Copyright © 2005, European Society of Cardiology
Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection
aDepartment of Investigative and Cardiac Biology, UW2510 GlaxoSmithKline 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
bUniversity of Pennsylvania, School of Veterinary Medicine 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
cComparative Medicine and Investigative Support, School of Veterinary Medicine 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
dSafety Assessment GlaxoSmithKline School of Veterinary Medicine 709 Swedeland Road, PO Box 1539 King of Prussia, PA 19406, USA
* Corresponding author. Tel.: +1 610 270 6052; fax: +1 610 270 5080. Email address: robert.n.willette{at}gsk.com
Received 9 July 2004; revised 23 November 2004; accepted 22 December 2004
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Objective: Evidence suggests important relationships among chronic inflammatory processes, endothelial dysfunction, hypertension and target organ damage. The present study examined the effects of chronic treatment with an anti-inflammatory p38 mitogen-activated protein kinase (MAPK) inhibitor (SB-239063AN) in the N
-nitro-L-arginine methyl ester-treated spontaneously hypertensive rat (SHR+L-NAME) model of severe hypertension and accelerated target organ damage. Methods: SHRs were divided into control (n=16), L-NAME (n=26) and L-NAME+SB-239063AN (n=24) groups. L-NAME was delivered by the drinking water ad lib (50 mg/L) and SB-239063AN was administered by the diet (1200 ppm) for 4 weeks. Arterial blood pressure (telemetry) and target organ damage (kidney, heart, and vasculature) were examined. Results: The introduction of L-NAME to the drinking water elicited a severe/sustained increase in blood pressure and significant morbidity and mortality. Chronic treatment with SB-239063AN had no effect on the initial blood pressure response (7 days) to L-NAME but attenuated subsequent increases in diastolic blood pressure and significantly reduced morbidity/mortality (42% vs. 5%, p<0.002). Renal dysfunction characterized by increased total protein and albumin excretion was apparent within 2 weeks in the SHR+L-NAME groups. Treatment with SB-239063AN delayed the onset of proteinuria and albuminuria. SB-239063AN treatment also significantly reduced L-NAME-induced interstitial fibrosis in the kidney and restrictive concentric hypertrophy in the left ventricle (end-diastolic volume 0.24 ± 0.05 vs. 0.41 ± 0.05 ml; p<0.05). Endothelial dysfunction was also not altered by SB-239063AN treatment (Rmax 49 ± 6% vs. 45 ± 9%). Conclusions: The results demonstrate that morbidity/mortality and accelerated target organ damage induced by inhibition of nitric oxide synthase in SHR was attenuated by treatment with a selective p38 MAPK inhibitor, SB-239063AN. The organ protection observed in the heart and kidney was not associated with preservation of endothelial function.
KEYWORDS Hypertension; MAP kinase; p38 MAPK inhibitor; Renal function; Endothelial function; Nitric oxide; Systolic blood pressure
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Loss of endothelial-dependent vasorelaxation and vascular inflammation are frequently associated with hypertension and hypertension target organ damage, such as progressive renal disease. Evidence suggests that a reduction in bioavailable NO contributes to endothelial dysfunction and that the mechanisms responsible involve scavenging of NO by excess reactive oxygen species (ROS) generated by endothelium, inflammatory cells and vascular smooth muscle [1,2]. In addition, the generation of ROS activates inflammatory mitogen-activated protein kinase (MAPK) pathways (p38 and JNK-1) through the redox regulation of ASK-1 [3–6]. In fact, enhanced activation of vascular p38 MAPK has been localized by phospho-p38 MAPK immunohistochemistry in blood vessels from hypertensive animals [7].
Recent studies have demonstrated that chronic treatment with p38 MAPK inhibitors, potent anti-inflammatory agents, significantly reduced target organ damage in the salt-sensitive stroke-prone spontaneously hypertensive rat (SS-SHRSP). In this model, organ protection induced by the p38 MAPK inhibitors was also associated with endothelial protection and amelioration of salt-induced hypertension [7].
The purpose of the present study was to examine the role of endothelial protection in the overall target organ protection observed following chronic treatment of hypertension with a p38 MAPK inhibitor. Specifically, renal and cardiac target organ damage was accelerated in spontaneously hypertensive rats (SHR) by treatment with N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. This model allows target organ protection to be examined separately from endothelial protection or systemic hemodynamic changes associated with preservation of nitric oxide. Structural and functional protection was evaluated following chronic treatment with a selective p38 MAPK inhibitor, SB-239063AN.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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2.1. Animals and experimental protocol
Male spontaneously hypertensive rats (SHR), n=66, (Taconic Farms) were included in the study at 10 weeks of age. Experiments were conducted in accord with the Guide for Care and Use of Laboratory Animals (NIH Publication 85-23) and experimental protocols were reviewed and approved by the GlaxoSmithKline Animal Care and Use Committee.
All animals initially received a normal powder chow and water ad lib. Rats were then randomized into three groups, SHR (n=16), SHR+L-NAME (n=26) and SHR+L-NAME+SB-239063AN (n=24). All rats were housed in metabolism cages for 48 h for urine collection and food and water consumption measurements at baseline and weekly thereafter. Three days prior to the addition of L-NAME (50 mg/L) to the drinking water, SB-239063AN (1200 ppm) was added to the powdered chow of the treatment group and both were continued for the duration of the study. Blood pressure (BP) telemetry studies were performed in a subset of animals, SHR; n=8, +L-NAME; n=10 and +L-NAME+SB-239063AN; n=8. Briefly, animals were anesthetized with 1.5–2.0% Isoflurane and a telemetry transmitter (TA11PA-C40; Data Sciences International, St. Paul, MN) was implanted. The transmitter catheter was inserted into the femoral artery and advanced to the lower abdominal aorta. Baseline measurements of systolic and diastolic blood pressure, heart rate, and activity were obtained before starting treatments. Recordings were obtained for 2 days prior to metabolism studies and continuously during the first week following introduction of L-NAME. BP data was acquired and averaged for 10 s intervals every 10 min. During week two of the study, rats from the SB-239063AN group were randomly selected (n=7) for the determination of plasma drug concentrations. As described previously, rats were promptly euthanized when they showed signs of morbidity [7].
Albuminuria was determined using an immunoturbidometric assay (Olympus America, Mellville NY, OSR6167) optimized for the determination of rat urinary albumin and total urinary protein by a colorometric assay (Quantimetrx, Redondo Beach CA, 5210-12), both analyzed in an Olympus AU640 chemical analyzer (Olympus America, NY). Urinary albumin and total protein excretion were determined weekly from 24 h urine collections. Albumin and protein excretions were calculated by multiplying the urine volume by the protein concentration.
2.2. Echocardiographic analysis
Transthoracic echocardiograms (GE/Vingmed SystemV) were performed, as described previously [8], on all animals at baseline and on 8 animals from each group at week 4. Transthoracic echocardiograms (GE/Vingmed System V) were performed on each animal prior to treatments and at the end of the study (4 weeks). Inhalation anesthesia was induced with 4–5% isoflurane, and maintained at 1.5–2.0% during the procedure. The leading edge method was used to determine left ventricular (LV) thickness and volumes [9]. Relative wall thickness (RWT) was calculated as RWT=(AWd+PWd)/LVDd, where AWd is diastolic anterior wall thickness, PWd is diastolic posterior wall thickness, and EDV and EDS are LV end-diastolic and LV end systolic volume, respectively. Stroke volume and cardiac output were also determined by a modified Simpson's method [9].
2.3. Vascular reactivity of the isolated rat aorta
Vascular reactivity studies were performed as previously described [9]. Briefly, proximal descending thoracic aortae were removed under isoflurane anesthesia and placed in oxygenated (95% O2 5% CO2) Krebs solution (pH 7.4) with the following composition (mM): NaCl 112.0, KCl 4.7, CaCl2 2.5, KH2PO2 1.2, MgSO4 1.2, NaHCO3 25.0 and dextrose 11.0. The isolated aortae were cut into four 2–3 mm rings and each segment was suspended by two 0.1 mm diameter tungsten wire hooks in a 10 ml organ bath at 37 °C (pH 7.4). The tissues were equilibrated at 1.0 g resting tension for approximately 60 min and changes in isometric force were measured using force-displacement transducers (MLT0201/D; Letica Scientific Instruments) and recorded using Chart 5.0 software (ADInstruments).
Following a conditioning protocol, each vessel was contracted to equilibrium with an EC80 concentration of phenylephrine and endothelial-dependent vasorelaxation was induced by carbachol (10 nM to 100 µM). Endothelial-independent vasorelaxation, induced by sodium nitroprusside (SNP, 0.01 nM to 100 nM) was examined in a similar manner.
2.4. Histological analysis of hearts and kidneys
The heart and kidneys were rapidly removed, weighed, and prepared for paraffin embedding and histologic staining. Microscopic examination of Masson's trichrome and H&E stained sections were performed to assess changes in the organs. All slides were scored, blinded to treatment, on two separate days by a certified histopathologist (author K. F.). The two scores were then compared with each other and any discrepancy was eliminated by examining the slide a third time to derive a final consensus score. In practice, differences in scores occurred with less than 20% of the slides, and in no case was there a difference of greater than 1 point between first and second scoring attempts. Each slide was scored separately for a series of several specific histopathologic lesions on the basis of their presence/absence and distribution within the heart or kidney (e.g. arteriolar medial hyalinosis, intimal hypertrophy, myocardial myofiber degeneration, renal interstitial fibrosis, glomerulosclerosis, etc. See Tables 2 and 3
) by assigning a score of 0–3, with 0 representing absence of the lesion, 1=focal, 2=multifocal, and 3=diffuse distribution.
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2.5. Statistical analysis
The Kaplan–Meier Method (GraphPad Software, San Diego CA) was used to analyze survival curves. The Kruskal-Wallis method with Dunn's post test (GraphPad Software, San Diego CA) was used for analysis of urine albumin and protein. For all other analysis, a one-way ANOVA with Bonferroni post test was used to determine significance. p
0.05 was considered to be significant. |
3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. General characterization in the L-NAME SHR
Previous studies have shown that the addition of L-NAME (50 mg/L) to the drinking water induced a sustained 30–40 mmHg increase in mean arterial blood pressure, apparent within 1 day, with little or no effect on HR. Prolonged L-NAME treatment resulted in 100% morbidity/mortality in SHR within 2 months (data not shown). In the present study, continuous exposure to L-NAME for 4 weeks reduced survival 42% in SHR (Fig. 1a). Chronic treatment with SB-239063AN throughout the L-NAME exposure period reduced morbidity and mortality in the SHR+L-NAME (Kaplan–Meier log-rank test, P=0.0002). No morbidity/mortality was observed in age-match SHR not receiving L-NAME. The SHR+L-NAME group did have a lower body weight (p<0.01) than the SHR, but it did not differ from the SHR+L-NAME+SB-239063AN. Water consumption did not differ among groups.
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3.2. Assessment of renal dysfunction
A 24 h urine collection was obtained in all groups at study entry (baseline) and weekly for a total of 4 weeks. The addition of L-NAME in the SHR was associated with a significant increase in urinary total protein and albumin excretion throughout the 4-week study (Fig 1b and c). Chronic treatment of the SHR+L-NAME with SB-239063AN delayed renal dysfunction, i.e. no significant increase in proteinuria and albuminuria at 2 weeks (Fig 1b and c). No significant changes in proteinuria were noted in SHR not receiving L-NAME. Creatinine clearance was not significantly altered in the three groups (1.38 ± 0.20, 2.54 ± 0.58, 2.04 ± 0.50 ml/min; ANOVA, P=0.209; SHR, +L-NAME, +L-NAME+SB-239063AN, respectively). Peak to trough plasma concentrations of SB-239063AN were in the range of 300–100 ng/ml, respectively (Fig. 2).
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3.3. Echocardiographic assessment of the heart
Echocardiography was performed on all rats at baseline and in a randomly chosen subset (n=8) of each group at the end of the study. SHR receiving L-NAME demonstrated a pattern of changes consistent with that of restrictive concentric myocardial hypertrophy–hypertensive cardiomyopathy (Table 1). Compared to the SHR+L-NAME group, chronic treatment with SB-239063AN significantly improved EDV (0.24+0.05 vs. 0.41+0.05 ml, respectively) and tended to reduce LV hypertrophy and dysfunction (LV mass and cardiac output).
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3.4. Histopathologic evaluation
The renal and cardiac histopathologic analysis is summarized in Tables 2 and 3
, respectively. Vascular changes in the kidney and heart were characterized by a spectrum of alterations including medial hypertrophy, medial necrosis, and obliterative arteriosclerosis. Groups receiving L-NAME also had more severe necrotic and fibrotic alterations. Perivascular or medial inflammation was uncommonly and inconsistently found in the rats from this study. Myocardial degenerative lesions corresponded directly with the location of vascular alterations and were much more pronounced in the right ventricular free wall than in the left ventricle (Table 3). Often the lesions were more common on or near the subendocardial area and were more frequent at the heart base rather than at the apex. No significant effects of treatment were noted.
As illustrated in Fig. 3 and Table 2, fibrotic changes in the kidney are a predominant feature of the SHR+L-NAME model. Treatment with SB-239063AN significantly decreased renal peritubular and interstitial fibrosis induced by L-NAME (1.6 ± 0.3 vs. 0.6 ± 0.3, p<0.05; SHR+L-NAME vs. SHR+L-NAME+SB-239063AN, respectively).
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3.5. Vascular reactivity
Vascular reactivity was assessed in isolated proximal thoracic descending aortae in all groups. Treatment with L-NAME for 4 weeks reduced endothelial-dependent vasorelaxation induced by carbachol when compared to age- and time-matched control SHR not receiving L-NAME (Rmax 49 ± 6% vs. 80 ± 4%, SHR+L-NAME vs. SHR, respectively, p<0.01). Chronic treatment with SB-239063AN (4 weeks) had no effect on the attenuated endothelial-dependent vasorelaxation observed in the L-NAME+SHR group (Fig. 4). Phenylephrine-induced contraction and SNP-induced relaxation were similar in all groups.
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3.6. Telemetry blood pressure
In a subset of each group, blood pressure was monitored chronically in freely moving animals using intra-arterial radio-telemetry techniques. Initially, the introduction of L-NAME to the drinking water of SHR induced a pronounced increase in systolic and diastolic blood pressure (Fig. 5a and b) as compared to the control SHR (p<0.01) beginning at Day 1. However, the effects of L-NAME to further increase diastolic pressure, i.e. beyond 7 days, were attenuated by treatment with SB-239063AN (Fig. 5b). The delayed effects on blood pressure may reflect renal protection observed in treated animals (Fig. 3 and Table 2).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The present results demonstrate that the accelerated hypertensive target organ damage induced by inhibition of nitric oxide synthase in the SHR was attenuated by chronic treatment with a p38 MAPK inhibitor, SB-239063AN. The organ protection observed in the heart and kidney was not associated with significant changes in systolic blood pressure or preservation of endothelial function. Previous studies performed in the salt-sensitive stroke-prone spontaneously hypertensive rat (SS-SHRSP) have also demonstrated that p38 MAPK inhibitors provide impressive target organ protection in the heart, brain and kidney [7,9,10]. Unlike the present study, the protective effects observed in the SS-SHRSP were associated with significant preservation of endothelial-dependent vasorelaxation and inhibition of salt-sensitive hypertension. The authors postulated that inappropriate activation of the p38 MAPK pathway contributes to excessive generation of reactive oxygen species (ROS) and consequent reduction in bioavailable nitric oxide (NO). Thus, it was unclear in the SS-SHRSP studies whether the target organ protection afforded by p38 MAPK inhibitors was merely secondary to preservation of endothelial protection and attenuation of salt-sensitive hypertension. The present results demonstrate that p38 MAPK inhibitors attenuate hypertensive target organ damage in the kidney and heart independent of generalized endothelial protection. When taken together, it appears that p38 MAPK inhibitors attenuate hypertensive target organ damage via endothelial-dependent and endothelial-independent mechanisms.
At the level of the kidney, evidence suggests that p38 MAPK plays an important role in renal physiology, development/malformation and nephropathy. In normal rats, dietary salt activates p38 MAPK and increases TGF-β and NO in cortex and outer and inner medulla [11]. Activation of p38β MAPK also influences Na+ transport in cells from the inner medullary collecting duct by modulating the osmotic regulation of natriuretic peptide receptor–A [12]. In the normal human kidney, activated p38 MAPK (phospho-p38 MAPK) is localized to a small number of podocytes, parietal epithelium, and tubular cells [13]. However, in human glomerulonephritis p38 MAPK activation is greatly increased in intrinsic cells (podocytes, endothelium and tubular cells) as well as in infiltrating cells, i.e. macrophage, neutrophils, and myofibroblasts [13]. The localization pattern of activated p38 MAPK in glomerulonephritis is consistent with its proposed role in renal inflammation where it regulates the transduction and production of pro-inflammatory cytokines [14–16]. A similar pattern of p38 MAPK activation has been described in a rat model of crescentic glomerulonephritis where treatment with a p38 MAPK inhibitor, FR167653, significantly reduced renal dysfunction, glomerulosclerosis, and interstitial fibrosis, as well as, indices of renal inflammation and cellular proliferation [17].
In a variety of animal models, the p38 MAPK pathway has been shown to play an important role in the nephropathy of hypertension and type-II diabetes. For example, salt-accelerated hypertension in the type-II diabetic Wistar fatty rat is associated with renal dysfunction and enhanced activation of p38 MAPK and expression of TGF-β in the kidney [18]. Evidence suggests that p38 MAPK acts in the kidney to transduce the diabetic complications of elevated glucose [19] and stretch in mesangial cells [20]. In a hypertensive high-renin rat model of renal damage (TGR(mRen2)27), chronic treatment with a p38 MAPK inhibitor (SB-239063) attenuated glomerular and interstitial damage [21]. Similar treatment protocols also reduced cortical filtration and perfusion abnormalities, as well as, histopathologic changes in a series of SS-SHRSP studies [10].
In addition to its pro-inflammatory role, p38 MAPK may also play a role in renal fibrosis by regulating the expression of early extracellular matrix proteins. In renal interstitial fibroblasts, the increase in fibronectin expression induced by angiotensin-II is associated with activation of p38 MAPK and is blocked by p38 MAPK inhibitors [22]. Inhibitors of p38 MAPK also inhibit fibronectin expression induced by TGF-β in vascular smooth muscle cells [23] and, in the present study, decreased interstitial fibrosis in the L-NAME SHR. Thus, biochemical, immunohistochemical and pharmacological evidence suggests that excessive local activation of p38 MAPK in a variety of renal cell types (interstitial and infiltrating) contributes to renal dysfunction and histopathologic changes, including fibrosis. In the present study, renal protection may also underlie the late effects of SB-239063AN to reduce diastolic blood pressure (beyond 7 days) in the L-NAME treated SHR.
The role of p38 MAPK in cardiac hypertrophy has recently been reviewed [24]. In neonatal cardiomyocytes, manipulation of the p38 MAPK pathway suggests that p38 MAPK signaling mediates agonist-induced hypertrophy. In contrast, loss and gain of function studies performed in transgenic animal models targeting the p38 MAPK pathway suggest that p38 MAPK signaling buffers the hypertrophic response. However, a series of studies, exemplified by Behr et al. [8], indicate that chronic treatment with p38 MAPK inhibitors consistently blunted the concentric hypertrophy and loss of end-diastolic volume observed in SS-SHRSPs and prevented decompensation. Similar results were observed in the present L-NAME+SHR study. Chronic treatment with a p38 MAPK inhibitor attenuated the LV wall thickening and preserved end-diastolic volume without significant effects on the elevated arterial blood pressure or endothelial dysfunction in this model. The results suggest that activation of p38 MAPK plays an important role in cardiac remodeling associated with hypertension. In addition, the role of p38 MAPK in cardiac remodeling appears to be very different in multifactorial "disease" models vs. targeted genetic models.
In summary, the accelerated target organ damage induced by inhibition of NOS in the SHR was attenuated by treatment with a p38 MAPK inhibitor, SB-239063AN. Chronic NOS inhibition in this model obviates NO-dependent effects of p38 MAPK inhibitors on endothelial dysfunction and arterial blood pressure, suggesting alternate renal and cardiac protective mechanisms. In conclusion, it is likely that p38 MAPK inhibitors attenuate hypertensive target organ damage via endothelial-dependent and endothelial-independent mechanisms that may reflect generalized/systemic and localized actions, respectively.
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Notes |
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Time for primary review 18 days
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References |
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