(Hypertension. 1996;28:367-371.)
© 1996 American Heart Association, Inc.
Articles |
Nitric Oxide and the Regulation of Blood Pressure in the Hypertension-Prone and Hypertension-Resistant Sabra Rat
Wellcome Research Laboratories, Langley Court, Beckenham, Kent, UK, and Hadassah University Hospital, Mount Scopus, Israel (D.B.-I.).
Correspondence to Prof S. Moncada, The Cruciform Project, St Martin's House, 140 Tottenham Court Rd, London W1P 9LN, UK.
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Abstract |
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We examined the role of nitric oxide (NO) in the inherited resistance or susceptibility to hypertension in the Sabra hypertension-prone (SBH) and hypertension-resistant (SBN) rat. Basal mean arterial blood pressure was significantly greater in SBH than in SBN rats. Phenylephrine elevated blood pressure to a similar extent in both substrains, whereas the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) had a greater pressor effect in SBN rats. The vasoconstrictor potency of phenylephrine was significantly higher in endothelium-intact aortic rings from the SBH rat, whereas the vasoconstrictor potency of L-NMMA was higher in those from the SBN substrain. Acetylcholine-induced endothelium-dependent relaxation was greater in aortic rings from SBN rats. The vasodilator potency of glyceryl trinitrate was significantly higher in aortic rings from SBH rats and was enhanced after endothelium removal. Both the activity of calcium-dependent NO synthase from aortic endothelial cells and the basal concentration of nitrite/nitrate in plasma were significantly greater in SBN than in SBH rats. In normotensive Wistar rats, basal mean arterial blood pressure, the pressor effect of L-NMMA, endothelial NO synthase activity, and plasma nitrite/nitrate concentrations were all between the values in SBH and SBN rats. These results indicate that a decrease in NO generation plays a role in the susceptibility of SBH rats to hypertension. Furthermore, the resistance to hypertension in the SBN strain may be related to increased NO generation.
Key Words: nitric oxide • blood pressure • rats, Sabra • endothelium
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Introduction |
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An array of physiological systems that regulate BP have been implicated in the pathogenesis of hypertension, including the autonomic nervous, humoral, and renin-angiotensin systems; sodium and water balance; and structural changes in the vasculature.1 More recently, alterations in the vascular endothelium, in particular, a deficiency in the L-arginine–NO pathway, have been suggested to play a major role in hypertension.2 3 Indeed, vascular endothelial NO synthase maintains vasodilator tone by releasing small amounts of NO in response to receptor stimulation and shear stress. This is clearly illustrated by the fact that inhibition of NO synthase leads to generalized vasoconstriction and a significant hypertensive response.2 3
Studies in humans suggest that hypertension is associated with a decrease in NO generation,4 5 whereas experiments in animal models have yielded conflicting results, with NO generation reported to be normal,6 7 decreased,8 or enhanced.9 Interpretation of the role of NO in experimental hypertension is confounded by the different inherent characteristics of these various models, genetic strains, and/or experimental designs. It is likely, however, that hypertension may be associated with either a high or low generation of NO from the vascular endothelium; the former may result from increased shear stress in response to an excessive vasoconstrictor tone,10 and the latter may occur because of an intrinsic deficiency in NO generation, in which case a normal vasoconstrictor tone would appear to be enhanced.11 12
SBH and SBN rats are derived from the Hebrew University Sabra rat colony and were originally selected for their sensitivity (SBH) or resistance (SBN) to DOCA-salt hypertension. The basal BP of the SBH rat in the absence of DOCA-salt treatment, although still within the normal range, is significantly elevated compared with that in the SBN rat. Their differing tendency toward hypertension also is evident when the rats are exposed to other hypertensive stimuli, such as high dietary salt without DOCA or renal clipping.13 SBH and SBN rats exhibit several characteristics that may be relevant to their susceptibility or resistance to hypertension; these include differences in central and peripheral catecholamine concentrations, vasopressin concentrations in brain nuclei, 
2-adrenoceptor properties,14 water and sodium handling,15 16 and baroreflex sensitivity.17 In this study, we investigated whether these substrains also exhibit differences in the L-arginine–NO pathway that may contribute to their differing susceptibility to hypertension.
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Methods |
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Male SBN and SBH rats (Hadassah, Jerusalem, Israel; 250 to 350 g) and normotensive Wistar rats (Charles River, Kent, UK; 250 to 350 g) were housed in a temperature-controlled room with water and standard rat chow (sodium content, 0.6%) ad libitum. All studies were in accordance with the UK Home Office regulations for the care and use of animals (Animals [Scientific Procedures] Act, 1986). BP, vascular reactivity in vitro, NO synthase activity in aortic endothelial cells, and plasma concentrations of nitrite and nitrate were determined as follows.
BP Measurements
Rats (3 SBN, 3 SBH, 5 Wistar) were anesthetized briefly with isofluorane (2%). Cannulas were implanted in the femoral artery and femoral vein, tunneled subcutaneously to exit at the upper back, and connected to a swivel tether system for continuous BP monitoring and drug administration, respectively. Normal physiological saline (154 mmol/L) containing heparin (10 U/mL) was administered as a continuous infusion via the femoral artery (100 µL/h) and femoral vein (75 µL/h) for maintenance of cannula patency. After surgery and a 2-hour recovery period, phenylephrine (37.5 to 600 µg/kg per hour IV) was administered as a 10-minute continuous infusion and L-NMMA (0.3 to 100 mg/kg IV) as a bolus over 30 seconds. Increases in BP were measured during the 10-minute period between successive doses of each compound.
Studies in Isolated Vascular Tissue
Rats (n=5-6) were anesthetized briefly with isofluorane (2%) followed by exsanguination. The thoracic aorta was removed, trimmed of adhering fat and connective tissue, and cut into 3-mm rings. The endothelium was removed from some rings by gentle rubbing of the internal surface with a pipe cleaner. The rings were mounted under 1 g resting tension on stainless steel hooks in 20-mL organ baths filled with Krebs' buffer ([mmol/L] NaCl 118, KCl 4.8, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 24, and glucose 11) and gassed with 95% O2/5% CO2 at 37°C. Tension was recorded with Grass FTO3 isometric transducers on a four-channel multi-pen recorder (Rikadenki). The tissues were allowed to equilibrate for 90 minutes, during which time the Krebs' buffer was changed at 30-minute intervals. Cumulative contraction curves to phenylephrine were obtained in each ring. In a separate series of experiments, the tissues from each substrain were precontracted with the phenylephrine concentration that produced approximately 90% of the maximal response (EC90). Cumulative relaxation curves to acetylcholine (0.01 to 1 µmol/L) were then obtained on each ring for assessment of endothelium integrity. After washout, the tissues were allowed to equilibrate for a further 90 minutes, during which time the Krebs' buffer was changed at 30-minute intervals. A cumulative contraction curve to the NO synthase inhibitor L-NMMA (1 to 300 µmol/L) was obtained in each ring in the presence of a threshold concentration of phenylephrine (4 to 16 nmol/L). In a separate series of experiments, tissues with and without endothelium were precontracted with phenylephrine (approximate EC90), and cumulative relaxation curves to the NO donor GTN (0.5 to 4000 nmol/L) were obtained in each tissue.
Measurement of NO Synthase Activity in Aortic Endothelial Cells
Rats (n=5-6) were anesthetized with isofluorane (2%), and the aorta was excised and washed briefly in Krebs' buffer gassed with 95% O2/5% CO2. The aorta was cut longitudinally, and the endothelial cells were removed with a plastic scraper into homogenization buffer (pH 7.4; 50 mmol/L Tris, 3.2 mmol/L sucrose, 1 mmol/L dithiothreitol, 10 µg/mL leupeptin, 10 µg/mL soybean trypsin inhibitor, and 2 µg/mL aprotinin), freeze-clamped in liquid nitrogen, and stored at -80°C. On the day of assay, the frozen cells were sonicated for 3 seconds (three times) at 4°C. The homogenate was centrifuged at 10 000g for 20 minutes at 4°C. The resultant supernatant, containing both soluble and particulate NO synthase, was added to assay buffer (pH 7.2; containing 50 mmol/L KH2PO4 [pH 7.2], 1 mmol/L MgCl2, 0.2 mmol/L CaCl2, 50 mmol/L valine, 20 µmol/L l-citrulline, 20 µmol/L l-arginine, 1 mmol/L dithiothreitol, 100 µmol/L NADPH, 3 µmol/L tetrahydrobiopterin, 3 µmol/L flavin adenine dinucleotide, 3 µmol/L flavin mononucleotide, and 0.05 µCi [14C]l-arginine [ul], approximately 1 µmol/L). After a 20-minute incubation at 37°C, the reaction was terminated by addition of 1:1 (vol/vol) Milli-Q distilled water/Dowex-AG50W (200 to 400, 8% cross-linked, Na+ form) for removal of substrate. The resin was left to settle for 30 minutes at room temperature, and the supernatant was carefully removed. NO synthase activity in the supernatant was determined by the conversion of [14C]l-arginine (ul) to [14C]l-citrulline (ul). The activity of the Ca2+-dependent enzyme was determined as the difference between the [14C]l-citrulline generated from control samples containing the NO synthase inhibitor N-iminoethyl-l-ornithine (L-NIO, 1 mmol/L)18 and samples containing EGTA (3 mmol/L) and L-NIO (1 mmol/L). The soluble protein content of the supernatant was determined by the Coomassie blue binding method with the use of Bio-Rad protein reagent with bovine serum albumin as a standard. NO synthase activity is expressed as picomoles NO per minute per milligram protein.
Measurement of Plasma Nitrite/Nitrate
Rats (n=4-6) were anesthetized with isofluorane (2%), and blood samples (approximately 0.5 mL) were obtained after exsanguination via the carotid artery. Plasma nitrite concentration was determined by first reducing the nitrate enzymatically with nitrate reductase from Aspergillus. Briefly, plasma samples were diluted 1:4 with Milli-Q distilled water and incubated with assay buffer (50 mmol/L KH2PO4, 0.6 mmol/L NADPH, 5 mmol/L flavin adenine dinucleotide, and 20 mU nitrate reductase, pH 7.5) for 1 hour at 37°C. A standard curve for reduced nitrate was constructed by incubation of sodium nitrate (1 to 100 µmol/L) with the assay buffer. The resultant nitrite concentrations were determined by chemiluminescence as described previously19 and are expressed as the amount of total plasma nitrite and nitrate in micromoles per liter.
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Materials |
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[14C]l-Arginine (ul) was from Amersham, protein reagent and bovine serum albumin from Bio-Rad, picofluor from Packard Chemical Supplies, isofluorane from Rhone-Poulenc Rorer, GTN from Schwarz-Pharma, and biopterin from Dr B Schircks Laboratories. L-NMMA and L-NIO were synthesized at Wellcome Research Laboratories by Dr H. Hodson. All other materials were obtained from Sigma Chemical Co.
Statistics
Statistical significance (P<.05) was analyzed with Student's t test or one-way ANOVA test for multiple comparisons followed by Dunnett's adjusted analysis as appropriate. Results are expressed as mean±SE (n=3-6).
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Results |
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BP Measurements
Basal mean arterial BPs of SBN and SBH rats were 96±5 and 116±3 mm Hg (P<.05), respectively; basal heart rates were 330±5 and 318±5 bpm (n=3 for each). Phenylephrine (37.5 to 600 µg/kg per hour IV), administered as a 10-minute continuous infusion, elevated BP in a dose-dependent manner in SBN and SBH rats to 143±5 mm Hg (change, 46±1) and 170±5 mm Hg (change, 53±3), respectively, at 600 µg/kg per hour IV (n=3, Fig 1a
); heart rate fell to 289±9 and 267±10 bpm. L-NMMA (1 to 100 mg/kg IV), administered as a bolus over 30 seconds, elevated BP in a dose-dependent manner to a greater extent in SBN than in SBH rats to 154±1 mm Hg (change, 64±5) and 130±9 mm Hg (change, 26±2), respectively, at 100 mg/kg IV (n=3, Fig 1b, P<.05); heart rate fell to 294±3 and 295±10 bpm.
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) and SBH (
) rats. MAP indicates mean arterial pressure.Basal mean arterial BP of the normotensive Wistar rats was 108±4 mm Hg and basal heart rate was 350±9 bpm (n=5). L-NMMA (1 to 100 mg/kg IV), administered as a bolus over 30 seconds, elevated BP in these rats in a dose-dependent manner to 151±9 mm Hg (change, 42±3) at 100 mg/kg IV (n=5).
Studies in Isolated Vascular Tissue
The vasoconstrictor potency of phenylephrine (1 to 1000 nmol/L) and the maximal force of contraction of the aortic rings were significantly greater in SBH rats (EC50, 35±2 nmol/L; 3.7±0.2 g, n=5, Fig 2a, P<.05) compared with SBN rats (EC50, 81±14 nmol/L; 2.7±0.1 g, n=6, Fig 2a). The vasoconstrictor potency of phenylephrine and the maximal force of contraction of the rings were significantly enhanced after endothelium removal in SBN rats (EC50, 10±4 nmol/L; 4.8±0.8 g, n=3, P<.05) and to a lesser extent in SBH rats (EC50, 18±3 nmol/L; 3.8±0.2 g, n=3).
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In the presence of a threshold concentration of phenylephrine (4 to 16 nmol/L; approximately 5% of maximal contraction), the vasoconstrictor potency of L-NMMA (1 to 300 µmol/L) and the maximal force of contraction of the rings were significantly greater in SBN rats (EC50, 17.3±1.2 µmol/L; 3.3±0.1 g, n=3, Fig 2b
, P<.05) than in SBH rats (EC50, 73.1±18.2 µmol/L; 1.4±0.4 g, n=3, Fig 2b). Acetylcholine (0.1 to 1 µmol/L) caused a greater endothelium-dependent relaxation of the rings from SBN rats (87±3%) than of those from SBH rats (52±6%) at 1 µmol/L (n=3 for each, Fig 3, P<.05).
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The vasorelaxant potency of GTN was significantly greater in aortic rings from SBH rats (EC50, 4.2±0.2 nmol/L; n=3, Fig 4b) than in those from SBN rats (EC50, 15.7±2.6 nmol/L; n=3, Fig 4a, P<.05). The vasorelaxant potency was significantly enhanced after endothelium removal in rings from SBN rats (EC50, 1.7±0.1 nmol/L; n=3, Fig 4a, P<.05) and to a lesser extent in those from SBH rats (EC50, 1.7±0.1 nmol/L; n=3, Fig 4b, P<.05).
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NO Synthase Activity in Aortic Endothelial Cells
The activity of the Ca2+-dependent enzyme from aortic endothelial cells was significantly greater in SBN rats (30±2 pmol/min per milligram protein) than in SBH rats (23±1 pmol/min per milligram protein, Fig 5a, n=5 for each, P<.05). The activity of this enzyme from aortic endothelial cells of Wistar rats was 26±2 pmol/min per milligram protein (n=6). There was no significant Ca2+-independent NO synthase activity in aortic endothelial cells obtained from SBN, SBH, or Wistar rats.
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Plasma Nitrite/Nitrate Measurements
The basal concentration of plasma nitrite/nitrate was significantly greater in SBN than in SBH rats (25±2 and 5±1 µmol/L, respectively; n=4-5, Fig 5b, P<.05). The basal concentration of these metabolites in the plasma of Wistar rats was 10±1 µmol/L (n=6).
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Discussion |
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Our results confirm previous observations indicating that the hypertension-prone (SBH) substrain of the Sabra rat exhibits a slight but significantly higher basal BP than its hypertension-resistant counterpart (SBN).17 Investigation of the endothelial L-arginine–NO pathway revealed striking differences between the two substrains. The pressor response to the NO synthase inhibitor L-NMMA was significantly less in the SBH rat than in the SBN rat. This difference in responsiveness to L-NMMA was also observed in isolated rings of aorta from each substrain. Taken together, these results indicate that the basal release of NO or the effect of NO on its receptor, the soluble guanylate cyclase,3 is lower in the SBH than in the SBN rat.
To ascertain whether the reactivity of soluble guanylate cyclase was different in the two substrains, we examined the vasorelaxant response to the NO donor GTN. Since we have previously shown that removal of endothelium and thus of NO shifts the dose-responsiveness curve to exogenous NO to the left,20 we examined the response to GTN in endothelium-denuded and endothelium-intact tissues. The relaxation response to GTN was greater in endothelium-intact aorta from SBH than from SBN rats. After endothelium removal, the response to GTN was indistinguishable in the aorta from SBH and SBN rats, demonstrating that the effect of NO itself was similar in both substrains. Since the vasorelaxant response to acetylcholine was less in the SBH than in the SBN endothelium-intact aorta, this further suggests that the difference between the substrains lies in the ability of the endothelium to generate NO, not only under basal conditions but also upon stimulation. This was confirmed by the lower and higher endothelial NO synthase activities and corresponding lower and higher concentrations of nitrite/nitrate in the plasma of the SBH and SBN rats, respectively.
The contractile response to phenylephrine in the intact aortic ring was greater in SBH than in SBN rats. Endothelium removal abolished this difference between the substrains, suggesting that the lower basal release of NO from the endothelium and resultant reduced vasorelaxant tone in the SBH substrain provided a reduced physiological antagonism to the constrictor effect of phenylephrine.20 However, this difference could not be observed in vivo, where, although the pressor response to phenylephrine in the SBH rat was apparently greater, as described previously,17 the absolute change from the basal BP in both substrains was similar. The reason or reasons for this remain to be determined.
Although we did not study NO generation using the Sabra rat as a control, our results show that the NO-dependent vasodilatation in the normotensive Wistar rat, as determined by the basal BP, pressor effect of L-NMMA, endothelial NO synthase activity, and plasma nitrite/nitrate concentrations, lies between that of the SBH and SBN rat. These results suggest that a decrease in NO generation may play a role in the susceptibility of SBH rats to hypertension and that the resistance to hypertension in the SBN strain may be related to an increased generation of NO. Further studies are necessary for assessment of whether this pathway influences the other potential determinants of hypertension in these rats.
A deficiency in NO production has also been suggested to occur in DOCA-treated rats and the Dahl/Rapp salt-sensitive strain, which develop hypertension on exposure to high salt intake.21 These rats exhibit reduced responsiveness to endothelium-dependent vasodilators.22 In contrast, the spontaneously hypertensive rat exhibits increased sympathetic nervous activity with a normal,6 7 decreased,8 or enhanced9 responsiveness to endothelium-dependent vasodilators or inhibitors of NO synthase. However, these previous studies did not measure NO release quantitatively. Further work is therefore required for determination of whether the endothelium generates more NO when an increase in vasoconstrictor tone is the origin of hypertension.
Interestingly, sodium excretion in response to sodium loading is lower in SBH, DOCA-treated, and Dahl/Rapp salt-sensitive strains than in SBN and normotensive rats,16 whereas sodium excretion in response to sodium loading or vasopressin is greater in spontaneously hypertensive than in normotensive rats.23 24 Since NO appears to play a role in facilitating sodium excretion,25 26 27 an effect that is partially independent of its vasodilator actions,25 it is possible that a decrease in NO generation will lead to a hypertension associated with reduced sodium excretion. Indeed, renal production of NO is reduced in the salt-sensitive Dahl/Rapp rat on a high salt regimen,28 and administration of L-arginine increases urinary excretion of nitrate and abolishes the hypertension in these rats.21 Thus, the concomitant reduction in endothelium-dependent dilatation and increase in sodium retention may represent two aspects of hypertension determined by a deficiency in NO generation. By contrast, in situations in which vasoconstrictor activity (which may be of different origins) is increased, NO generation may be increased as a counteractive mechanism, with normal or increased sodium excretion.23 24 It would be interesting to investigate whether the subpopulation of hypertensive individuals known to be salt sensitive29 have impaired NO generation.
It is now clear that the L-arginine–NO pathway plays a pivotal role in the regulation of BP in humans. To what extent defects in this pathway reflect the various pathologies associated with human hypertension—including enhanced responsiveness to vasopressors, increased platelet activation, vasospasm, the development of atheroma, and renal abnormalities—will be the subject of significant research in the future. Moreover, further understanding of the mechanism underlying these pathologies should lead to the development of novel antihypertensive treatments.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors thank Dr Emilia Padoin, Tara Andrews, and Jayne Monkhouse for their assistance with this work and Annie Higgs for critical appraisal of the manuscript.
Received August 17, 1995;
first decision October 2, 1995; first decision March 26, 1996;
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References |
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M. McIntyre, C. A. Hamilton, D. D. Rees, J. L. Reid, and A. F. Dominiczak Sex Differences in the Abundance of Endothelial Nitric Oxide in a Model of Genetic Hypertension Hypertension, December 1, 1997; 30(6): 1517 - 1524. [Abstract] [Full Text]
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A. Lippoldt, V. Gross, K. Schneider, A. Hansson, S. Nadaud, W. Schneider, M. Bader, C. Yagil, Y. Yagil, and F. C. Luft Nitric Oxide Synthase and Renin-Angiotensin System Gene Expression in Salt-Sensitive and Salt-Resistant Sabra Rats Hypertension, September 1, 1997; 30(3): 409 - 415. [Abstract] [Full Text]
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