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Am J Physiol Heart Circ Physiol 277: H1946-H1955, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 5, H1946-H1955, November 1999

Limitation of arteriolar myogenic activity by local nitric oxide: segment-specific effect of dietary salt

Timothy R. Nurkiewicz and Matthew A. Boegehold

Department of Physiology, West Virginia University School of Medicine, Morgantown, West Virginia 26505-9229


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The purpose of this study was to determine if local nitric oxide (NO) activity attenuates the arteriolar myogenic response in rat spinotrapezius muscle. We also investigated the possibility that hypertension, dietary salt, or their combination can alter any influence of local NO on the myogenic response. Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) fed low-salt (0.45%, LS) or high-salt (7%, HS) diets were enclosed in a ventilated airtight box with the spinotrapezius muscle exteriorized for intravital microscopy. Mean arterial pressure was unaffected by dietary salt in WKY but was significantly higher and augmented by dietary salt in SHR. In all experiments, elevation of microvascular pressure by box pressurization caused a 0-30% decrease in the diameter of large (arcade bridge) arterioles and a 21-27% decrease in the diameter of intermediate (arcade) arterioles. Inhibition of NO synthase with NG-monomethyl-L-arginine (L-NMMA) significantly enhanced myogenic responsiveness of arcade bridge arterioles in WKY-LS and SHR-LS but not in WKY-HS and SHR-HS. L-NMMA significantly enhanced the myogenic responsiveness of arcade arterioles in all four groups. Excess L-arginine reversed this effect of L-NMMA in all cases, and arteriolar responsiveness to the NO donor sodium nitroprusside was not different among the four groups. High-salt intake had no effect on the passive distension of arterioles in either strain during box pressurization. We conclude that 1) local NO normally attenuates arteriolar myogenic responsiveness in WKY and SHR, 2) dietary salt impairs local NO activity in arcade bridge arterioles of both strains, and 3) passive arteriolar distensibility is not altered by a high-salt diet in either strain.

microcirculation; local blood flow control; hypertension


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ARTERIOLAR MYOGENIC activity contributes significantly to local blood flow regulation in many vascular beds (12, 24, 35). The production of endothelium-derived relaxing factors represents another potentially important regulatory mechanism that is also intrinsic to the arteriolar wall (10, 21, 26). Although an intact endothelium is not required for the generation of myogenic activity in most vascular beds (13), endothelial factors such as nitric oxide (NO) have been shown to modulate the intensity of arteriolar myogenic activity in vitro (28, 46) and in vivo (10, 12, 24).

Spontaneous hypertension is characterized by an augmentation of arteriolar myogenic responsiveness in some vascular beds (14, 21, 22), but we have not found this to be the case in the spinotrapezius muscle of spontaneously hypertensive rats (SHR) (40). As with normotensive rats, inhibition of NO synthase (NOS) enhances the myogenic activity of renal afferent arterioles isolated from SHR, leading to a leftward shift of the pressure-diameter curve (20). To our knowledge, the importance of NO as a modulator of myogenic activity in vivo has not been evaluated for any vascular bed in SHR. If NO normally limits arteriolar myogenic activity in rat spinotrapezius muscle, then the absence of enhanced myogenic responsiveness in SHR spinotrapezius muscle could reflect a compensatory increase in local NO production and/or vascular smooth muscle responsiveness to NO. Alternatively, the production of some other endothelium-derived dilator or its effect on vascular smooth muscle could be increased under these conditions.

In normotensive rats, high dietary salt increases renal NO production (34), which could explain the reduced myogenic responsiveness of renal microvessels isolated from salt-fed rats (47). In contrast, we have reported that dietary salt reduces arteriolar NO activity in spinotrapezius muscle of normotensive rats (3, 5), which is consistent with a subsequent report in which endothelium-dependent dilation was impaired in gracilis muscle resistance arteries from Sprague-Dawley rats fed a high-salt diet (32). Although a salt-dependent suppression of microvascular NO activity should result in increased myogenic responsiveness, we have recently shown that arteriolar myogenic responses are attenuated in the spinotrapezius muscle of salt-fed Wistar-Kyoto rats (WKY) (40). This unexpected finding could be due to a difference between rat strains in the effect of dietary salt on local NO activity or to a lack of interaction between NO and myogenic behavior in this vascular bed.

In light of these unresolved issues, we undertook the current study to determine if local NO activity normally attenuates the arteriolar myogenic response in rat spinotrapezius muscle and to investigate the possibility that any such influence of NO could be changed by hypertension and/or dietary salt. Arteriolar responses to acute increases in transmural pressure were evaluated before and after local NOS inhibition in WKY and SHR fed low (0.45%, LS)- or high (7%, HS)-salt diets. Both large- and intermediate-sized arterioles were also studied to evaluate the possibility that segmental differences in NO activity exist in this vascular bed.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

All surgical and experimental procedures were approved by the West Virginia University Animal Care and Use Committee.

Animals. Male WKY and SHR (Harlan Sprague Dawley, Indianapolis, IN) were received at 4 wk of age and immediately placed on a whole grain, low-salt diet containing 0.45% NaCl (TD 88311, Tekland, Madison, WI). After 1 wk, half of the rats from each strain were randomly selected and placed on a high-salt diet containing 7% NaCl (TD 92100, Tekland), with the remaining rats continued on the low-salt diet. All rats were studied 4-5 wk after assignment to LS or HS groups.

Surgical preparation of the spinotrapezius muscle. Each rat was anesthetized with thiopental sodium (100 mg/kg ip) and placed on a heating pad to maintain a 37°C rectal temperature. The trachea was intubated to ensure a patent airway, and the right carotid artery was cannulated to measure arterial pressure. In some experiments, the right femoral vein was also cannulated to measure central venous pressure. The right spinotrapezius muscle was exteriorized for microscopic observation as previously described (40), leaving its innervation and all feed vessels completely intact. Throughout the surgery and subsequent experimental period, the muscle was continuously superfused with an electrolyte solution (in mM: 119 NaCl, 25 NaHCO3, 6 KCl, and 3.6 CaCl2) warmed to 35°C and equilibrated with 95% N2-5% CO2 (pH 7.35-7.40). Superfusate flow rate was maintained at 4-6 ml/min to minimize equilibration with atmospheric oxygen (40).

After the spinotrapezius muscle was surgically prepared, the rat was placed in an airtight, ventilated Plexiglas box (Fig. 1). The muscle was exteriorized from the box through a small slot and enclosed in a superfusate bath chamber. Fresh air was continuously circulated through the box, and box pressure (monitored with a mercury manometer and a Gould p23id pressure transducer) could be increased by raising the air inflow rate. Increases in box pressure cause simultaneous and equivalent increases in systemic arterial and venous pressure, leading to increased transmural pressures throughout the vasculature of the exteriorized tissue without changing heart rate, respiration rate, neurogenic vascular tone, or renin-angiotensin system activity (35). This technique has been used to study arteriolar myogenic responses in numerous vascular beds (35, 40).


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  		Fig. 1.   Plexiglas box preparation used to study myogenic responses. Animal is enclosed in an airtight box except for the spinotrapezius muscle. Box pressure is raised by increasing air flow through the box.

Intravital microscopy and measurement of microvascular variables. The animal preparation was transferred to the stage of an Olympus BHMJ intravital microscope (Hyde Park, NY) that was coupled to a charge-coupled device video camera (Dage-MTI, Michigan City, IN). Video images were displayed on a Sony high-resolution video monitor and videotaped for off-line analysis. Observations were made with an Olympus ×20 water-immersion objective (final video image magnification = ×1,460). Arteriolar red cell velocities were measured on-line with an optical Doppler velocimeter (Microcirculation Research Institute, Texas A&M University), and arteriolar inner diameters were measured during videotape replay with a video image-shearing monitor (IPM, San Diego, CA).

Branches of three different arteries enter the spinotrapezius muscle, where they connect to form an arteriolar structure known as the arcade bridge (45). The arcade bridge gives rise to a network of interconnected arcade arterioles that extends throughout the muscle. In the experiments described below, both arcade bridge and arcade arterioles were studied to identify any longitudinal differences in NO-dependent control that may exist in this portion of the network.

Inhibition of NO synthesis. To inhibit local NO synthesis, a stock solution of NG-monomethyl-L-arginine (L-NMMA) was continuously infused by a syringe pump at 0.4 ml/min into the superfusate delivery line. Stock L-NMMA concentration was adjusted to produce a final superfusate concentration of 10-4 M. We have previously found that L-NMMA at this concentration maximally inhibits the dilation of spinotrapezius muscle arterioles to ACh (5), an agonist that acts by increasing endothelial NO production in this vascular bed (38). The specificity of L-NMMA as a NOS inhibitor was verified in a separate series of control experiments (experimental protocol 3).

Experimental protocol 1. One to three arcade bridge or arcade arteriole segments were studied per animal. After a 2-min control period, box pressure was raised to 10, 20, or 30 mmHg above atmospheric pressure for 2 min. We have recently demonstrated that the arterial and venous pressure increases evoked by box pressurization are completely transmitted to the spinotrapezius muscle arterioles in each of the experimental groups studied here (40). Box pressurization was followed by a minimum 2-min recovery period to allow vessel diameter and red cell velocity to return to control levels. This sequence was repeated a total of three times for each selected arteriole to assess responsiveness to each of the three pressure increases delivered in random order. To evaluate the possible influence of endogenous NO on myogenic responsiveness, the pressurization sequences were repeated for each vessel after 10 min of exposure to L-NMMA. Continuous superfusate delivery of L-NMMA was maintained throughout all pressurization steps to maximally inhibit NOS activity. At the end of every experiment, adenosine was added to the superfusate at a final concentration of 10-4 M to determine the passive diameter of each vessel that we studied.

Experimental protocol 2. To evaluate arteriolar responsiveness to NO in each experimental group, the NO donor sodium nitroprusside (SNP) was iontophoretically applied to individual arcade bridge arterioles. Glass micropipettes were beveled at a 23-25° angle to an outer tip diameter of 1-3 µm and filled with a 0.05 M solution of SNP in distilled water. The pipette tip was placed in light contact with the arteriolar wall, and a current programmer (model 260, World Precision Instruments, New Haven, CT) was used to deliver continuous 2-min ejection currents of 5, 10, and 20 nA. A recovery period of at least 2 min followed each application. The order of the 5- and 10-nA ejection currents was randomized, but the 20-nA ejection was always performed last because of a considerably slower recovery from this stimulus.

Experimental protocol 3. Because some L-arginine analogs could influence arteriolar tone via NO-independent mechanisms (27), we evaluated the specificity of L-NMMA as an inhibitor of NOS in arcade bridge and arcade arterioles of each experimental group. L-NMMA inhibits endothelial NO synthesis by competing with L-arginine for the binding site on the NOS enzyme (42) and by inhibiting L-arginine transport into the cell (6). Because both of these actions are reversed in the presence of excess L-arginine (6, 42), we reasoned that a reversal of the effect of L-NMMA on myogenic behavior by L-arginine would indicate a specific effect on the NO pathway.

With the use of the current experimental paradigm, the systemic pressure increases induced by higher levels of box pressurization are 20-30% lower in SHR than in WKY (40). Therefore, we compared responses to +20 mmHg box pressurization in WKY with responses to +30 mmHg box pressurization in SHR to evaluate L-NMMA specificity in the presence of an identical myogenic stimulus in all groups. Control, pressurization, and recovery periods (see Experimental protocol 1) were conducted first under the normal superfusate, then during L-NMMA exposure, and finally during simultaneous exposure to L-NMMA and excess L-arginine (5 × 10-3 M in superfusate).

Passive arcade bridge and arcade arteriole diameters were found to be decreased in salt-fed rats of each strain (see RESULTS). This effect could be due to hypertrophy or remodeling of the arteriolar wall and/or a change in its passive distensibility (8, 36). To gain some insight into the passive mechanical characteristics of arterioles in each group, we explored relative pressure-diameter relationships for passive arcade bridge and arcade arterioles at the end of some experiments in experimental protocols 1 and 3. After arteriolar tone was abolished by 10 min of continuous exposure to adenosine (10-4 M), arteriolar diameter was measured at normal pressure and then after box pressure was sequentially raised by 10, 20, and 30 mmHg. Each pressure step was maintained for 1 min, and a recovery period followed the final step to verify that vessels were not irreversibly damaged by passive distension. Superfusion with adenosine was continued throughout these procedures to ensure a sustained suppression of arteriolar tone.

Data and statistical analysis. Arteriolar diameter (D, µm) and centerline red cell velocity (Vcl, mm/s) were sampled at 10-s intervals during all control, pressurization, and recovery periods. Resting vascular tone (T) was calculated for each vessel as follows: T = [(Dpass - Dc)/Dpass] × 100, where Dpass is passive diameter under adenosine and Dc is the diameter measured during the control period. A tone of 100% represents complete vessel closure, whereas 0% represents the passive state. Arteriolar myogenic responses were evaluated by comparing the minimum arteriolar diameter reached during box pressurization (Dmin) to the immediately preceding control diameter: D (% of control) = (Dmin/Dc) × 100. The effect of L-NMMA on any myogenic response was quantified as the difference between the normalized minimum diameter reached during box pressurization under L-NMMA and that reached during box pressurization under the normal superfusate.

Mean red cell velocity (Vmean) was calculated as Vcl/1.6, where 1.6 represents the ratio of Vcl to Vmean for vessels down to 10 µm in diameter (50). Paired values for D and Vmean were used to calculate arteriolar volume flow (Q , nl/s) and wall shear rate (WSR, s-1) as follows: Q = Vmean × (pi  × D2/4) and WSR = 8 × (Vmean/D). WSR was used as an index of wall shear stress, and its calculation assumes a parabolic velocity profile. Control values for all microvascular variables were calculated as the mean of 12 samples obtained during the 2-min control period.

All data are reported as means ± SE. Statistical analysis was performed by commercially available software (SigmaStat, Jandel Scientific; Prism, Graphpad Software). Two-way repeated-measures ANOVA was used to determine the effects of strain, diet, and strain-diet interactions on the measured variables. One-way ANOVA was used to determine differences within a group subjected to repeated measures. For all ANOVA procedures, the Student-Newman-Keuls method for post hoc analysis was used to isolate pairwise differences among specific groups. Analysis of covariance was used to determine differences in regression line slopes. Significance was assessed at the 95% confidence level (P < 0.05) for all tests.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

General characteristics of all rats used in this study are reported in Table 1. In both the WKY and SHR strains, rats fed high salt were slightly but significantly older at the time of use than those fed low salt, but there were no significant differences in body weight among the four groups. Mean arterial pressure was significantly higher in SHR fed low salt than in WKY fed either low or high salt. The high-salt diet significantly increased arterial pressure in SHR but not in WKY.

                              
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  		Table 1.   Profiles of experimental animals used in experimental protocols 1-3

General characteristics of all arterioles studied are reported in Table 2. Arcade bridge arteriole resting diameters were significantly smaller in SHR than in WKY. In contrast, there was no strain-related difference in passive arcade bridge diameters, reflecting a significant increase in the resting tone of SHR arcade bridge arterioles. Arcade arteriole resting diameters were not different among the four experimental groups. The high-salt diet significantly reduced the passive diameters of both arcade bridge and arcade arterioles in each strain.

                              
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  		Table 2.   Characteristics of arterioles studied in experimental protocols 1-3

The effects of L-NMMA on resting arteriolar diameters and hemodynamic variables are reported for each group in Tables 3 and 4. At the arcade bridge level (Table 3), resting volume flow was significantly lower in SHR than in WKY, but there were no strain-related differences in resting WSR. Exposure to L-NMMA did not alter resting arcade bridge diameter, tone, or volume flow in any group. Resting arcade bridge WSR was reduced by L-NMMA only in the WKY-LS group. At the arcade arteriole level (Table 4), there were no strain-related differences in resting flow or WSR, but salt loading significantly reduced resting volume flow and WSR in both strains. Exposure to L-NMMA did not alter resting arcade arteriole diameter, tone, volume flow, or WSR in any group.

                              
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  		Table 3.   Resting microvascular variables for arcade bridge arterioles before and during exposure to L-NMMA (experimental protocol 1)


                              
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  		Table 4.   Resting microvascular variables for arcade arterioles before and during exposure to L-NMMA (experimental protocol 1)

Upon box pressurization under the normal superfusate, arcade bridge arterioles in each group displayed a moderate constriction or maintained their normal resting diameter, indicating myogenic activation (Fig. 2). We have recently reported that upon box pressurization to the levels used here, the increase in arcade bridge pressure is identical to the increase in arterial pressure (40). Therefore, the data in Fig. 2 are plotted as a function of steady-state arterial pressure during each box pressurization. This analysis reveals that myogenic responsiveness is significantly enhanced by L-NMMA in the WKY-LS and SHR-LS groups only. For these two groups, the paired pressure-diameter values for the normal and L-NMMA superfusates are significantly different at each level of increased pressure. In addition, the slopes of the first-order regression lines fit to the pressure-diameter data are significantly more negative in the presence of L-NMMA. In contrast, arcade bridge arterioles in the WKY-HS and SHR-HS groups did not display augmented myogenic responsiveness during exposure to L-NMMA. The line equations for each group are given in the legend of Fig. 2.


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  		Fig. 2.   Myogenic responsiveness of arcade bridge arterioles before (open circle ) and during () exposure to 10-4 NG-monomethyl-L-arginine (L-NMMA) in each experimental group. Equations of first-order regression lines are as follows. A: low-salt Wistar Kyoto rats (WKY-LS) under normal superfusate, y = -0.6x + 135.4, r2 = 0.89; with L-NMMA, y = -1.1x + 164.3, r2 = 0.95. B: high-salt WKY (WKY-HS) under normal superfusate, y = -0.3x + 116.5, r2 = 0.63; with L-NMMA, y = -0.4x + 124.4, r2 = 0.85. C: low-salt spontaneously hypertensive rats (SHR-LS) under normal superfusate, y = -0.6x + 165.6, r2 = 1.0; with L-NMMA, y = -1.4x + 246.4, r2 = 0.93. D: high-salt SHR (SHR-HS) under normal superfusate, y = -1.0x + 207.3, r2 = 0.96; with L-NMMA, y = -0.93x + 187.9, r2 = 0.81. * P < 0.05 vs. paired value for normal superfusate. For WKY-LS and SHR-LS, slope of the pressure-diameter line under L-NMMA is significantly different from that under normal superfusate (P < 0.05).

At the arcade arteriole level, box pressurization under the normal superfusate caused a similar degree of constriction in all experimental groups (Fig. 3). These data are also plotted as a function of steady-state arterial pressure during each box pressurization and indicate that arcade arteriole myogenic responsiveness is enhanced by L-NMMA in all groups. The paired pressure-diameter values for the normal and L-NMMA superfusates are significantly different at the +20- and +30-mmHg pressure steps for WKY-LS, WKY-HS, and SHR-LS and at +30 mmHg for SHR-HS. In addition, the slopes of the regression lines fit to the pressure-diameter data for WKY-LS, WKY-HS, and SHR-HS are significantly more negative in the presence of L-NMMA. The line equations for each group are given in the legend of Fig. 3.


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  		Fig. 3.   Myogenic responsiveness of arcade arterioles before (open circle ) and during () exposure to L-NMMA in each experimental group. Equations of first-order regression lines are as follows. A: WKY-LS under normal superfusate, y = -0.8x + 161.6, r2 = 0.94; with L-NMMA, y= -1.9x + 254.3, r2 = 0.99. B: WKY-HS under normal superfusate, y = -0.8x + 166.6, r2 = 1.00; with L-NMMA, y = -1.4x + 219.1, r2 = 1.00. C: SHR-LS under normal superfusate, y = -0.9x + 209.2, r2 = 0.78; with L-NMMA, y = -1.4x + 219.1, r2 = 1.00. D: SHR-HS under normal superfusate, y = -1.0x + 227.6, r2 = 0.90; with L-NMMA, y = -2.0x + 349.2, r2 = 0.98. * P < 0.05 vs. paired value for normal superfusate. For WKY-LS and WKY-HS and SHR-HS, slope of the pressure-diameter line under L-NMMA was significantly different from that under the normal superfusate (P < 0.05).

Figure 4 compares the effect of L-NMMA on the myogenic responsiveness of arcade bridge vs. arcade arterioles in each group. In WKY-LS and SHR-LS, the myogenic responses of arcade bridge and arcade arterioles were similarly enhanced by L-NMMA at all pressure steps, except for a significantly greater effect in the arcade arterioles of WKY-LS during the +30-mmHg pressure increase. In WKY-HS and SHR-HS, L-NMMA consistently enhanced the myogenic responsiveness of arcade arterioles only.


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  		Fig. 4.   Effect of L-NMMA on arcade bridge vs. arcade arteriole myogenic responses in each experimental group. A: WKY-LS. B: WKY-HS. C: SHR-LS. D: SHR-HS. Values represent the change in response under L-NMMA at each pressurization step. Hatched bars, arcade bridge arterioles. Solid bars, arcade arterioles. * P < 0.05 vs. arcade bridge value.

Figure 5 displays the responsiveness of arcade bridge arterioles to iontophoretically applied SNP in each experimental group. The responses to SNP at each current dose represent significant dilations from control diameter. There were no differences among groups in the response to SNP at any current dose.


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  		Fig. 5.   Responsiveness of arcade bridge arterioles to sodium nitroprusside (SNP) in each experimental group. open circle , WKY-LS; , WKY-HS; , SHR-LS; , SHR-HS. Solid lines, low-salt groups; dashed lines, high-salt groups. SNP at each current-dose produced a significant dilation in all groups (P < 0.05). In each group, the response to 20 nA SNP was significantly greater than the response to 5 nA SNP (* P < 0.05) and not different from the passive diameter measured under 10-4 M adenosine (passive).

Figure 6 illustrates the specificity of L-NMMA under the conditions of this study. As shown earlier, L-NMMA significantly enhanced the myogenic responsiveness of arcade bridge arterioles in WKY-LS and SHR-LS. This effect was completely reversed when excess L-arginine was added to the superfusate (Fig. 6, top). As expected, L-arginine had no effect on the myogenic constriction of arcade bridge arterioles in WKY-HS and SHR-HS, in which L-NMMA had no initial effect. L-NMMA's enhancement of myogenic responsiveness in arcade arterioles was completely reversed by excess L-arginine in each group (Fig. 6, bottom).


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  		Fig. 6.   Specificity of L-NMMA's effects on arcade bridge (A) and arcade arteriole (B) myogenic responses. WKY-LS and WKY-HS were subjected to a 20-mmHg box pressure increase. SHR-LS and SHR-HS were subjected to a 30-mmHg box pressure increase. Open bars, normal superfusate; solid bars, superfusion with L-NMMA (10-4 M); hatched bars, superfusion with L-NMMA (10-4 M) + L-arginine (5 × 10-3 M). * P < 0.05 vs. normal superfusate and vs. L-NMMA + L-arginine.

After abolition of vascular tone, box pressurization caused the passive distension of arcade bridge and arcade arterioles in each experimental group (Fig. 7). Because microvascular pressures were not directly measured in this study, true passive pressure-diameter relationships could not be defined. However, we found no differences among groups (for either vessel type) in the passive diameter changes that occurred over a comparable range of arterial pressure increases. After box pressure was returned to normal, all arterioles regained their original passive diameter (data not shown), indicating that they were not damaged by this distension.


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  		Fig. 7.   Pressure-diameter relationships for passive vessels. A: WKY. B: SHR. open circle , Low-salt diet, arcade bridge arterioles; , high-salt diet, arcade bridge arterioles; , low-salt diet, arcade arterioles; , high-salt diet, arcade arterioles.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We present four major findings in this study. First, local NO activity normally attenuates the myogenic behavior of arcade bridge and arcade arterioles in spinotrapezius muscle of normotensive and hypertensive rats. Second, high dietary salt intake impairs this influence of local NO on arcade bridge arterioles. Third, high-salt intake, hypertension, or their combination does not alter arteriolar smooth muscle responsiveness to NO. Fourth, passive arteriolar distensibility is not altered in the spinotrapezius muscle of salt-loaded rats.

Resting microvascular characteristics associated with salt loading and hypertension. The distribution of cardiac output among different organs suggests that vascular resistance is uniformly increased throughout most of the peripheral circulation in SHR (39). However, the specific microvascular changes that are responsible for this increased resistance can vary markedly among different organs (7). The reduction in resting arcade bridge volume flow (Table 3) despite increased arterial perfusion pressure (Table 1) confirms that spinotrapezius muscle vascular resistance is increased in SHR, and this increase is due at least in part to the active reduction in resting arcade bridge diameters that we and others have observed (Table 3) (29, 40).

High-salt intake for 4-5 wk decreased passive arcade bridge and arcade arteriole diameters in both WKY and SHR (Table 2), indicating that these changes are unrelated to the level of arterial pressure. This effect has been previously reported in WKY and SHR (40) and in Dahl salt-sensitive and salt-resistant rats (4). A decrease in passive diameter could reflect hypotrophic, eutrophic, or hypertrophic remodeling of the arteriolar wall (36). Because circulating ANG II is required for the maintenance of normal arteriolar wall structure (48) and its plasma levels are reduced by salt loading (18), we would expect that if arteriolar wall remodeling had occurred in our salt-fed rats it would most likely be hypotrophic in nature. Consistent with this, hypotrophic remodeling of mesenteric arterioles has been morphometrically documented in normotensive Dahl salt-resistant rats fed a high-salt diet for 6-7 wk (30).

Alternatively, it is possible that the salt-induced reduction in passive arteriolar diameter reflects a reduction in passive wall distensibility. High dietary salt has no effect on the passive distensibility of aortic segments from Sprague-Dawley or Dahl rats (1), but, to our knowledge, the effect of salt loading on passive distensibility has not been previously investigated at the microvascular level. A comparison of passive arteriolar responses to similar elevations in luminal pressure (Fig. 7) reveals that high dietary salt does not alter the passive pressure-diameter relationship over this modest pressure range in either WKY or SHR.

Hypertension could also alter passive arteriolar distensibility in spinotrapezius muscle. The passive distensibility of pial arterioles in stroke-prone SHR is greater than that in WKY, apparently due to a disproportionate increase in more compliant elements of the arteriolar wall (2). In contrast, intestinal arterioles in SHR show a decreased passive distensibility compared with those in age-matched WKY (8). Finally, the passive pressure-diameter curves of mesenteric, coronary and cremaster muscle resistance vessels from SHR are not different from those of their normotensive counterparts (14, 17, 23). Although the slopes of the passive pressure-diameter curves for spinotrapezius muscle arterioles appear to be similar in WKY and SHR (Fig. 7), these data do not permit a definitive conclusion as to whether passive distensibility is altered in SHR spinotrapezius muscle because the arterioles in SHR were not studied over the same range of luminal pressure as those in WKY.

Effect of local NO on arteriolar myogenic responses. To our knowledge, this is the first in vivo study to investigate the importance of local NO in modulating arteriolar myogenic behavior in normotensive, hypertensive, and salt-loaded rats. By using the "pressure-box" technique, transmural pressure was locally increased in a nonpharmacological manner, thereby avoiding any direct effect of an exogenous vasoactive agent on local NO activity. By limiting transmural pressure changes to vessels within the exteriorized muscle (35, 40), we also avoided activation of systemic baroreceptors and conduction of myogenic activity from vessels outside this vascular bed (44). We have recently reported that myogenic responses of spinotrapezius muscle arterioles are similar in SHR-LS and WKY-LS (40), which supports the growing consensus that myogenic activity is not uniformly increased in all vascular beds of the SHR (19, 23, 41).

Local NOS inhibition significantly enhanced the myogenic responsiveness of arcade bridge arterioles in WKY-LS and SHR-LS and in arcade arterioles from all four experimental groups (Figs. 2 and 3). This effect was completely reversed by excess L-arginine (Fig. 6), indicating that local NO normally attenuates the arteriolar myogenic response in spinotrapezius muscle of normotensive and hypertensive rats. Our findings are in agreement with recent work in the cremaster muscle of normotensive hamsters (10) and on the renal afferent arteriole of normotensive rabbits (25) and normotensive and hypertensive rats (20). NO also attenuates the constriction of arterioles in response to nonmyogenic stimuli, such as increased sympathetic nerve activity, in rat spinotrapezius muscle (31) and intestine (37). These studies clearly demonstrate that, despite the multiple origins of arteriolar tone, local NO activity plays an important role in determining the degree to which this tone is expressed.

The shear stress associated with resting blood flow is considered to be the main stimulus for basal NO release from the endothelium of rat spinotrapezius muscle arterioles (16). We have recently reported that the myogenic constriction of these arterioles is accompanied by an increase in WSR (and therefore wall shear stress) (40), which should increase endothelial NO production (5, 16). Although the current findings indicate that local NO effectively limits the myogenic constriction of spinotrapezius muscle arterioles, we have previously found no correlation between WSR (either the resting value or its subsequent increase) and the magnitude of myogenic constriction (40). Together, these findings suggest that a second shear-independent stimulus may become responsible for the majority of NO released during myogenic constriction. The findings of Dora and co-workers (11) raise the intriguing possibility that the initial stretch-induced increase in vascular smooth muscle calcium could lead to the diffusion of calcium through myoendothelial junctions and into adjacent endothelial cells. This secondary increase in endothelial cell calcium could then stimulate increased NO production (33).

Salt loading impaired the NO-dependent modulation of myogenic activity in arcade bridge arterioles of both WKY and SHR, as judged by unaltered myogenic responses in the presence of L-NMMA (Figs. 2 and 4). Because this salt-dependent impairment of local NO activity is similar to that previously reported in spinotrapezius muscle arterioles of Dahl salt-resistant rats (3, 5), it appears that this effect of dietary salt in normotensive rats is not strain specific. A more general effect of dietary salt on endothelial function is also suggested by earlier findings that rats fed high salt exhibit abnormally large cerebral infarctions after middle cerebral artery occlusion, apparently due to an impaired flow-dependent dilation of collateral vessels (9).

We have recently reported that high dietary salt attenuates the myogenic responsiveness of arcade bridge arterioles in WKY spinotrapezius muscle (40). The current study indicates that this reduced responsiveness occurs despite a suppression of local NO activity (Fig. 2), suggesting that the effects of dietary salt on myogenic behavior and NO activity are independent and unrelated.

Arcade bridge responsiveness to local application of the NO donor SNP was not different among experimental groups (Fig. 5), suggesting that the inherent responsiveness of arteriolar smooth muscle to NO is not altered in SHR or in salt-fed rats of either strain. These findings are consistent with observations on isolated arterioles from the SHR cremaster muscle (21) and previous in vivo observations in the spinotrapezius muscle of salt-loaded normotensive rats (5). Arteriolar responsiveness to NO has not been previously evaluated in salt-loaded SHR. Our finding that responsiveness to NO is not different between rat strains argues against the possibility that altered NO production in SHR could have been masked in this study by a compensatory change in smooth muscle responsiveness. Our finding that the attenuating influence of NO on myogenic constriction persists in SHR-LS, coupled with an unchanged arteriolar responsiveness to NO, strongly suggests that microvascular NO production is not suppressed in SHR, which is in agreement with previous studies (15, 20, 49).

The current study does not allow us to identify the cellular origin of the NO that limits arteriolar myogenic responses in rat spinotrapezius muscle. As mentioned above, the microvascular endothelium is a likely source for this NO (3, 5). Skeletal muscle fibers can also produce NO (43), but NO released from these sites would have similar access to both arcade bridge and arcade arterioles and would therefore not be consistent with the differential effect of dietary salt on NO activity in these two vessel types (Figs. 2-4).

This study provides further evidence that, in some vascular beds, local NO activity is suppressed by high dietary salt but unaltered by hypertension. Furthermore, salt-dependent alterations in NO activity and myogenic responsiveness appear to occur through distinctly separate mechanisms that warrant further investigation.


    ACKNOWLEDGEMENTS

We gratefully acknowledge the expert technical assistance of Kim Wix.


    FOOTNOTES

This investigation was supported by National Heart, Lung, and Blood Institute Grants HL-44012 and HL-52019.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: M. A. Boegehold, Dept. of Physiology, PO Box 9229, Robert C. Byrd Health Sciences Center, West Virginia Univ., Morgantown, WV 26506-9229 (E-mail: mboegehold{at}hsc.wvu.edu).

Received 19 January 1999; accepted in final form 22 June 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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