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1Tulane Hypertension and Renal Center of Excellence, and Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and 2Houston Veterans Affairs Medical Center and Departments of Medicine and Pharmacology, Baylor College of Medicine, Houston, Texas 77030
Submitted 5 May 2003 ; accepted in final form 18 December 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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hypertension; vascular tone; carbon monoxide
Decreased endothelium-dependent vasodilation, associated with endothelial dysfunction, is an important characteristic of some forms of hypertension (33). Severely salt-sensitive models of hypertension, such as Dahl/Rapp salt-sensitive (11, 27) or deoxycorticosterone acetate (DOCA)-salt hypertension (26, 43), are generally thought to be associated with endothelial dysfunction. Some studies suggest that minimally salt-sensitive spontaneously hypertensive rats (SHR) display increased vascular NO production (11, 33), whereas others reported decreased NO bioavailability in these animals (12, 22, 23). We previously found increased blood carboxyhemoglobin (HbCO) and vascular HO-1 protein levels (17) in Dahl/Rapp salt-sensitive rats with salt-induced hypertension. Skeletal muscle arterioles isolated from these hypertensive Dahl/Rapp salt-sensitive rats showed impaired endothelium-dependent vasodilation in response to ACh, but acute in vitro pretreatment with an HO inhibitor abolished the difference between hypertensive high-salt and normotensive low-salt groups (17). These data suggest that increased endogenous HO function contributes to endothelial dysfunction during Dahl/Rapp salt-sensitive hypertension. However, it was unclear whether HO-mediated endothelial dysfunction extends to all forms of hypertension.
Previous studies by Hayakawa and Raij (10, 11) and Raij (33) suggested that, in contrast to SHR, severely salt-sensitive forms of hypertension are associated with decreased NO production. Therefore, we hypothesized that HO-mediated arteriolar endothelial dysfunction develops in DOCA-salt hypertensive (DOCA) rats, but not in SHR. To test this hypothesis, we measured vascular HO-1 content and blood HbCO levels in DOCA rats and SHR. To examine endothelial function, we conducted experiments using skeletal muscle arterioles from these hypertensive rats and examined the responses to an endothelium-dependent vasodilator in the presence or absence of an inhibitor of endogenous carbon monoxide production.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Animals. Male Sprague-Dawley rats (75–100 g, n = 25), SHR (SHR/NHsd, 10–12 wk old, n = 10), and Wistar-Kyoto (WKY) rats (WKY/NHsd, 10–12 wk old, n = 12) were purchased from Harlan (Indianapolis, IN). All animals were housed in a controlled environment and had free access to standard rodent diet (Harlan Teklad, Madison, WI). Male Sprague-Dawley rats were anesthetized (isoflurane), and a left retroperitoneal exposure was performed for left unilateral nephrectomy (n = 14) or sham surgery (n = 11). After a 3-day postsurgical recovery period, nephrectomized rats received DOCA injections (25 mg/kg sc, twice a week) and had free access to saline (0.9% NaCl) drinking solution for 4 wk (DOCA group). Rats subjected to sham surgery received vehicle injections (sesame oil, 1 ml/kg sc, twice a week) and had free access to tap water for 4 wk (sham group). SHR and WKY rats had free access to tap water until the day of the experiments. All procedures were approved by the institutional animal care committee.
Blood pressure and HbCO measurements and tissue extractions. On the day of the experiment, rats were weighed and anesthetized with a single dose of thiobutabarbital (120 mg/kg ip), and a carotid arterial catheter was implanted for acute determination of blood pressure and heart rate and for blood sample collections. The carotid catheter was connected to a pressure transducer (model TSD 104A, Biopac Systems, Santa Barbara, CA) coupled to a polygraph system (Biopac Systems) and a personal computer. After stable readings were obtained, three blood samples (100–150 µl) were drawn in 5-min intervals for measurement of HbCO levels (OSM3 carboxyhemoglobinometer, Radiometer America, Westlake, OH). Animals were then heparinized (1,000 U/kg iv), and the heart, right kidney, a segment of the abdominal aorta, and the gracilis anticus muscles were removed and placed into ice-cold modified Krebs buffer. Right kidney and heart wet weights were then determined.
HO-1 protein measurements. Abdominal aortic segments were harvested, snap frozen in liquid nitrogen, and stored at –70°C until analyzed. HO-1 protein expression was determined by Western blotting, as previously detailed (24). Briefly, tissue samples were thawed at room temperature and lysed in electrophoresis buffer [125 mM Tris·HCl (pH 6.8), 12.5% glycerol, and 2% SDS], boiled, and sonicated. Proteins (20 µg) were separated by SDS-PAGE and electrophoretically transferred to nitrocellulose membranes. Ponceau staining (36) was used to verify equal protein loading in all lanes. After repeated washing, the membranes were blocked for 1 h in PBS containing Tween 20 (0.1%) and nonfat milk (5%). Blots were incubated with the HO-1 antibody (1:500 dilution) for 1 h. Membranes were then incubated for 1 h with horseradish peroxidase-conjugated goat anti-rabbit antibody (1:7,500 dilution). Blots were developed by the enhanced chemiluminescence method (Amersham), and relative protein levels were quantified by scanning densitometry (LKB Ultrascan XL laser densitometer).
HO-1 immunohistochemistry. Gracilis anticus muscles were harvested and fixed overnight (10% formalin). Specimens were embedded in paraffin and sectioned. Immunohistochemical staining for HO-1 was performed by using the avidin-biotin method (Vectastain Elite ABC kit, Vector Laboratories, Burlingame, CA) as previously described (19). Briefly, sections were deparaffinized and hydrated, and endogenous peroxidase activity was quenched. After incubation with rabbit polyclonal antibody (Stressgen Biotechnologies, Victoria, BC, Canada) against HO-1 (1:3,000 dilution) or incubation with vehicle only for control slides, sections were treated with biotinylated anti-rabbit IgG antibody. After incubation with the ABC reagent, sections were developed with 3,3'-diaminobenzidine solution and counterstained with hematoxylin. HO-1 immunoreactivity was indicated by a brown color.
Isolated microvessel experiments. Segments of first-order gracilis muscle arterioles were isolated by microdissection (38). Individual arteriolar segments were cannulated at both ends with glass micropipettes in a water-jacketed vessel chamber (38). The distal micropipette was connected to a stopcock and the proximal micropipette to a reservoir, the height of which was adjusted to 108.8 cm to achieve 80 mmHg intraluminal pressure. The vessel chamber was continuously superfused with gassed buffer (14% O2-5% CO2-balance N2 at 37°C) via a nonrecirculating system. For internal diameter measurements, the vessel chamber was mounted on the stage of a microscope that was fitted with a video camera leading to a video caliper and a television-video-cassette recorder. With this setup, a magnified image of the arteriolar segment was viewed on the television screen, and the internal diameter was measured by manual adjustment of the white guides superimposed by the video caliper (17–19). After a 60-min stabilization period, the HO inhibitor CrMP (15 µmol/l) or matched vehicle was included in the superfusion buffer 20 min before the experiment. This pretreatment regimen was continued throughout the remainder of the experiment. After the pretreatment period, increasing concentrations of an endothelium-dependent vasodilator, ACh (1 nmol/l–3 µmol/l), were tested.
Statistics. Values are means ± SE. Vascular response data were analyzed by ANOVA using a statistical package (SYSTAT). When significant differences were observed, orthogonal contrasts were performed as a post hoc analysis (37). All other data were analyzed by t-tests. P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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HO-1 protein measurements. Abdominal aortic segments isolated from the severely salt-sensitive DOCA rats showed approximately sixfold higher HO-1 protein levels than did sham controls (Fig. 1). However, HO-1 protein levels were not increased in abdominal aortic segments of SHR rats compared with WKY controls (Fig. 2).
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HO immunohistochemistry. First-order gracilis muscle arterioles isolated from DOCA rats showed enhanced immunostaining for HO-1 in the vascular wall compared with the sham group (Fig. 3). In contrast, there was no difference in HO-1 staining between SHR and WKY arterioles (Fig. 3). Control sections, where the HO-1 antibody was omitted, did not show signs of immunostaining (data not shown).
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Isolated microvessel experiments. During the stabilization period, internal diameter of isolated skeletal muscle arterioles decreased spontaneously in all four groups: from 214 ± 4 to 138 ± 6 µm in sham rats (n = 18), from 174 ± 7 to 132 ± 6 µm in DOCA rats (n = 24), from 219 ± 6 to 126 ± 6 µm in WKY rats (n = 15), and from 199 ± 5 to 127 ± 7 µm in SHR (n = 14). Pretreatment with the HO inhibitor CrMP (15 µmol/l) promoted arteriolar vasoconstriction in all four groups [from 139 ± 6 to 102 ± 6 µm in sham rats (n = 9), from 131 ± 8 to 104 ± 6 µm in DOCA rats (n = 12), from 121 ± 6 to 73 ± 7 µm in WKY rats (n = 7), and from 130 ± 12 to 90 ± 11 µm in SHR (n = 7)], whereas vehicle pretreatment had no significant effect on internal diameter [from 136 ± 10 to 136 ± 8 µm in sham rats (n = 9) from 133 ± 8 to 129 ± 8 µm in DOCA rats (n = 12), from 130 ± 10 to 125 ± 11 µm in WKY rats (n = 8), and from 124 ± 8to124 ± 7 µminSHR (n = 7)].
In skeletal muscle arterioles isolated from DOCA rats, responses to an endothelium-dependent vasodilator, ACh (1 nmol/l–3 µmol/l), were attenuated compared with responses from sham controls [maximum difference (
max) = 79 ± 6 µm (n = 9) and 44 ± 5 µm (n = 12) in vehicle-pretreated sham-operated and DOCA rats, respectively, P < 0.05; Fig. 4A]. Acute in vitro pretreatment with an inhibitor of HO, CrMP (15 µmol/l), enhanced ACh-induced vasodilatory responses in the DOCA arterioles and abolished the difference between DOCA and sham groups [max = 83 ± 12 µm (n = 9) and 76 ± 7 µm (n = 12) in CrMP-pretreated sham-operated and DOCA rats, respectively, P > 0.05; Fig. 4B]. In contrast, ACh-induced vasodilator responses (Fig. 5) were not different between arterioles isolated from the SHR and control WKY groups with or without CrMP pretreatment [max = 82 ± 5 µm(n = 8) and 84 ± 3 µm(n = 7) in vehicle-pretreated WKY rats and SHR, respectively, and 99 ± 10 µm (n = 7) and 102 ± 5 µm (n = 7) in CrMP-pretreated WKY rats and SHR, respectively, P > 0.05 for both].
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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DOCA is an aldosterone mimetic that similarly promotes sodium and water retention. Uninephrectomized rats that are treated with DOCA and receive saline drinking solution (DOCA group) develop severe hypertension (34, 35). DOCA-salt hypertension is a model of severely salt-sensitive high blood pressure that is associated with end-organ damage, such as cardiac hypertrophy and severe renal injury (34). We also found higher blood pressure and higher heart and kidney weights, consistent with cardiac and renal injury, in DOCA than in sham control rats.
The SHR is a genetic model of minimally salt-sensitive hypertension, and, with age, this strain progressively develops hypertension in the absence of exacerbating dietary factors (8). Hayakawa and Raij reported that, at comparable levels of systemic hypertension, Dahl/Rapp salt-sensitive rats develop renal injury (10) and cardiac hypertrophy (11), whereas SHR do not (10, 11). We similarly found that although mean arterial pressures in SHR were comparable with those in the DOCA group, SHR did not show increased heart and kidney weights, potentially arguing against cardiac and renal injury.
Carbon monoxide is a vasoactive by-product of HO-catalyzed breakdown of heme (6, 20). Carbon monoxide generated in vivo is highly stable but, eventually, diffuses into the bloodstream, where it binds to hemoglobin to form HbCO (20). HbCO can be measured from a small blood sample (100–150 µl) with the use of a clinical-grade machine (47). We previously found that blood HbCO levels may be used as an index to evaluate the status of the endogenous carbon monoxide system (47) and reported that HbCO levels are increased in Dahl/Rapp salt-sensitive rats with salt-induced hypertension (17). Our present study found higher blood HbCO levels in DOCA rats than in sham animals. However, blood HbCO levels did not differ between SHR and control WKY groups. These data serve as a cursory index that salt-sensitive hypertension in DOCA rats is accompanied by increased endogenous carbon monoxide production. Furthermore, this increase in endogenous carbon monoxide production may not be a consequence of high blood pressure per se but may be, rather, associated with the salt-sensitive trait.
The major endogenous source of carbon monoxide production is the HO-catalyzed enzymatic degradation of heme (6, 20, 40). Numerous tissues (28), including vascular endothelial and smooth muscle cells, express HO (5, 9). Three HO isoforms have been described (28, 30). HO-1 (heat shock protein 32) is the inducible isoform because its gene expression can be increased severalfold by various stimuli (28). HO-2 is regarded as a constitutive isoform, because its expression is relatively constant (28). Little is known about HO-3, except for a single report indicating that it has negligible catalytic activity with respect to the other two isoforms (30). ANG II-induced hypertension was reported to increase cardiac (14), aortic (15), and renal (1) expression of HO-1. We previously found that vascular HO-1 expression is increased in Dahl/Rapp salt-sensitive rats with salt-induced hypertension (17). In contrast, a recent report suggested that HO-1 expression is decreased in 8-wk-old, but not in adult, SHR (31). Our present data show higher HO-1 protein levels in abdominal aortic segments and first-order gracilis muscle arterioles isolated from DOCA rats than from the sham group. However, HO-1 levels were not different between SHR and WKY groups. These data suggest that DOCA-salt hypertension is accompanied by increased vascular HO-1 protein content, which may contribute to the increased endogenous carbon monoxide production.
Severely salt-sensitive hypertension (33), such as Dahl/Rapp salt-sensitive (11, 27) or DOCA-salt hypertension (26, 43), is reported to be associated with endothelial dysfunction. Some studies suggest that minimally salt-sensitive SHR display increased vascular NO production (11, 33), whereas others reported decreased NO bioavailability in these animals (12, 22, 23). Carbon monoxide has been shown to inhibit NO synthase (29, 41, 46) and promote endothelium-dependent vasoconstriction (18). Furthermore, induction of HO-1 has been shown to attenuate muscarinic agonist-induced NO release (41) and vasorelaxation (21) in isolated renal arteries. We previously reported impaired ACh-induced vasodilation in skeletal muscle arterioles isolated from hypertensive Dahl/Rapp salt-sensitive rats, but acute in vitro pretreatment with an HO inhibitor abolished the difference between hypertensive and normotensive groups (17). These data suggested that increased endogenous HO function may contribute to endothelial dysfunction during Dahl/Rapp salt-sensitive hypertension.
Our present study shows that skeletal muscle arterioles isolated from DOCA rats show attenuated vasodilator responses to an endothelium-dependent vasodilator, ACh, compared with sham controls. Furthermore, acute in vitro pretreatment with an inhibitor of endogenous carbon monoxide production, CrMP, enhanced arteriolar responses to ACh in the DOCA arterioles and diminished the differences between the DOCA and sham groups. CrMP is a photostable (44), specific (2), competitive inhibitor of HO that has been shown to decrease carbon monoxide formation in isolated gracilis muscle arterioles (49). In contrast, ACh-induced responses were not different between SHR and WKY arterioles with or without pretreatment with the HO inhibitor. Our HbCO and HO-1 protein measurements indicate that endogenous carbon monoxide production is increased in DOCA rats, but not in SHR. These data suggest that DOCA-salt hypertension is accompanied by increased endogenous carbon monoxide production, which may contribute to arteriolar endothelial dysfunction. Furthermore, this increase in endogenous carbon monoxide production and the subsequent endothelial dysfunction may not be a consequence of high blood pressure per se but may be, rather, associated with salt retention and/or high salt intake.
Numerous studies suggest an important role for the reninangiotensin-aldosterone system in the development of endothelial dysfunction during hypertension (16). Recent studies emphasize the role of increased mineralocorticoid activity in hypertensive vascular injury (34). However, other studies suggest that high salt intake alone can promote endothelial dysfunction (4, 25, 39). Given the series of interventions required to establish DOCA-salt hypertension (unilateral nephrectomy, DOCA, and high salt intake), one can generate multiple combinations of "controls" to examine the respective contributions of each of these factors to arteriolar endothelial dysfunction in this model. Although such studies are required to explore the detailed mechanism of HO-mediated endothelial dysfunction in DOCA-salt hypertension, they are beyond the scope of the present study.
In the present study, we compared arteriolar responses between the hypertensive and normotensive animals at matched constant intraluminal pressure of 80 mmHg. Because the arterioles from hypertensive (DOCA and SHR) animals are likely adapted to the higher intraluminal pressures, our experiments may not accurately reflect their responsiveness in vivo. However, because the mean arterial pressures in DOCA rats and SHR are comparable, we have no reason to believe that the lower pressure per se would affect their responsiveness differently. Furthermore, other studies also used matched normal pressures to compare isolated arteriolar responses between hypertensive SHR and normotensive WKY animals (12, 22, 23) and found altered flow-induced dilator responses (22, 23) but similar ACh-induced vasodilator responses (12). Therefore, we believe that the intraluminal pressure used in our in vitro study is not enough to explain the observed differences between DOCA and SHR arteriolar responses.
Studies regarding the functional status of the vascular NO system in SHR appear to be contradictory. Some investigators suggest that vascular NO production is increased in SHR (11, 33). They suggest that severely salt-sensitive models of hypertension, such as Dahl salt-sensitive rats, are more susceptible to end-organ damage than are SHR because they are unable to increase vascular NO formation in response to the enhanced hemodynamic forces associated with high blood pressure (11, 33). In contrast, other studies suggest that vascular NO formation and/or bioavailability is decreased in SHR (12, 22, 23). Because decreased vascular NO function is a key feature associated with endothelial dysfunction, understandably the issue of endothelial function in SHR is similarly controversial. The reason for this diversity in the scientific literature is unknown. The SHR is a genetic model of hypertension, and it is possible that the last two decades may have yielded some genetic drifts among different laboratories and breeders. In fact, an established stroke-prone substrain of SHR (SHRSP) exhibits severe hypertension, enhanced salt sensitivity, and endothelial dysfunction (decreased vasodilator responses to ACh) and develops malignant nephrosclerosis and stroke compared with the parent SHR strain (8). Nonetheless, there are studies reporting endothelial dysfunction in regular SHR also (13, 22, 23, 42). Some of those investigations used large blood vessels, such as aortic rings (48), which are not resistance vessels. However, there are reports of decreased vascular NO function also in resistance vessels isolated from SHR (13, 22, 23, 42).
Our present study does not find evidence of endothelial dysfunction in skeletal muscle arterioles isolated from SHR, although we only used an endothelium-dependent vasodilator, ACh, to examine arteriolar endothelial function. Although agonists such as ACh are frequently used to examine endothelial function (17, 21, 27, 38, 39), it is important to recognize that such manipulations only test certain aspects of endothelial function. Therefore, the possibility exists that different methods of endothelial stimulation, e.g., shear stress-mediated flow-induced dilation vs. agonist stimulation, may yield different results. Investigators who reported impaired shear force-induced dilation (22, 23) and enhanced myogenic tone (13, 42) in SHR did not see attenuated ACh-induced vasodilation in skeletal muscle arterioles isolated from SHR (12). Perhaps by using different, perhaps larger, blood vessels or alternative methods of endothelial stimulation we might be able to demonstrate altered endothelial function in SHR. However, our aim was not to resolve the apparent controversy in the scientific literature regarding endothelial function in SHR. Our present study simply demonstrates a phenomenon of HO-mediated attenuation of ACh-induced vasodilation that is clearly present in DOCA rats, but absent in SHR. Our results show that such phenomena are not equally present in all forms of hypertension and, therefore, suggest that factors other than high blood pressure per se contribute to the development of HO-mediated altered endothelial function in some forms of hypertension.
The issue of salt sensitivity in SHR requires clarification. Some reports suggest that, on increased dietary salt intake, SHR display higher blood pressure; therefore, SHR should be classified as salt sensitive (3, 32). Others compare the salt sensitivity of blood pressure in SHR and SHRSP and suggest that SHR are only minimally salt sensitive (8). Blood pressure responses to salt intake are continuously distributed; therefore, the definition of salt sensitivity is arbitrary: it simply means that the blood pressure changes more than the currently defined increment (45). Salt sensitivity is defined as a 
10% increase in blood pressure in response to high sodium intake (1 wk at 249 meq/day) (45). Therefore, SHR should be regarded as salt sensitive. Nonetheless, the degree of salt sensitivity is much less in SHR than in SHRSP, DOCA rats, or Dahl salt-sensitive rats.
In summary, our data show that, at similar levels of hypertension, vascular HO-1 protein levels and blood HbCO levels are increased in DOCA rats, but not in SHR. Arterioles isolated from the DOCA animals displayed attenuated endothelium-dependent vasodilator responses, and acute in vitro treatment with an inhibitor of endogenous carbon monoxide production abolished the differences between the DOCA and sham arterioles. In contrast, endothelium-dependent vasodilator responses were not different between SHR and WKY arterioles with or without the HO inhibitor. These data suggest that DOCA-salt hypertension is accompanied by increased endogenous carbon monoxide production, which may contribute to arteriolar endothelial dysfunction. Furthermore, this increase in endogenous carbon monoxide production and the subsequent endothelial dysfunction may not be a consequence of high blood pressure per se but may be, rather, associated with salt retention and/or high salt intake.
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ACKNOWLEDGMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants R01 HL-64577 (to R. A. Johnson) and R01 HL-59976 (to W. Durante), National Center for Research Resources Institutional Development Award P20 RR-017659 (to F. K. Johnson), an American Heart Association Established Investigator Grant (to W. Durante) and Southeast Affiliate Postdoctoral Fellowship 0020335B (to F. K. Johnson), and a Health and Excellence Fund Grant from the Louisiana Board of Regents.
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FOOTNOTES |
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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. Section 1734 solely to indicate this fact.
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REFERENCES |
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-aminolevulinic acid increase carboxyhemoglobin levels in the anesthetized rat (Abstract). FASEB J 16: A851, 2002.
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