Structure and Function of Small Arteries in Salt-Induced Hypertension
Effects of Chronic Endothelin-Subtype-A–Receptor Blockade
Abstract The involvement of endothelin in salt-induced hypertension is unclear. In the Dahl rat model, we studied the effects of a selective endothelin-subtype A (ETA) receptor antagonist, LU135252, on blood pressure, vascular structure, and function. Dahl salt-sensitive and salt-resistant rats were treated for 8 weeks with 4% NaCl alone or in combination with LU135252 taken orally (60 mg/kg per day). The geometry and reactivity of basilar and mesenteric arteries were studied in vitro under perfused and pressurized conditions using a video dimension analyzer. Chronic salt administration increased systolic blood pressure by 37±3 mm Hg and media-lumen ratio of the basilar and mesenteric arteries in salt-sensitive rats (P<.05). These structural changes were caused by eutrophic remodeling in basilar and hypertrophic remodeling in mesenteric arteries. Endothelium-dependent relaxations to acetylcholine and contractions to endothelin-1 were impaired in mesenteric arteries of salt-sensitive rats on a high NaCl diet. LU135252 prevented part of the increase in systolic blood pressure and structural and functional alterations but increased plasma endothelin 1 levels (P<.05 versus salt-treated, salt-sensitive rats). LU135252 had no effect on these parameters in salt-resistant rats. These findings suggest that the long-term pressor effect of salt administration is mediated in part by the action of endogenous endothelin acting via ETA receptors. Thus, chronic ETA receptor blockade may be useful therapeutically to lower arterial pressure and prevent endothelial dysfunction and hypertrophic remodeling of resistance arteries in salt-sensitive forms of hypertension.
- basilar artery
- mesenteric resistance artery
- vascular remodeling
- endothelin receptors
- endothelium-derived relaxing factor
- rats, Dahl
Hypertension is an important risk factor for cardiovascular disease. In human essential hypertension, excessive salt intake has been suggested to be one of the contributing factors for the development of hypertension, particularly when associated with renal insufficiency.1 2 It also is well established that sustained hypertension is associated with morphological alterations, such as eutrophic and hypertrophic remodeling in small arteries to adapt to elevated wall stress, and thereby may protect the microcirculation.3 4 5 6
The vascular endothelium plays an important functional role in maintaining homeostasis in normal vessels by releasing vasoactive substances such as NO7 and ET-18 that modulate smooth muscle tone and proliferation.9 10 Although a role of endothelium-derived NO on vascular structure has been suggested from cell culture experiments,10 11 observations gathered in vivo in models of chronic NO inhibition do not support this hypothesis.12 13 Long-term salt treatment has been shown to exert morphological vascular changes due to hypertrophy in mesenteric arteries14 and to suppress endothelium-dependent responses mediated by NO in aorta of DS rats.15
ET-1 is a potent vasoconstrictor and mitogen in vivo and in vitro16 17 and exerts its biological effects via activation of specific receptors. Although vascular smooth muscle cells harbor ETA and ETB receptors, the former seems to be the major contributor to the vascular effects of the peptide.18 19 The ETB receptor is also present on endothelial cells and mediates the formation of NO and prostacyclin.20 21 In the vessel wall, NO and prostacyclin inhibit ET-1 production via a cGMP-dependent mechanism.22
There is strong evidence suggesting that endothelin is involved in hypertrophic remodeling (increased CSA) of resistance arteries. Indeed, the use of the combined ETA/ETB-receptor antagonist bosentan prevents the development of the structural alterations in deoxycorticosterone acetate–salt hypertensive rats and moreover had only a mild to moderate antihypertensive effect.23 In DS rats on a salt diet, acute administration of BQ-123, an ETA receptor antagonist, and bosentan lowers systolic blood pressure.24 However, the contribution of endothelin to structural and functional vascular alterations in salt-induced hypertension is not known. Therefore, we investigated the effects of chronic selective ETA receptor blockade with an orally active ETA receptor antagonist, LU135252, on salt-induced hypertension, with special emphasis on vascular structure and endothelium-dependent and -independent vascular reactivity of small arteries.
Male DS and DR rats 13 weeks of age were obtained from Charles River WIGA GmbH (Sulzfeld, Germany) and held at the animal facilities of the University Hospital Bern for up to 4 weeks. Rats were distributed in random order into six groups: two control groups (control-DS and control-DR fed standard chow and water ad libitum), two salt-treated groups (salt-DS and salt-DR fed chow containing 4% salt [special rat diet from Harlan]), and two salt plus LU135252 groups (salt-DS+LU135252 and salt-DR+LU135252 fed 60 mg/kg per day of LU135252, which was mixed with salted, powdered chow). The dosage of LU135252 that blocked ETA receptors was based on previous studies.25 26 27 The rats were treated for 8 weeks, and the chow intake was monitored every second day. The dose of LU135252 averaged 62±2 mg/kg per day in the salt-DS+LU135252 group and 69±5 mg/kg per day in the salt-DR+LU135252 group (L=NS). Systolic arterial pressure and heart rate were measured by the tail-cuff method using a pulse transducer (model LE 5000, Letica), and body weight of the rats was monitored before, after 4 weeks’, and at the end of 8 weeks’ treatment. Housing facilities and all experimental protocols were approved by the local authorities for animal research (Kommission für Tierversuche des Kantons Bern) in Bern, Switzerland.
The rats were anesthetized (thiopental 50 mg/kg body weight IP) and decapitated. The proximal part of the basilar artery and a segment of a fourth branch of the mesenteric artery (closest to the ileum) were isolated and dissected free under a microscope (Leica Wild M3C) in cold (4°C) modified Krebs-Ringer bicarbonate solution (mmol/L NaCl 118.6, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.1, Na+2, Ca2+-EDTA 0.026, and glucose 10.1).
The isolated vessels were transferred to small vessel chambers (Living Systems Instrumentation) filled with Krebs-Ringer bicarbonate solution. The solution, circulating from a 250 mL reservoir at a flow rate of 50 mL/minute, was aerated continuously with 95% O2/5% CO2 gas at 37°C. The proximal and distal ends of the vessels were mounted and sutured on two small glass microcannulas (afferent and efferent cannula, respectively) positioned in the vessel chamber. The axial length of the vessel was adjusted longitudinally under a microscope by positioning the afferent cannula. The perfusion pressure was set at a level that has been shown previously to be optimal for contractions to serotonin and norepinephrine in basilar (35 mm Hg)12 and mesenteric arteries (30 mm Hg),18 respectively. The perfusion chamber was positioned on the stage of an inverted microscope (Nikon, TSM-F) with a video camera (Burle). The amplified image was transmitted to a monitor and a video dimension analyzer (V91, Living Systems Instrumentation), allowing for measurements and recording of lumen diameter and media thickness.
Basilar arteries were equilibrated for 60 minutes in calcium-free Krebs solution to prevent myogenic tone. The perfusion pressure was increased from 25 to 55 mm Hg in 10 mm Hg steps, and efferent pressure was adjusted to maintain constant flow. At each pressure, vascular structure was determined. In normal Krebs solution, Ca2+ induced contractions in the basilar artery in all groups of DS rats, and we therefore did not investigate vascular reactivity. Mesenteric arteries were equilibrated for 60 minutes and perfused intraluminally with Krebs solution containing 1% BSA. Their resting lumen diameter and media thickness were recorded using Krebs solution because no myogenic tone was observed in this artery. Between each protocol, the system was washed with Krebs solution and equilibrated for 30 minutes. The mesenteric arteries were first contracted with a single dose of angiotensin II (10−7 mol/L). Concentration-response curves to norepinephrine (10−9 to 3×10−5 mol/L) then were obtained. Endothelium-dependent relaxations to acetylcholine (10−10 to 10−4 mol/L) and endothelium-independent relaxations to sodium nitroprusside (10−10 to 3×10−5 mol/L) were obtained after half-maximal contraction to norepinephrine. At the end of the protocol, a concentration-response curve to ET-1 (10−11 to 3×10−8 mol/L) was performed.
The following drugs were used for in vitro experiments and were administered extraluminally in the circulating Krebs buffer solution: acetylcholine hydrochloride, L-norepinephrine bitartrate, sodium nitroprusside dihydrate, angiotensin II (all from Sigma Chemical Co), and ET-1 (Novabiochem/Calbiochem AG). LU135252 [(+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid], the active (+)− isomere of LU127043, a low-molecular-weight, nonpeptide, selective ETA receptor antagonist, was provided by Knoll AG.
Measurement of ET-1 Plasma Levels
Arterial blood samples were obtained before death through a catheter inserted in the left femoral artery. The blood was immediately transferred to a tube containing EDTA and centrifuged at 4°C for 10 minutes. Plasma was separated at 4°C and kept at −80°C until assay. Plasma ET-1 levels were determined as described in detail elsewhere.27
For statistical analysis, the sensitivity of the vessels to the drugs was expressed as a negative logarithm of the concentration that caused half-maximal relaxation or contraction (pD2). In addition, maximal contraction or relaxation (expressed as a percentage of the decrease in the basal intraluminal diameter or of the increase in the intraluminal diameter from the diameter obtained after precontraction, respectively) was determined for each individual concentration-response curve by nonlinear regression analysis using MatLab software. The CSA, growth index, and remodeling index were calculated as described elsewhere,4 12 as was the circumferential wall stress.5 28 The distensibility of the basilar artery is expressed as micrometer change per millimeter of mercury pressure increase and represents the slope of the pressure–lumen diameter curve. All results are given as mean±SEM. In all experiments, n=number of rats. For multiple comparisons, results were analyzed by ANOVA followed by Bonferroni’s correction,29 and for simple comparison between two values, a paired Student t test was used when appropriate. The growth indexes among the groups were compared by one sample analysis. Pearson’s correlation coefficients were calculated by linear regression. A value of P<.05 was considered significant.
Body Weight, Systolic Blood Pressure, and Heart Rate
Before treatment, mean body weight did not differ within groups. After 8 weeks, body weight increased in all groups. However, in the salt-fed DS group the weight gain was slightly reduced (P<.05 versus control-DS and salt-DS+LU135252, Table 1⇓). Systolic blood pressure was increased by chronic administration of salt in DS rats only as compared with control DS (P<.05, n=8, Fig 1A⇓, Table 1⇓). The ETA receptor antagonist LU135252 prevented part of the salt-induced pressure rise (P<.05 versus salt-DS rats, n=8, Fig 1A⇓). Changes in heart rate did not reach statistical significance (Table 1⇓).
Plasma ET-1 Level
After chronic salt treatment, plasma levels of ET-1 tended to increase from 2.0±0.1 to 2.8±0.3 pg/mL in DS rats. After concomitant treatment with LU135252, the levels of the peptide markedly increased (4.6±0.2 pg/mL) versus salt-DS rats (P<.05). However, plasma ET-1 levels did not differ among control-DR (2.2±0.3 pg/mL), salt-DR (2.5±0.3 pg/mL), and salt-DR+LU135252 (2.4±0.2 pg/mL) groups (n=4 to 6).
In the basilar and small mesenteric arteries, chronic salt administration increased media thickness and media-lumen ratio only in the salt-sensitive rats (Table 2⇓). These changes were accompanied by a decrease in lumen diameter in the basilar artery (P<.05 versus the control DS group, Table 2⇓) without modification of the CSA or growth index (Fig 1B⇑). Hence, this effect mainly was due to remodeling (remodeling index of 88%). In contrast, however, in the mesenteric artery of salt-treated DS the lumen diameter was unchanged, and an increase of CSA was observed (Table 2⇓), leading to a significant growth response (P<.05; Fig 1B⇑). In DR rats on a high-salt diet, there were no alterations in the structure of small arteries compared with the vessels of controls (Table 2⇓).
All the vascular structural changes induced by chronic treatment with salt for 8 weeks were prevented by concomitant oral administration of ETA receptor antagonist LU135252 in both vascular beds (Table 2⇑, Fig 1B⇑). In the basilar artery, LU135252 tended to increase the lumen diameter slightly (Table 2⇑).
The media-lumen ratio was correlated positively with systolic blood pressure in basilar (r=.53, P<.01, n=20, data not shown) and mesenteric (r=.793, P<.0001, n=23) arteries (Fig 2A⇓). The CSA was correlated positively with systolic blood pressure in mesenteric arteries (r=.715, P<.001, Fig 2B⇓) but not in basilar arteries (r=.245, P=.30, data not shown). The values for circumferential wall stress were the same within arteries in DS and DR groups (Table 2⇑). The distensibility of the basilar artery, as determined by the pressure–lumen diameter curves, was similar among groups of DS (control-slope, 1.3±0.1 μm/mm Hg, Fig 3⇓) or DR rats (control-slope 1.5±0.1 μm/mm Hg), suggesting that the observed vascular remodeling was not due to an increase in vascular stiffness.
Vascular Reactivity of Mesenteric Arteries
In small mesenteric arteries half-maximally precontracted with norepinephrine, endothelium-dependent relaxations to acetylcholine were impaired by chronic salt treatment in the DS rats (P<.05 versus control for maximal relaxation and sensitivity, Fig 4A⇓). Concomitant treatment with LU135252 prevented these alterations (P<.05 versus salt-DS rats, n=6 to 7).
Sodium nitroprusside caused concentration-dependent relaxations that were shifted 3.2-fold to the right after chronic salt treatment (P<.05 versus control DS rats, Table 3⇓), whereas concomitant LU135252 administration prevented this effect (P<.05 versus salt-DS rats, Table 3⇓). Furthermore, LU135252 treatment improved the maximal response (P<.05). In DR rats, there were no differences within groups (Table 3⇓).
In mesenteric arteries, responses to angiotensin II (10−7 mol/L) were enhanced in the salt-DS group (27±5%, P<.05 versus control-DS rats, 13±3%). This increase in contraction was prevented by chronic LU135252 treatment (12±2%, P<.05 versus salt-DS rats, n=7). The responses to angiotensin II did not differ among control-DR (12±2%), salt-DR (12±1%), and salt-DR+LU135252 groups (15±3%, n=6).
The maximal contractions and the sensitivity to ET-1 were blunted in the salt-DS group (P<.05 versus control-DS rats, Fig 5A⇓); however, additional chronic treatment with LU135252 normalized the response (P<.05 versus salt-DS group, n=7 to 8). The maximum of the contractions to norepinephrine (10−9 to 3×10−5 mol/L) was slightly reduced in salt-DS rats only (P<.05 versus control-DS, Table 3⇑). This attenuation was almost normalized in salt-DS rats receiving LU135252 (P=NS versus salt-DS rats). The sensitivity to norepinephrine was comparable in all groups (Table 3⇑, n=6 to 8). In DR rats there were no changes in vascular reactivity to ET-1 (Fig 5B⇓) or to norepinephrine (Table 3⇑).
The present study shows that the increases in systolic blood pressure, media thickness, and media-lumen ratio of the basilar and mesenteric arteries in DS rats after long-term administration of salt can be reduced greatly by concomitant administration of LU135252, a selective nonpeptide ETA receptor antagonist. Furthermore, in DS rats on a high-salt diet, impaired endothelium-dependent and -independent vascular responses were normalized by chronic LU135252 treatment.
Chronic treatment with salt increased media thickness and the media-lumen ratio of basilar and mesenteric arteries only in DS rats. However, different mechanisms appear to be involved; in basilar arteries, the lumen and external diameters were decreased without change in CSA. Hence, this structural alteration was due mainly to a rearrangement of the same amount of vascular material around a smaller lumen, a process of so-called inward eutrophic remodeling4 6 (remodeling index, 88%). Thus, growth did not contribute significantly to the increased media-lumen ratio in basilar arteries. Similar results were observed in small cerebral arteries of stroke-prone spontaneously hypertensive rats,5 during chronic NO deficiency,12 and in essential hypertension.30 In contrast, in small mesenteric arteries, an increased CSA was observed due to addition of material on the abluminal side of the artery consistent with hypertrophic remodeling, as documented by the growth index.4 6 Thus, eutrophic remodeling may be the preferable process in basilar arteries, whereas hypertrophic remodeling is involved in small mesenteric arteries, allowing the adaptation to the increase in blood pressure during hypertension in Dahl rats.
The most remarkable observation of our study was that concomitant treatment with ETA receptor antagonist LU135252 prevented part of the increase in systolic blood pressure, media thickness, and the media-lumen ratio in both vascular beds. However, in basilar arteries LU135252 did not significantly increase the reduced internal or external diameter of salt-DS rats (Fig 3⇑) and thus did not prevent eutrophic remodeling. In contrast, morphological alterations observed in mesenteric arteries of hypertensive DS rats were prevented by concomitant LU135252 treatment. Thus, it appears that endothelin contributes mainly as a promoter of growth to the development of hypertrophic remodeling of mesenteric arteries rather than eutrophic remodeling of basilar arteries. Similar observations have been made in cerebral arterioles of stroke-prone, spontaneously hypertensive rats.28
In chronic hypertension, an increase in the vascular media-lumen ratio by eutrophic or hypertrophic remodeling is important to normalize the wall stress of small arteries to allow the vessel to work under optimal conditions.3 4 This was confirmed in the present study by the normal wall stress provided by the structural adaptation and the relationship between systolic blood pressure and the media-lumen ratio. Furthermore, there was good correlation between CSA of mesenteric arteries and systolic blood pressure; hence the antihypertensive effect of LU135252 could be responsible at least in part for the normalization of hypertrophic remodeling.
The circulating renin-angiotensin system, on the other hand, is suppressed in DS rats on a high-salt diet.2 31 This may explain why an angiotensin type 1 receptor antagonist failed to prevent hypertension and left ventricular hypertrophy in DS rats.32 Hence, mechanisms other than the production of endogenous angiotensin II must be involved in vascular hypertrophic remodeling in this model of salt-induced hypertension.32 Endothelin, therefore, is a likely candidate to explain some of the vascular changes observed in this model. Our results are also in line with the overexpression of ET-1 found in other forms of low renin–angiotensin system activity, such as in deoxycorticosterone acetate–salt rats,33 which respond in a similar fashion to endothelin receptor blockade.23 34 Interestingly, whereas salt itself had no significant effects on ET-1 plasma levels, LU135252 treatment more than doubled plasma levels of the peptide in salt-treated DS rats. An increase in plasma levels of ET-1 during receptor blockade is a known phenomenon23 34 that is probably related to displacement of ET-1 from its receptor as well as reduced clearance of the peptide from the circulation (Shaw et al, 1997, unpublished data).
In addition to increased systolic blood pressure and changes in vascular structure after salt administration in DS rats, the salt diet impaired endothelium-dependent relaxations to acetylcholine in mesenteric arteries. This appears to involve in part an altered responsiveness of vascular smooth muscle cells to NO. Indeed, the sensitivity of the vessels to the NO donor sodium nitroprusside, which exerts its effects via the activation of soluble guanylyl cyclase and the subsequent formation of cGMP,35 was also impaired after chronic salt treatment. However, the response to acetylcholine was impaired to a greater degree. Indeed, the maximal relaxations to sodium nitroprusside were not affected. Hence, an impaired endothelial production of NO also must contribute to the blunted endothelium-dependent relaxations in hypertensive DS rats, as previously reported in the aorta.15 With treatment of LU135252, endothelium-dependent and -independent relaxations were normalized. The improvement could be mediated by the increased plasma levels of ET-1 during treatment with LU135252 and thus the selective activation of ETB receptors (because only ETA receptors were blocked), which in turn may lead to the release of NO and prostacyclin20 and improve endothelium-dependent relaxations. In line with this interpretation, bosentan, which blocks ETA and ETB receptors, administered to deoxycorticosterone acetate–salt hypertensive rats does not improve the relaxations to acetylcholine.23 Accordingly, in isolated, perfused rat mesenteries, ET-1 produces concentration-dependent vasodilation that is unaffected by BQ-123, an ETA receptor antagonist, but abolished when both ETA and ETB receptors are blocked.21 Moreover, other vasodilator mechanisms, such as endothelium-dependent hyperpolarization, may also be involved. ET-1 and ET-3 cause endothelium-dependent hyperpolarization in rat mesenteric artery through endothelial ETB receptors.36 Finally, the reduction in blood pressure achieved by LU135252 treatment may be responsible for normalization of endothelial function, as seen with other agents.37
ET-1–induced contractions were reduced in mesenteric arteries of DS rats on a high salt diet, and chronic ETA receptor blockade improved the maximal response and the sensitivity to ET-1. Prevention of receptor downregulation or improvement of signal transduction pathways may explain these findings. Similar results have been reported in resistance arteries of deoxycorticosterone acetate–salt hypertensive rats.23 In contrast, contractions to angiotensin II were enhanced in hypertensive DS rats and normalized after concomitant treatment with LU135252 in vitro. This may reflect upregulation of angiotensin receptors because plasma renin activity and hence angiotensin levels are markedly reduced in salt-induced hypertension.2
Maximal contractions to norepinephrine were also reduced in salt-hypertensive DS rats, and chronic ETA receptor blockade improved these alterations. It has been reported that responses to norepinephrine are increased markedly after 1 to 3 weeks on a high-salt diet. However, the responses are impaired after 6 weeks of salt treatment.38 Thus, prolonged salt-induced hypertension may lead to receptor downregulation or reduced signal transduction of adrenergic receptors.
In conclusion, this study demonstrates that long-term salt treatment in DS rats leads to an increased media-lumen ratio by eutrophic remodeling in basilar arteries and hypertrophic remodeling in mesenteric arteries. Endothelin may play a role in the increase in systolic blood pressure and vascular hypertrophy but less so in eutrophic remodeling. Furthermore, treatment with LU135252 normalized the blunted endothelium-dependent and -independent vascular responses of mesenteric arteries in salt-induced hypertension. Thus, chronic, selective ETA receptor blockade with LU135252 may be an alternative for lowering systolic blood pressure and improving vascular structure and function in salt-dependent forms of hypertension.
Selected Abbreviations and Acronyms
|DR||=||Dahl salt-resistant (rat)|
|DS||=||Dahl salt-sensitive (rat)|
|ETA||=||endothelin subtype A|
|ETB||=||endothelin subtype B|
This study was supported by the Swiss National Foundation (grant Nos. 32-32541.92/2 and 32-32591.92) and Knoll AG, Ludwigshafen, Germany. Livius V. d’Uscio is a recipient of a stipend from the Intermedia Foundation (Bern, Switzerland). Matthias Barton was supported by the Deutsche Forschungsgemeinschaft (Ba 1543-1). Pierre Moreau holds a fellowship from the Medical Research Council of Canada. Michael Kirchengast, Knoll AG (Ludwigshafen, Germany), supplied the LU135252 and helped design the protocol. The authors thank Christian Binggeli for his excellent support in software programming.
- Received December 26, 1996.
- Revision received January 23, 1997.
- Accepted March 10, 1997.
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