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Am J Physiol Heart Circ Physiol 279: H269-H278, 2000;
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Vol. 279, Issue 1, H269-H278, July 2000

Reinforcement of arteriolar myogenic activity by endogenous ANG II: susceptibility to 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 whether endogenous ANG II augments arteriolar myogenic behavior in striated muscle. Because circulating ANG II is decreased during high salt intake, we also investigated whether dietary salt could alter any influence of ANG II on myogenic behavior. Normotensive rats fed low-salt (0.45%, LS) or high-salt (7%, HS) diets were enclosed in a ventilated box with the spinotrapezius muscle exteriorized for intravital microscopy. Dietary salt did not affect resting arteriolar diameters. Microvascular pressure elevation by box pressurization caused greater arteriolar constriction in LS rats (up to 12 µm) than in HS rats (up to 4 µm). The ANG II-receptor antagonists saralasin and losartan attenuated myogenic responsiveness in LS rats but not HS rats. The bradykinin-receptor antagonist HOE-140 had no effect on myogenic responsiveness in LS rats but augmented myogenic responsiveness in HS rats. HOE-140 with the angiotensin-converting enzyme inhibitor captopril attenuated myogenic responsiveness to a greater extent in LS rats than in HS rats. We conclude that endogenous ANG II normally reinforces arteriolar myogenic behavior in striated muscle and that attenuated myogenic behavior associated with high salt intake is due to decreased circulating ANG II and increased local kinin levels.

microcirculation; myogenic response; renin-angiotensin system; bradykinin; local blood flow control


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ARTERIOLAR MYOGENIC BEHAVIOR contributes importantly to local blood flow regulation in many vascular beds (27, 33, 36, 40). Although this behavior reflects an inherent property of vascular smooth muscle, endogenous vasoactive substances can modulate the relative magnitude of myogenic activity. For example, we have recently shown that endogenous nitric oxide (NO) normally attenuates the myogenic responsiveness of proximal arterioles in the rat spinotrapezius muscle (37), which is consistent with findings in the hamster cremaster muscle (9) and in isolated porcine coronary arterioles (27).

Norepinephrine (NE) augments the myogenic activity of resistance arteries and arterioles, apparently through the stimulation of intracellular signaling pathways common to both adrenergic and myogenic stimuli (8, 11, 20, 21, 29, 31, 32, 39). Important events within these shared pathways include the activation of phospholipase C (PLC), protein kinase C (PKC), and voltage-dependent calcium channels (8, 20, 23, 29, 38). Because ANG II induces vasoconstriction through the same channels and intracellular pathways as NE (1, 43, 45), it is possible that endogenous ANG II at its normal physiological levels could also enhance arteriolar myogenic activity in vivo. In support of this possibility, exogenous ANG II applied at subconstrictor concentrations augments the myogenic responsiveness of renal afferent arterioles in vitro, and the PKC inhibitor chelerythrine reverses this augmentation (24).

Through its diverse effects on the cardiovascular and renal systems, circulating ANG II plays a central role in the regulation of blood pressure, vascular structure, and salt and water balance (16, 43, 45, 47). A high-salt diet leads to a decrease in circulating ANG II levels (17), and we and others have reported that a high-salt diet also leads to attenuated arteriolar myogenic activity in the spinotrapezius muscle (36) and kidney (44) of normotensive rats. These observations are consistent with the postulate that endogenous ANG II reinforces myogenic activity under normal conditions. To gain a better understanding of the interactions among dietary salt, ANG II, and myogenic activity, we undertook the current study to determine whether endogenous ANG II normally enhances the arteriolar myogenic response in rat spinotrapezius muscle and to investigate the possibility that any such influence of ANG II is reduced by dietary salt. Arteriolar responses to acute increases in transmural pressure were evaluated before and after ANG II-receptor antagonism or angiotensin-converting enzyme (ACE) inhibition in Wistar-Kyoto rats fed low-salt or high-salt diets.


    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 Wistar-Kyoto rats (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 (Teklad TD 88311, Madison, WI). After 1 wk, half the rats were randomly selected and placed on a high-salt diet containing 7% NaCl (Teklad TD 92100), with the remaining rats continued on the low-salt diet. All rats were studied 4-5 wk after assignment to "low-salt" (LS) or "high-salt" (HS) groups.

Surgical preparation of 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 the pilot experiments to verify captopril effectiveness and in Experimental protocol 3, the right femoral vein was also cannulated for drug infusion. The right spinotrapezius muscle was exteriorized for microscopic observation as previously described (36), 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 (36).

After the spinotrapezius muscle was surgically prepared, the rat was placed in an airtight ventilated Plexiglas box (36). 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 P23 ID pressure transducer) could be increased by raising the air inflow rate. Increases in box pressure cause simultaneous and equal 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 (33). This technique has been used to study arteriolar myogenic responses in numerous vascular beds (5, 33, 36, 50).

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 fitted with 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 offline analysis. Observations were made with an Olympus ×20 water-immersion objective (final video image magnification, ×1,460). 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 (42). In the experiments described below, arcade bridge arterioles were studied because these microvessels display attenuated myogenic activity in rats fed a high-salt diet (36).

ANG II-receptor antagonism and ACE inhibition. The effects of endogenous ANG II were blocked by receptor antagonism or angiotensin-converting enzyme (ACE) inhibition. The optimal superfusate concentrations of the ANG II-receptor antagonists used in this study were based on the effective blockade of arteriolar responses to a 0.1-ml bolus of ANG II (10-6 M, Sigma, St. Louis, MO), added directly to the muscle bath. When ANG II is applied in this manner, 10-6 M is the highest concentration that can be used without altering arterial pressure (data not shown). In these pilot experiments, arteriolar responses to ANG II were evaluated before and during exposure to the nonselective ANG II-receptor antagonist saralasin (RBI, Natick, MA) or the selective ANG II type 1 (AT1)-receptor antagonist losartan (a gift from Merck Research Laboratories, Rahway, NJ). The ANG II-induced arteriolar constriction was effectively blocked by saralasin at a superfusate concentration of 10-6 M and by losartan at a superfusate concentration of 10-5 M (see RESULTS).

Systemic ACE inhibition was achieved by intravenous administration of captopril (RBI). In pilot experiments to determine the optimal dose of captopril for ACE inhibition, arterial pressure changes in response to ANG I and ANG II (50 ng in a 0.1-ml iv bolus) were measured before and after captopril administration. We found that an intravenous captopril dose of 10 mg/kg (in a 0.15-ml bolus) effectively blocks the systemic response to ANG I but not ANG II (see RESULTS), indicating complete ACE inhibition.

Experimental protocol 1. The nonselective ANG II-receptor antagonist saralasin was initially used to evaluate the influence of endogenous ANG II on arteriolar myogenic activity. Arteriolar responses to acute increases in transmural pressure were first assessed under the normal superfusate. After a 2-min control period, box pressure was raised to 10, 20, or 30 mmHg above atmospheric pressure for 2 min. Box pressurization was followed by a minimum 2-min recovery period to allow vessel diameter 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. The pressurization sequences for each vessel were then repeated after 10 min of exposure to saralasin (10-6 M in superfusate). Continuous superfusate delivery of saralasin was maintained throughout the pressurization steps to maximally block ANG II receptors. At the end of every experiment, adenosine (Ado, 10-4 M) was added to the superfusate to determine the passive diameter of each vessel that we studied.

In separate control experiments to verify the ability of Ado to produce maximal dilation (n = 11 arcade bridge arterioles), we found that arteriolar diameters increased from 46 ± 2 to 66 ± 1 µm upon exposure to 10-4 M Ado and did not increase further following subsequent exposure to a mixture of 10 µM sodium nitroprusside + 1 µM nifidepine in Ca2+-free solution. This finding suggests that Ado at a superfusate concentration of 10-4 M is sufficient to produce completely passive arterioles in the exteriorized spinotrapezius muscle.

Experimental protocol 2. Because peptide analogs such as saralasin can act as partial agonists under some conditions (30), we also used the nonpeptide AT1-receptor antagonist losartan (10-5 M in superfusate) to more clearly determine the influence of endogenous ANG II on arteriolar myogenic activity. These experiments were identical to those described in protocol 1, except that losartan was added to the superfusate before repeating the pressurization series for each vessel.

To determine whether either saralasin or losartan could have direct nonspecific effects on vascular smooth muscle contractility, we also assessed the effect of these antagonists on arteriolar responsiveness to topically applied NE. These experiments were conducted on rats fed the low-salt diet. Arteriolar diameters were measured before and after addition of NE to the muscle bath in a 0.1-ml volume at 3 × 10-6 M and 3 × 10-5 M concentrations (using a randomized order of application, with 5-min recovery periods between applications). Saralasin or losartan was then added to the superfusate at the concentrations described (see ANG II-receptor antagonism and ACE inhibition), and arteriolar responses to NE were reevaluated after a 10-min equilibration period.

Experimental protocol 3. In the final series of experiments, we used the ACE inhibitor captopril as an alternate approach to assess the influence of endogenous ANG II on arteriolar myogenic activity. These experiments were also identical to those described in protocol 1, except that captopril (10 mg/kg iv) was administered 30 min before repeating the pressurization sequences. Because peptidases such as ACE also actively degrade arteriolar bradykinin (15), all rats were pretreated with the selective B2-bradykinin-receptor antagonist HOE-140 (RBI) to rule out the possibility that any effect of captopril on myogenic activity could be due to enhanced kinin levels rather than reduced ANG II production. In pilot experiments to determine the optimal dose of HOE-140, we found that near-maximal arteriolar dilation in response to topically applied bradykinin (Sigma, 10-5 M, added to the bath in a 0.1-ml bolus) was effectively blocked by 12 µg/kg iv HOE-140 (see RESULTS). This dose of HOE-140 was administered to the rats at least 20 min before starting the captopril experiments. Before Ado was applied at the end of these experiments, 0.1 ml of 10-5 M bradykinin was added to the bath to determine whether bradykinin receptors were still blocked at this time. These postexperimental bradykinin applications had no effect on arteriolar diameter, verifying that there had been complete receptor blockade for the duration of the experiment. This finding is consistent with an earlier report that the half-life for HOE-140 in vivo is greater than 5 h (51).

Data and statistical analysis. Arteriolar diameter (D, µm) was 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 the passive diameter under Ado, and Dc is the diameter measured during the control period. A tone of 100% represents complete vessel closure, whereas 0% represents the passive state.

All data are reported as means ± SE. Statistical analysis was performed using commercially available software (Sigmastat, Jandel Scientific; Prism, Graphpad Software). Two-way repeated-measures ANOVA was used to determine 1) the effects of diet, treatment, and diet-treatment interactions on measured variables; 2) the effects of pressure, treatment, and pressure-treatment interactions on variables within each dietary group; and 3) the effects of two different treatments and their interactions on variables within each dietary group. 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. At the time of study, rats fed the high-salt diet weighed significantly less than those fed the low-salt diet. The HS rats were also significantly older (by ~3 days) than their LS counterparts. In contrast to these modest age and weight differences between dietary groups, resting arterial pressure was unaffected by the high-salt diet. The general characteristics of all arterioles studied are presented in Table 2. The high-salt diet had no effect on resting arteriolar diameter but significantly decreased passive arteriolar diameter. Consequently, calculated resting tone was significantly lower in the HS rats than in the LS rats.

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


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

Under normal conditions, the myogenic responsiveness of arterioles in HS rats was significantly reduced compared with that in LS rats (Fig. 1). Measurements made under the normal superfusate in protocols 1 and 2 are combined in Fig. 1. In Figs. 1-11, arteriolar diameters are plotted as a function of steady-state arterial pressure at each box pressurization step. We have previously shown that the pressure increase in arcade bridge arterioles is identical to the arterial pressure increase during box pressurization (36). The line equations for each group are given in Fig. 1.


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  		Fig. 1.   Myogenic responsiveness of arcade bridge arterioles in Wistar-Kyoto rats fed a low-salt diet of 0.45% NaCl (WKY-LS) and a high-salt diet of 7% NaCl (WKY-HS). Values represent combined data from protocols 1 and 2. Equations of first-order regression lines: WKY-LS, y = -0.4x + 78.6, r2 = 1.00; WKY-HS, y = -0.1x + 55.7, r2 = 0.94. *P < 0.05 vs. paired value in WKY-LS. The slope of the pressure-diameter line for WKY-HS is significantly different from that for WKY-LS (P < 0.05).

Figure 2 illustrates the effectiveness of saralasin and losartan as ANG II-receptor antagonists in rat spinotrapezius muscle. Under normal conditions, topical ANG II caused respective arteriolar constrictions of 20 ± 3 and 18 ± 2 µm in the LS and HS rats during the saralasin pilot experiments (Fig. 2A), and respective constrictions of 17 ± 3 and 15 ± 2 µm in the LS and HS rats during the losartan pilot experiments (Fig. 2B). The magnitude of these constrictions was not different between LS and HS rats. Addition of either antagonist to the superfusate did not affect resting arteriolar diameters in the LS rats (55 ± 3 µm before vs. 55 ± 2 µm after saralasin, and 46 ± 2 µm before vs. 45 ± 2 µm after losartan) or in the HS rats (46 ± 1 µm before vs. 45 ± 2 µm after saralasin, and 40 ± 2 µm before vs. 39 ± 2 µm after losartan). However, each antagonist effectively blocked arteriolar responses to topical ANG II (respective constrictions of 1.4 ± 1.0 and 0.6 ± 0.4 µm in the LS and HS rats under saralasin, and respective constrictions of 0.5 ± 0.4 and 0.4 ± 0.3 µm in the LS and HS rats under losartan).


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  		Fig. 2.   Arcade bridge arteriole constriction in response to 0.1 ml topical ANG II (10-6 M) before and after nonselective ANG II-receptor antagonism with saralasin (A) or selective AT1-receptor antagonism with losartan (B). Solid bars, WKY-LS; hatched bars, WKY-HS. *P < 0.05 vs. corresponding value under normal superfusate.

In protocol 1, box pressurization under the normal superfusate caused arterioles to moderately constrict (in LS rats) or maintain their normal resting diameter (in HS rats) (Fig. 3). As observed in the pilot experiments, saralasin did not affect resting diameter in either dietary group. Saralasin modestly attenuated myogenic responsiveness only in the LS rats, as indicated by a significantly greater arteriolar diameter at the +30-mmHg pressure step. Furthermore, the slope of the first-order regression line fit to the LS pressure-diameter values is significantly less negative in the presence of saralasin. In the HS rats, saralasin had no significant effect on arteriolar diameter at any pressure step or on the slope of the line fit to the pressure-diameter values. For equations of the lines fit to these data, please refer to Fig. 3.


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  		Fig. 3.   Myogenic responsiveness of arcade bridge arterioles before and during exposure to the nonselective ANG II-receptor antagonist saralasin in WKY-LS and WKY-HS. Equations of first-order regression lines: WKY-LS, normal superfusate, y = -0.4x + 72.9, r2 = 1.00, under saralasin, y = -0.2x + 62.0, r2 = 0.92; WKY-HS, normal superfusate, y = -0.1x + 54.8, r2 = 0.81, under saralasin, y = -0.1x + 47.7, r2 = 0.77. *P < 0.05 vs. paired value under normal superfusate. In WKY-LS, the slope of the pressure-diameter line under saralasin is significantly different from that under the normal superfusate (P < 0.05).

In protocol 2, losartan did not affect resting diameters in either group but modestly attenuated myogenic responsiveness in LS rats only (Fig. 4). In the LS rats, losartan had no significant effect on arteriolar diameter at any pressure step, but significantly decreased the slope of the first-order regression line fit to the pressure-diameter values. In the HS rats, losartan had no significant effect on arteriolar diameter at any pressure step or on the slope of the line fit to the pressure-diameter values. Figure 4 contains the line equations for each group.


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  		Fig. 4.   Myogenic responsiveness of arcade bridge arterioles before and during exposure to the selective AT1-receptor antagonist losartan in WKY-LS and WKY-HS. Equations of first-order regression lines: WKY-LS, normal superfusate, y = -0.5x + 84.1, r2 = 1.00, under losartan, y = -0.3x + 71.23, r2 = 0.99; WKY-HS, normal superfusate, y = -0.2x + 58.5, r2 = 0.99, under losartan, y = -0.2x + 61.6, r2= 0.94. In WKY-LS, the slope of the pressure-diameter line under losartan is significantly different from that under the normal superfusate (P < 0.05).

As shown in Fig. 5, neither saralasin nor losartan had any effect on the magnitude of arteriolar constriction in response to topically applied NE at two different submaximal concentrations. This finding suggests that these antagonists did not reduce arteriolar responsiveness to vasoconstrictor stimuli in a nonspecific manner.


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  		Fig. 5.   Arcade bridge arteriole constriction in response to 0.1 ml topical norepinephrine (NE) under the normal superfusate, in the presence of saralasin, or in the presence of losartan. Data are from WKY-LS. Solid bars, 10-6 M NE; hatched bars, 10-5 M NE. *P < 0.05 vs. response to 10-6 M NE.

Figure 6 illustrates the effectiveness of systemically administered captopril as an ACE inhibitor in this study. As mentioned earlier, resting arterial pressure was not different between dietary groups (LS, 100 ± 5 mmHg; HS, 87 ± 7 mmHg). Under control conditions, intravenous infusion of ANG I increased arterial pressure by 48 ± 2 mmHg in LS rats and by 58 ± 6 mmHg in HS rats, whereas intravenous infusion of ANG II increased arterial pressure by 65 ± 4 mmHg in LS rats and by 80 ± 7 mmHg in HS rats. In both groups, the increase in arterial pressure following ANG II infusion was significantly greater than that following ANG I infusion. After captopril administration, resting arterial pressure was significantly decreased to 75 ± 4 mmHg in LS rats and 68 ± 7 mmHg in HS rats, and the arterial pressure increase following ANG I infusion was dramatically reduced in both groups (increases of 14 ± 3 mmHg in LS rats and 5 ± 2 mmHg in HS rats). In contrast, captopril had no effect on the increase in arterial pressure following intravenous infusion of ANG II in either group (increases of 76 ± 3 mmHg in LS rats and 77 ± 6 mmHg in HS rats).


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  		Fig. 6.   Effect of intravenous infusions of ANG I and ANG II (50 ng in a 0.1-ml bolus) on arterial pressure before (A) and after treatment with the angiotensin-converting enzyme (ACE) inhibitor captopril (B). Solid bars, WKY-LS; hatched bars, WKY-HS. *P < 0.05 vs. response to ANG I under same conditions; dagger P < 0.05 vs. response to ANG I under control conditions.

In preparation for its use in combination with captopril, we also evaluated the effectiveness of HOE-140 as a selective B2-bradykinin-receptor antagonist in rat spinotrapezius muscle (Fig. 7). Under control conditions, topical bradykinin significantly dilated arterioles from their control diameter of 45 ± 2 µm to a diameter of 60 ± 2 µm, which was not different from the passive diameter measured in the presence of Ado (61 ± 2 µm). Administration of HOE-140 did not alter resting arteriolar diameters (45 ± 2 µm before vs. 43 ± 2 µm after HOE-140) but effectively blocked arteriolar responses to topical bradykinin (diameter = 45 ± 2 µm, measured 1 min after bradykinin application).


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  		Fig. 7.   Arcade bridge arteriole diameters before (resting) and after 0.1 ml topical bradykinin (+BK) under control (A) conditions and after treatment with the selective B2-bradykinin-receptor antagonist HOE-140 (B) in WKY-LS. Also shown are the passive arteriolar diameters in the presence of adenosine (+Ado). *P < 0.05 vs. corresponding resting value.

Figure 8 illustrates the effect of captopril on myogenic responsiveness in LS and HS rats treated with HOE-140. Captopril did not alter resting arteriolar diameters in either the LS group or the HS group (42 ±1 µm before vs. 42 ± 1 µm after administration in LS rats, and 41 ± 1 µm before vs. 42 ± 1 µm after administration in HS rats). However, captopril significantly decreased resting arterial pressure in both groups (from 81 ± 3 to 65 ± 1 mmHg in LS rats and from 76 ± 2 to 70 ± 1 mmHg in HS rats), with this reduction being significantly greater in the LS rats. In both groups, the reduced arterial pressure after captopril prohibits a meaningful comparison of arteriolar diameters before versus after captopril at the +10-, +20-, or +30-mmHg pressure steps. However, the slopes of the first-order regression lines fit to the pressure-diameter values can be compared, and the significantly reduced slope of this line after captopril administration in LS and HS rats indicates reduced myogenic responsiveness. Although captopril had a significant effect on myogenic responsiveness in both groups, this effect was noticeably greater in the LS rats. The line equations for each group are given in Fig. 8. After captopril treatment, the slopes of the first-order regression lines fit to the pressure-diameter values in these HOE-140-treated LS and HS rats are nearly identical (Fig. 9).


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  		Fig. 8.   Myogenic responsiveness of arcade bridge arterioles before and during exposure to the ACE inhibitor captopril in WKY-LS and WKY-HS treated with the selective B2-bradykinin-receptor antagonist HOE-140. Equations of first-order regression lines: WKY-LS, control, y = -0.5x + 79.1, r2 = 0.99, with captopril, y = -0.2x + 52.0, r2 = 0.99; WKY-HS, control, y = -0.3x + 69.4, r2 = 0.96, with captopril, y = -0.2x + 52.1, r2 = 0.98. In both groups, the slope of the pressure-diameter line during captopril exposure is significantly different from that under control conditions (P < 0.05).



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  		Fig. 9.   Myogenic responsiveness of arcade bridge arterioles after exposure to the ACE inhibitor captopril in WKY-LS and WKY-HS treated with the selective B2-bradykinin-receptor antagonist HOE-140. See Fig. 8 for line equations.

HOE-140 by itself did not affect resting arteriolar diameters in either group (42 ± 1 µm before vs. 42 ± 1 µm after HOE-140 in LS and 42 ±1 µm before vs. 43 ± 2 µm after HOE-140 in HS rats) and did not affect myogenic responsiveness in LS rats (Fig. 10). However, HOE-140 significantly augmented myogenic responsiveness in HS rats, as judged by a significant slope increase of the first-order regression line fit to the pressure-diameter values. The line equations for each group are given in Fig. 10.


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  		Fig. 10.   Myogenic responsiveness of arcade bridge arterioles in WKY-LS and WKY-HS rats treated with the selective B2-bradykinin-receptor antagonist HOE-140. Equations of first-order regression lines: WKY-LS, control, y = -0.5x + 83.3, r2 = 1.00, with HOE-140, y = -0.5x + 79.1, r2 = 0.99; WKY-HS, control, y = -0.2x + 55.3, r2 = 0.96, with HOE-140, y = -0.3x + 69.4, r2 = 0.96. For WKY-HS, the slope of the pressure-diameter line during HOE-140 exposure is significantly different from that under control conditions (P < 0.05).

As previously mentioned, the average resting arteriolar tone in HS rats was significantly lower than that in LS rats (Table 2). To assess the possibility that differences between these groups in the effects of saralasin, losartan, or captopril on myogenic behavior may have been somehow linked to the differences in resting tone, we plotted the effect of each inhibitor as a function of resting tone for each group (Fig. 11). These data indicate that there was a wide range of individual values for resting tone in both LS and HS rats, but there was no relationship between the level of tone and the subsequent effect of any agent on myogenic responsiveness in either group. The slopes of the regression lines fit to these data (not shown) were not significantly different from zero. Therefore, differences between groups in the effects of these agents are most likely related to existing differences in renin-angiotensin system activity rather than differences in the mechanical state of the arteriolar wall.


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  		Fig. 11.   Treatment-induced change in myogenic responsiveness plotted as a function of initial resting arteriolar tone in WKY-LS and WKY-HS. Individual values from all three pressurization steps are combined for preparations studied before and after exposure to saralasin (top), losartan (middle), and captopril (bottom). Slope analysis of regression lines fit to each data set (not shown) revealed no significant relationship between the level of resting tone and the effect of any treatment on myogenic responses in either dietary group.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The two major findings of this study are that 1) proximal spinotrapezius muscle arterioles in rats fed a low-salt diet exhibit a pronounced myogenic responsiveness that is modestly reduced by ANG II-receptor antagonists and more dramatically reduced by ACE inhibition, and 2) these arterioles in rats fed a high-salt diet exhibit a blunted myogenic responsiveness that is unaffected by ANG II-receptor antagonists and only modestly reduced by ACE inhibition. These findings suggest that endogenous ANG II normally reinforces arteriolar myogenic responsiveness in rat striated muscle, and that the attenuated myogenic activity associated with high salt intake may be due in part to a decrease in this influence of ANG II, possibly related to the reduction in circulating ANG II that accompanies a high-salt diet (17, 34).

Reinforcement of myogenic responsiveness by ANG II. Renally released renin converts angiotensinogen to the decapeptide ANG I, from which the octapeptide ANG II is ultimately cleaved by ACE (43). In addition to this traditionally accepted pathway for ANG II generation, there is a growing consensus that local tissue systems can also produce the necessary enzymes and substrates for ANG II production and/or sequester them from the circulation (7). The vascular effects of systemic or locally produced ANG II are mediated by either AT1 or AT2 receptors (43). Events mediated by AT1-receptor activation include vasoconstriction, vascular wall hypertrophy, and increased microvascular density (34, 43, 47, 48, 53), whereas the AT2 receptor mediates vasodilation, wall hypotrophy, and microvascular rarefaction (16, 22, 34, 43). Our findings suggest that AT1 receptors may be the predominant ANG II receptor in arcade bridge arterioles of the rat spinotrapezius muscle. These vessels constricted powerfully in response to topical ANG II but displayed no significant response to ANG II during exposure to the selective AT1-receptor antagonist losartan (Fig. 2). If AT2 receptors were present in sufficient numbers to influence the responsiveness of these vessels to ANG II, then we should have observed some ANG II-induced arteriolar dilation during AT1-receptor antagonism. The ability of AT2 receptors to reduce vascular resistance during AT1-receptor antagonism has been previously documented in the rat and in AT1-receptor knockout mice (22, 34).

One of the major purposes of this study was to determine the normal effect of endogenous ANG II on the myogenic responsiveness of spinotrapezius muscle arterioles. At concentrations that abolished arteriolar responses to exogenous ANG II (Fig. 2), the nonselective ANG II-receptor antagonist saralasin and the selective AT1-receptor antagonist losartan significantly reduced arteriolar myogenic responsiveness in LS rats (Figs. 3 and 4). Treatment with the ACE inhibitor captopril, at a dose sufficient to almost completely block systemic responses to ANG I (Fig. 6), had an even greater attenuating effect on myogenic responsiveness in these rats (Fig. 8). It is intriguing that ACE inhibition attenuated myogenic responsiveness to a greater degree than ANG II-receptor antagonism. There are several possible explanations for this observation. First, although responses to exogenous ANG II were effectively blocked, the saralasin and losartan concentrations we used may have been insufficient to completely block the actions of endogenous ANG II. Second, saralasin may have acted as a partial agonist, although this would not explain the similarly modest effect of losartan, which is a selective nonpeptide antagonist (30). Third, local renin-angiotensin systems may not have been completely suppressed by receptor antagonism (6, 7, 10, 46). Fourth, atypical ANG II receptors may exist that are not susceptible to antagonism with the agents we used (43).

In both dietary groups, the fall in arterial pressure following captopril administration represents a potential complicating factor in interpreting the effect of captopril on myogenic responsiveness. This is because any reduction in prevailing intravascular pressure could shift the vessels to a different point on the smooth muscle length-tension curve, leading to a nonspecific change in responsiveness to vasoconstrictor stimuli. However, as shown in Fig. 8, there is a large degree of overlap between "control" and "captopril" conditions in the arterial pressure range over which myogenic behavior was assessed (especially in the HS rats). Within this common pressure range for each group, the slope of the line fit to the captopril data is clearly less than that of the line fit to the control data, indicating a captopril-induced reduction in myogenic responsiveness that cannot be attributed to lowered intravascular pressure.

Few studies have addressed the possibility that ANG II modulates arteriolar myogenic behavior. In contrast with our findings, the myogenic responsiveness of rat cremaster muscle arterioles does not appear to be altered by infusion of ANG II (13). However, our findings are consistent with those in the kidney, where the myogenic responsiveness of afferent arterioles is enhanced after treatment with subconstrictor concentrations of ANG II (24). The apparent effect of endogenous ANG II on arteriolar myogenic responsiveness in the rat spinotrapezius muscle appears to be similar to the enhancing effect of NE on the myogenic responsiveness of similar-sized arterioles in the rat cremaster muscle (29, 32). Because ANG II and NE stimulate vascular smooth muscle contraction through essentially identical transduction pathways, it would seem reasonable to assume that these hormones augment myogenic responsiveness through a common pathway. Potential vascular smooth muscle pathways common to both ANG II and NE involve the activation of PLC, PKC, and voltage-dependent calcium channels (1, 8, 23, 29, 43, 45).

Effect of ANG II on arteriolar function and structure in salt-fed rats. Independent of any effect on blood pressure, high dietary salt intake has been previously shown to impair the endothelium-dependent dilation of spinotrapezius muscle arterioles to ACh and increased shear stress (3, 4), to potentiate skeletal muscle resistance artery responsiveness to ANG II (49), to decrease the passive arteriolar diameter of cremaster (14) and spinotrapezius muscle arterioles (3, 36, 37), and to promote cremaster muscle arteriolar rarefaction (17). The effects of dietary salt on endothelium-independent aspects of microvascular structure and function are frequently attributed to a decrease in circulating ANG II (16, 18). In the current study, the influence of ANG II on peripheral vascular resistance is apparently decreased in HS rats, because the degree to which ACE inhibition lowered arterial pressure was less than that in LS rats (Fig. 8). This is consistent with previous reports that high dietary salt decreases endogenous ANG II levels (17, 34). Weber et al. (49) observed that a high salt intake also potentiates the responsiveness of gracilis muscle resistance arteries to ANG II, but this effect was not found in cremaster muscle arterioles. We also found no evidence for an effect of salt on arteriolar responsiveness to ANG II, although only one concentration of ANG II was used (Fig. 2).

We observed a salt-dependent reduction in the passive diameters of arcade bridge arterioles in the spinotrapezius muscle (Table 2), which is consistent with previous reports from this laboratory (3, 36, 37) and observations in rat cremaster muscle (14). These observations are consistent with findings that endogenous ANG II exerts an important trophic influence on the microvascular wall (47, 48) and that the cross-sectional wall area of mesenteric resistance arteries is decreased in Dahl-R rats fed a high-salt diet (28).

The myogenic responsiveness of proximal spinotrapezius muscle arterioles in HS rats was significantly less than that in LS rats (Fig. 1), which confirms our previous findings (36) and is consistent with other findings in renal interlobular arteries and afferent arterioles (44). In contrast, Weber et al. (49) found unaltered myogenic responsiveness in isolated gracilis muscle-resistance arteries from rats fed a high-salt diet. The discrepancy between these reports may be due to inherent differences in the rat strains, vascular beds, or vessel types that were studied.

Myogenic responsiveness was not altered by ANG II-receptor antagonism in HS rats (Figs. 3 and 4), and the degree to which ACE inhibition attenuated myogenic responsiveness in HS rats was clearly less than that in LS rats (Fig. 8). Additionally, arteriolar myogenic behavior was nearly identical in LS and HS rats after ACE inhibition (Fig. 9). Collectively, these findings indicate that the degree to which endogenous ANG II reinforces arteriolar myogenic responsiveness in rats fed a high-salt diet is less than that in rats fed a low-salt diet. As mentioned earlier, this may be due to the reduction in circulating ANG II levels that accompanies high salt intake (17, 34).

Effect of bradykinin on arteriolar myogenic responsiveness. Locally released bradykinin can act in an autocrine or paracrine manner to produce vasodilation (2, 12, 25, 26, 52). Because the ability of vascular wall ACE to actively degrade bradykinin is well documented (2, 6, 7, 10, 41, 43, 46), it was a primary concern in this study that any captopril-induced changes in arteriolar responsiveness were not due to an unintended enhancement of bradykinin activity. Simultaneous treatment with captopril and HOE-140 was therefore used to evaluate the effect of endogenous ANG II on myogenic activity. In the process of collecting these data, we were able to determine the effect of selective B2-bradykinin-receptor antagonism alone on myogenic activity. Our findings suggest that endogenous bradykinin activity does not alter myogenic responsiveness in LS rats but modestly limits myogenic responsiveness in HS rats (Fig. 10). It is possible that a high-salt diet not only reduces endogenous ANG II but also reduces ACE, which could lead to increased bradykinin levels. In support of this possibility, a high-salt diet downregulates kidney ACE mRNA in DOCA hypertensive rats (35), and a low-salt diet increases plasma ACE and decreases plasma bradykinin levels in humans (19). Increased local bradykinin levels could contribute to the impaired myogenic responses that we observed in HS rats (Fig. 1), but this effect could not be responsible for the total impairment, because 1) HOE-140 did not completely restore normal myogenic responsiveness in HS rats, and 2) the main findings of this study suggest that reduced endogenous ANG II activity is also important in this regard.

This study adds to this laboratory's continued investigation of the effects of dietary salt on arteriolar structure and function. The characterization of ANG II as a facilitator of arteriolar myogenic activity and its susceptibility to dietary salt provides a better understanding of the interplay between vascular control mechanisms at different levels of salt intake. Evidence that endogenous bradykinin influences myogenic activity in rats fed a high-salt diet provides further insight into the mechanisms that contribute to attenuated arteriolar myogenic responsiveness under these conditions.


    ACKNOWLEDGEMENTS

The authors gratefully acknowledge the expert technical assistance of Kim Wix in this study.


    FOOTNOTES

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

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).

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.

Received 3 September 1999; accepted in final form 6 January 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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