. In these studies we used NWR as controls because in preliminary studies we found that gracilis muscle arterioles of Wistar-Kyoto rats responded poorly, or not at all, to a variety of vasoactive stimuli. In addition, recent findings indicate that NWR may not be less appropriate as controls for SHR than Wistar-Kyoto rats.17 All experimental protocols were done in accordance with institutional guidelines. Systolic pressure of conscious rats was measured by the tail-cuff method. Rats were anesthetized with intraperitoneal injections of sodium pentobarbital (50 mg/kg). The procedure of isolation of gracilis muscle arterioles has been described previously.6 In brief, the gracilis 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) 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. The muscle was pinned to the silicone bottom of the dish and allowed to equilibrate for approximately 15 minutes, and the rats were then euthanatized by an overdose of sodium pentobarbital.
With the use of microsurgery instruments and an operating microscope (Olympus), a segment (approximately 1 mm in length) of an arteriole branching off from the main arteriole supplying the muscle was isolated from the gracilis muscle and surrounding tissue and transferred to the vessel chamber. The chamber contained a pair of glass micropipettes filled with physiological salt solution (PSS) at room temperature. The PSS 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, NaHCO324.0 , and EDTA 0.02. It was equilibrated with a gas mixture of 21% O2 and 5% CO2, balanced with N2, at pH 7.4 (37°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 sutures, the perfusion pressure was raised to 20 mm Hg to clear the clotted blood from the lumen. The other end of the vessel was then mounted on the distal pipette. As described previously,18 both proximal (inflow) and distal (outflow) micropipettes were connected with silicone tubing to a pressure-servo syringe system (Living Systems Inc). The system was arranged to have mirror symmetry, so the axis of symmetry was located perpendicularly at the middle of the arteriolar segment. Only pipettes with similar dimensions and equivalent resistances to flow were used, as assessed by the changes in perfusion pressure, in response to increments of flow by a Harvard perfusion pump. This resulted in equal resistances (R1 and R2) of the two sides of the system (from pressure transducer to the tip of the pipette).
To flush the vessel and cannulas, the system was perfused for several minutes. The perfusion pressure was then slowly (over approximately 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 pressure) to ascertain that there were no leaks in the system. If no leaks were detected (ie, perfusion pressure remained constant), the pressure-servo system was set in the automatic mode. The temperature was set to 37°C (YSI temperature controller) and the vessels were allowed to equilibrate for about 1 hour.
Experimental Procedure
In these experiments, the 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 the changing of 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 PSS. 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) for assessment of 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 prostaglandins in shear stress–induced dilation of gracilis muscle arterioles was studied in the following manner. After control responses were obtained, the prostaglandin synthesis inhibitor indomethacin (10-5 mol/L) was added to the suffusion solution. After an incubation period (approximately 30 minutes), the shear stress–diameter relationships were assessed. To determine the efficacy and specificity of indomethacin, arteriolar responses to arachidonic acid (10-5 mol/L) and prostaglandin E2 (10-8 mol/L) were obtained before and after the vessels were exposed to this inhibitor.
In the second series of experiments, after control responses were obtained, the vessels were subjected to NG-nitro-L-arginine (L-NNA, 10-4 mol/L), an inhibitor of NO synthesis. Then, after an incubation period of approximately 15 minutes, the control protocol was repeated. The arteriolar responses to acetylcholine (10-8 mol/L) and sodium nitroprusside (10-7 mol/L), known to be endothelium-dependent and endothelium-independent dilator agents, respectively, were examined before and after the vessels were exposed to L-NNA. After responses in the presence of L-NNA were obtained, indomethacin was administered and the shear stress–diameter relationship was again determined.
The diameter of vessels and peak responses were measured in various experimental conditions with an image shearing monitor (IPM, model 907) and recorded with a chart recorder (Multicorder, MC6625). The flow was measured by a ball flowmeter (Omega Engineering Inc) that was calibrated by a perfusion pump (Harvard Apparatus Co) in which flow rate was accurate in the range of 0 to 100 µL/min.18 WSS was calculated from diameter (2r) and flow data according to the equation
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where 
is the viscosity of perfusate (0.007 poise at 37°C),
Q is the perfusate flow, and r is the vessel radius. The relationships
between WSS and diameter and between perfusate flow and WSS were
obtained in control conditions and during use of inhibitors in both
strains of rats. Changes in diameter in response to vasoactive agents
were normalized to the corresponding passive diameter and expressed as
percent changes. Results are presented as mean±SEM. Statistical
analyses were done by ANOVA followed by the Tukey post hoc test,
regression analysis, and the paired and grouped Student's
t test, as appropriate. A probability value of <.05 was
considered significant. All salts and chemicals were obtained from
Sigma Chemical Co or Aldrich Co.
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Results |
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The systolic pressure of the SHR (201±2 mm Hg, n=6 rats) was significantly (P<.05) higher than that of the NWR (104±3 mm Hg, n=6 rats). The active diameters of arterioles of NWR and SHR, which were obtained in the presence of constant intravascular pressure (80 mm Hg) and static flow conditions, were not significantly different (Fig 1).
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The changes in the diameter of arterioles of NWR and SHR in response to stepwise increases in shear stress under control conditions are summarized in Fig 1. The nearly vertical increase in the shear stress–diameter curve at about 30 dyne/cm2 demonstrates the marked sensitivity of normal arterioles to increases in shear stress. In contrast, the diameter of SHR arterioles did not increase at all in this range of shear stress, and only above 60 dyne/cm2 did diameters increase. 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. As also indicated in Fig 1, the maximal increase in diameter was significantly less in arterioles from SHR than in those from NWR (18.9 and 43.0 µm, respectively). Interestingly, the dilator responses of arterioles to arachidonic acid, prostaglandin E2, acetylcholine, and sodium nitroprusside were not significantly different in SHR compared with NWR (Fig 2).
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We next investigated whether an impairment of NO or prostaglandin synthesis/release is responsible for the reduced shear stress–induced dilation of arterioles of SHR. The role of prostaglandins was assessed by inhibition of cyclooxygenase with indomethacin. Indomethacin elicited a significant reduction of shear stress–induced dilation in arterioles of NWR and practically eliminated the response to increases in shear stress in those of SHR (Fig 3).
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To examine the involvement of NO in the shear stress–induced response, we used an NO synthase blocker after obtaining control responses. In NWR, L-NNA significantly reduced shear stress–induced arteriolar dilation (Fig 4), because there was a significant difference between the slopes of the shear stress–diameter curves in control conditions and in the presence of L-NNA. In contrast, in arterioles of SHR, L-NNA did not significantly affect the arteriolar dilation in response to increases in shear stress (Fig 4). In the presence of L-NNA, additional administration of indomethacin eliminated the remainder of the shear stress–induced dilation of NWR arterioles and abolished completely the dilator response of SHR arterioles.
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The perfusate flow–shear stress relationship indicates that when the endothelial factors are not inhibited, shear stress in arterioles of NWR rats is maintained around 30 dyne/cm2, despite increases in perfusate flow (Fig 5). Under the same conditions, arterioles of SHR cannot maintain constant shear stress during increases in flow; hence, shear stress reaches a much higher value (90 dyne/cm2). In NWR arterioles, administration of L-NNA elevates the flow–shear stress curve to the same levels observed for SHR arterioles (Fig 6). In contrast, L-NNA did not affect the flow–shear stress relationship in SHR arterioles (Fig 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The salient findings of this study are that shear stress–induced dilation of arterioles of SHR is significantly reduced compared with that of vessels of NWR; this reduced arteriolar response seems to be due primarily to the loss of the NO-mediated portion of the shear stress–induced dilation, while the prostaglandin-mediated shear stress–induced response is retained.
Previous investigation of the peripheral circulation 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 These changes may explain the enhanced peripheral resistance observed in hypertension.3 The results of the present study suggest that an altered function of arteriolar endothelial cells may also be involved in the development and/or maintenance of increased peripheral resistance in hypertension.
Studies of ring preparations of aortas7 and mesenteric arteries8 9 of hypertensive rats, and studies in hypertensive humans,13 14 indicate that the endothelial synthesis of NO and perhaps other endothelial mechanisms of peripheral vessels could be impaired. There are fewer data, however, on how hypertension may alter the function of the endothelium of vessels participating in the regulation of microvascular resistance. In vivo19 and in vitro6 18 studies suggest that the endothelium contributes to circulatory homeostasis by a shear stress–dependent regulation of peripheral vascular resistance. Increases in WSS can take place during increases in blood or perfusate flow velocity, which are likely to occur when high blood pressure and reduced diameter of vessels are present concurrently, as in hypertension. Therefore, we aimed to test the idea that the shear stress–sensitive dilation of arterioles is altered in hypertension and to determine whether the dysfunction of this mechanism can be involved in the development of increased peripheral resistance in hypertension. To assess the magnitude of shear stress–induced dilation without the interference of changes in intravascular pressure and other parameters, we used isolated arterioles of genetically hypertensive rats. Arterioles of rat gracilis muscle were used in the present study because the microcirculation of skeletal muscle is responsible for a sizable fraction of peripheral resistance. We used relatively young rats to minimize structural changes in the arteriolar wall, although these rats do have a significantly elevated systemic blood pressure. Agonists and shear stress–induced responses were investigated in the presence of a perfusion pressure of 80 mm Hg because at this pressure there was no difference in tone between NWR and SHR arterioles. Use of different perfusion pressure in NWR and SHR arterioles could itself interfere with shear stress–induced dilation, as we have found previously.20
Attenuation of Shear Stress–Induced Dilation in
Hypertension
In response to increases in shear stress, arterioles of SHR
exhibited a greatly reduced dilation compared with those of NWR, as
indicated by the significant shift in the slope of the shear
stress–diameter curve of SHR arterioles compared with that of NWR
arterioles (Fig 1). Because previous studies showed that shear
stress–dependent dilation of skeletal muscle arterioles is mediated by
endothelium-derived prostaglandins and/or
NO,6 we hypothesized that a reduction in the release of
these factors might be responsible for the observed reduction in shear
stress–induced dilation.
Lack of NO-Mediated Shear Stress–Induced Dilation
In NWR, inhibition of either NO or prostaglandin synthesis alone
significantly reduced the dilation to shear stress. Combined
application of these two inhibitors virtually eliminated shear
stress–induced dilation of NWR arterioles. These results confirm our
previous findings that both NO and prostaglandins are involved in the
mediation of shear stress–induced dilation in gracilis muscle
arterioles from normotensive rats.6 In contrast, shear
stress–induced dilation in arterioles from SHR was markedly reduced
compared with that in NWR. In addition, inhibition of NO synthesis by
L-NNA did not affect shear stress–induced dilation in vessels from
SHR, suggesting that increases in shear stress do not elicit an
NO-mediated dilation of these arterioles. On the other hand, the
finding that indomethacin treatment virtually eliminated the reduced
dilation of SHR arterioles indicates that the
prostaglandin-mediated shear stress–induced dilation is still
present in SHR arterioles.
In the present study, the finding that there was no difference between the dilation of SHR and NWR arterioles in response to acetylcholine indicates that agonist-induced endothelium-derived relaxing factor/NO synthesis is preserved in arterioles of SHR. Similarly, in Dahl hypertensive rats under resting flow conditions in vivo, arterioles of spinotrapezius muscle showed an impaired basal release of NO but no appreciable change in the dilator response to acetylcholine.11
Findings by Hecker et al21 and others22 23 suggest that agonists and shear stress activate NO synthesis by different signal transduction pathways. Our findings support this notion by showing a reduction of shear stress–induced synthesis of endothelial NO in hypertension while acetylcholine-induced response is retained. The results of the present study cannot reveal whether the reason for the observed changes is genetically determined or due to the prevailing hemodynamic conditions (eg, increased flow velocity or pressure) to which these arterioles are exposed as hypertension develops. Whatever the reason, in hypertension there could be an alteration in the rheoreceptors or the endothelial signaling pathways that link the increase in shear stress to NO synthesis but not in those that link it to prostaglandin synthesis.
The relatively early attenuation of shear stress–induced vasodilation in hypertension could result in an imbalance of local dilator and constrictor mechanisms. An increase in vascular resistance due to the lack of this mechanism may be partly responsible for functional rarefaction observed in skeletal muscle microcirculation in hypertension.1 2 3 In addition, the continuous presence of elevated shear stress could further impair the dilator function of endothelium24 and may, by itself, initiate changes in the structure of vascular tissue4 25 and network,1 2 further aggravating increases in arteriolar resistance.
It is tempting to speculate that changes similar to those described here occur in arterioles of other vascular beds. If so, the loss of NO-mediated shear stress–induced vasodilation in hypertension could increase peripheral resistance and thereby lead to an elevation of blood pressure.26 Previous measurements of intravascular pressures in microvessels of normotensive and hypertensive rats revealed that because of a greater pressure drop from arteries to small arterioles in hypertensive vessels, the intravascular pressures in precapillary arteries of skeletal muscle of normotensive and hypertensive species are not significantly different.27 28 This could only be so if there were a greater power dissipation in this segment of circulation of the hypertensive species. Indeed, our data are in agreement with this idea by showing that shear stress was always higher in SHR than in NWR arterioles at corresponding flow values, suggesting that there could be an elevated shear stress in arterioles in vivo that might be primarily responsible for the increased power dissipation.19 29
In conclusion, the present study demonstrates a reduced shear stress–induced dilation of arterioles of genetically hypertensive rats. This impaired dilation appears to be due to a loss of NO synthesis and release in response to shear stress. In contrast, the prostaglandin-mediated dilation seems to be intact. Thus, the present findings suggest an important role for the altered regulation of shear stress in skeletal muscle arterioles in the pathogenesis of hypertension.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (HL-46813 and P01 HL-43023).
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References |
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