Aerosol inhalation of a hydrogen-rich solution restored septic renal function.

Sepsis-related acute kidney injury (AKI) is known to be caused by inflammation. We explored the renal protective effects of aerosol inhalation of a hydrogen-rich solution (HRS; hydrogen gas dissolved to saturation in saline) in a mouse model of septic AKI. Septic AKI was induced through 18 hours of cecal ligation and puncture. AKI occurred during the early stage of sepsis, as evidenced by increased blood urea nitrogen and serum creatinine levels, pathological changes, renal fibrosis and renal tubular epithelial cell apoptosis, accompanied by macrophage infiltration and M1 macrophage-associated pro-inflammatory cytokine (Il-6 and Tnf-α) generation in renal tissues. Aerosol inhalation of the HRS increased anti-inflammatory cytokine (Il-4 and Il-13) mRNA levels in renal tissues and promoted macrophage polarization to the M2 type, which generated additional anti-inflammatory cytokines (Il-10 and Tgf-ß). Ultimately, aerosol inhalation of HRS protected the kidneys and increased survival among septic mice. HRS was confirmed to promote M2 macrophage polarization in lipopolysaccharide-stimulated RAW 264.7 cells. The TGF-ß1 receptor inhibitor SB-431542 partly reversed the effects of HRS on renal function, fibrosis, tubular epithelial cell apoptosis and senescence in mice. Thus, HRS aerosol inhalation appears highly useful for renal protection and inflammation reduction in septic AKI.

Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model.

Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest blood pressure (BP) reductions to below this threshold regardless of antihypertensive class (1) should prevent MN and (2) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke-prone spontaneously hypertensive rats receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mm Hg) and MN (histological damage score 36±5; n=27) developed in the untreated stroke-prone spontaneously hypertensive rats but were prevented by all antihypertensive classes (enalapril [n=15], amlodipine [n=13], or a hydralazine/hydrochlorothiazide combination [n=15]) if the final 2-week systolic BP remained <190 mm Hg. More impressively, modest systolic BP reductions to 160 to 180 mm Hg (hydralazine/hydrochlorothiazide regimen) initiated at ≈4 weeks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2 to 3 weeks (post-therapy left kidney injury score 9±2, P<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hours before therapy to 20.5±3.6 mg 1 week later. These data clearly demonstrate the barotrauma-mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.

Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis.

Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis.

Protective effect of melatonin against radiation induced nephrotoxicity in rats.

PURPOSE: The degree of radiation injury to kidneys which are located within the limits of radiotherapy area is determined by the volume and the dose of radiation to which the organ is exposed. When the tolerance dose of the kidney is exceeded after a latent period of 6 months acute nephritis develops and after 18 months chronic nephritis ensues. Melatonin is known to prevent the oxidative injury of toxins and radiotherapy with its free radical scavenging capacity. METHODS AND MATERIALS: In this study 8 weeks old 24 Sprague -Dawley rats were allocated into 4 groups: Control group; Radiotherapy group (20 Gy bilaterally in 5 fractions); Melatonin group (10 mg/kg intraperitoneally), and Melatonin+radiotherapy group (20 Gy Radiotherapy in 5 fractions+ melatonin 10 mg/kg intraperitoneally). After a follow-up period of 6 months BUN was determined in all groups. After rats were euthanized the kidneys were removed for histopathological examination under both light and electron microscopes. RESULTS: After 6 months follow-up, both at light and electron microscopy levels, the rats in radiotherapy+melatonin group were significantly protected against the radiation injury comparing to radiotherapy group (p<0.05). CONCLUSION: It was shown in this experimental model that melatonin has protective effects against radiation injury to kidneys.

[Effect of Astragalus mongholicus on expression of hepatocyte growth factor in SD rats with unilateral ureteral obstruction].

OBJECTIVE: To study the effect of Astragalus mongholicus (AM) on the expression of hepatocyte growth factor (HGF) in SD rats with unilateral ureteral obstruction (UUO) and to elucidate the mechanisms underlying the renoprotective effects of AM. METHODS: Fifty four Sprague-Dawley rats were randomly divided into 3 groups: sham-operation group (SOR), UUO group (UUO) and UUO + AM group (AM). After administration of AM[10 g/ (kg x d)] for 3, 7 and 14 days,the histological changes of renal interstitial tissues were observed dynamically, and renal damage including tubular impairment and interstitial fibrosis were quantified on HE and Masson stained tissue sections. The protein expression of HGF and alpha-smooth muscle actin (alpha-SMA) was measured by immunohistochemistry. The mRNA expression of HGF and alpha-SMA were determined by real-time PCR. The expression of HGF and its receptor (C-met) were assessed by Western blot. RESULTS: Renal damage was exacerbated and the expression of alpha-SMA was significantly increased in UUO group compared with those of SOR group (P < 0.05) at each time point. HGF and C-met expression peaked at the 7th day after UUO and then decreased greatly. After AM intervention, tubular impairment and interstitial fibrosis were alleviated, up-regulations of alpha-SMA expressions was significantly suppressed, whileas the expression of HGF and C-met were significantly increased when compared with UUO group (P < 0. 05) at each time point. CONCLUSION: AM can ameliorate renal interstitial fibrosis induced by UUO in rats. The mechanisms of its antifibrotic effects may be related with the up-regulation of HGF and C-met expression, and the suppression of tubulo-epithelial mesenchymal transdifferentiation in renal intersitial progress.

[Effects of reduced glutathione on contents of hydroxyproline and oxidation stress reaction in kidney of unilateral ureteral obstruction in rat].

OBJECTIVE: To explore therapeutic effect of glutathione (GSH) on unilateral ureteral obstruction (UUO) induced renal interstitial fibrosis and its mechanism in rat. METHODS: Thirty-six adult healthy Wistar rats were randomly divided into 3 groups (each n=12): sham operation group, UUO group and GSH group. Rats in UUO group and GSH group underwent left unilateral ureteral ligation as described previously. Rats in sham group had their ureters manipulated but not ligated. In GSH group, GSH was injected intraperitoneally (100 mg.kg(-1).d(-1)) in different doses based on the animal's body weight, one day before UUO and then for consecutive 10 days after UUO. Meantime, same volume of physiological saline was given in sham operation and UUO groups as GSH group. Animals were sacrificed at 10 days after surgery. The pathological changes in obstructed kidney tissue were observed with hematoxylin and eosin (HE) and Masson stains. The contents of hydroxyproline (Hyp) and total anti-oxygen capability (T-AOC) were measured by chemical colorimetry method, the activity of total superoxide dismutase (T-SOD) was assayed by a modified xanthine/xanthine oxidase method, and the content of malondialdehyde (MDA) was determined by thiobarbituric acid method. RESULTS: Ten days after UUO, swelling and atrophy in renal parenchyma of obstructed kidneys were clearly observed. Fibrous material and monocyte infiltration were increased in the interstitial space. Furthermore, thickening of interstitial space of the tubular basement membrane and widening of the interstitial space of the renal cortex were noted. Hypertrophy or atrophy of juxtaglomerular tubules were also observed. There were cellular or albumin casts in a part of tubules. Interstitial fibrosis was observed in obstructed kidneys 10 days after UUO. The data indicated that ureteral obstruction significantly increased the contents of Hyp and MDA, but decreased the content of T-AOC and T-SOD activity, as compared with sham operation group [Hyp: (0.524+/-0.132) microg/mg, T-AOC: (1.48+/-0.21) U/mg, T-SOD: (12.77+/-0.76) U/mg, MDA: (2.65+/-0.32) nmol/mg, all P<0.01]. Compared with UUO group, pathological changes were milder and the contents of Hyp [(1.598+/- 0.252) microg/mg vs. (1.027+/-0.196) microg/mg, P<0.05] and MDA [(4.58+/-0.59) nmol/mg vs. (3.26+/- 0.34) nmol/mg, P<0.05] were significantly decreased in kidney of GSH group, meanwhile the content of T-AOC was increased [(0.67+/-0.19) U/mg vs. (0.94+/-0.17) U/mg, P<0.05], but the content of T-SOD did not show any change [(9.39+/-0.87) U/mg vs. (9.41+/-0.93) U/mg, P>0.05]. CONCLUSION: Reduced glutathione treatment attenuates UUO-induced renal interstitial fibrosis via decreasing content of Hyp in UUO kidney and preventing oxidation stress injury.

[Effects of atorvastatin on expression of peroxisome proliferation activated receptor gamma in unilateral ureteral obstruction in rats].

OBJECTIVE: To observe the expression of peroxisome proliferation activated receptor gamma (PPAR gamma) at different periods in renal interstitium and to study the effect of atorvastatin on the protein expression of PPAR gamma in unilateral ureteral obstruction (UUO) in a rat model. METHODS: Forty-five female Sprague-Dawley (SD) rats were divided into three groups: the sham operation group, the model group and the atorvastatin group. The latter two groups underwent UUO and then received vehicle only or atorvastatin (10 mg.kg(-1).d(-1)) by daily gastric gavage, from three days before the UUO operation to the day of sacrifice . The sham operation rats received vehicle. Five rats of each group were sacrificed respectively at 5, 10 and 15 days after surgery. Histological changes in renal tissue were observed by hematoxylin and eosin (HE) and Masson stain. Immunohistochemistry for PPAR gamma was performed in renal interstitium at each time point. RESULTS: Interstitial expansion and fibrosis in ureter obstructed kidney was prominent in the model group. Atorvastatin seemed to have ameliorated interstitial expansion and fibrosis in atorvastatin group. Detectable basic PPAR gamma expression was observed in renal inner medulla of rats in sham operation group, and it was mainly concentrated in collecting tubules. In UUO rats, PPAR gamma expression was found increased and extended to renal tubular epithelial cells. Increased PPAR gamma expression was found on the 5th day after UUO, and significant PPAR gamma expression was found on the 10 th day after UUO. The increased PPAR gamma expression was found to be downregulated on the 15 th day after UUO, but still significantly increased compared with that of the model group at the same time point (all P<0.01). Atorvastatin could significantly increase the expression of PPAR gamma as compared with the model group at each time point (all P<0.01). CONCLUSION: PPAR gamma expression was found increased, and it appeared in renal tubular epithelial cells in UUO rats, Atorvastatin may play a protective role in the kidney by activating PPAR gamma, thus alleviating renal interstitial fibrosis following UUO in rats.

Combination therapy with telmisartan and spironolactone alleviates L-NAME exacerbated nephrosclerosis with an increase in PPAR-gamma and decrease in TGF-beta(1).

To investigate whether the receptor blockades of angiotensin II type 1 and aldosterone receptors can prevent renal tissue injury in relation to the renal tissue mRNA levels of peroxisome proliferation-activated receptors-gamma (PPAR-gamma) and transforming growth factor-beta (1) (TGF-beta(1)) in spontaneously hypertensive rats (SHR) given N(G)-nitro-L-arginine methyl ester (L-NAME), which is considered a model of malignant hypertension. This study was performed in 5 groups of 17-week-old male SHR treated for 3 weeks as follows: group 1, control; group 2, L-NAME (50 mg/L in drinking); group 3, L-NAME plus aldosterone antagonist, spironolactone (SPRL, 100 mg/kg/day); group 4, L-NAME plus angiotensin II type 1 receptor blocker, telmisartan (TELM, 3 mg/kg/day); group 5, L-NAME plus combination therapy (COMB) with low-dose TELM (1 mg/kg/day) and SPRL (100 mg/kg/day). Urinary protein excretion and the glomerular injury score were significantly reduced in the SPRL, TELM, and COMB groups as compared with the L-NAME group, while significant blood pressure reduction was observed only in the TELM group. In the TELM and COMB groups, the perivascular cell infiltration and fibrosis area were significantly reduced together with the PPAR-gamma mRNA increase and TGF- beta(1) mRNA decrease. The urinary excretion of nitric oxides was significantly recovered and the wall to lumen ratio of the interlobular artery was significantly reduced only in the COMB group compared with the L-NAME group. Combined administration of 1 mg/kg/day telmisartan and 100 mg/kg/day spironolactone is thought to be effective in alleviating hypertensive renal injuries independently of blood pressure changes. The anti-inflammatory and antifibrotic effects due to PPAR-gamma activation and TGF-beta(1) inhibition may participate in the renoprotection of this combination therapy.

Prevention of mesangial sclerosis by bone marrow transplantation.

Previously we have shown that bone marrow (BM) transplantation (BMT) can attenuate progression of and even ameliorate mesangial sclerosis (MS) in Wt1-heterozygous mice. However, it is unclear whether BMT performed before the onset of disease will prevent the development of MS. To investigate whether intravenous (i.v.) or intrarenal (i.r.) administration of BM have equal effects on the progression of MS in Wt1-heterozygous mice, young Wt1-heterozygous mice that had not yet developed renal disease were used as recipients for BMT. After preconditioning with 750 cGy radiation, mice were transplanted with one million wild-type BM via i.v. or i.r. administration. All recipients and untreated controls were assessed for urinary albumin loss, renal pathology, and BM donor-derived renal cells over time. Representative kidney samples were subjected to transmission electron microscopy (TEM) analysis. Interestingly, i.r. and i.v. administration of BM cells gave comparable hematopoietic engraftment levels, and both were able to prevent the onset of MS as assessed by improved lifespan, renal function, renal histology, and TEM analysis. Taken together, we show for the first time that MS can be prevented if BMT is performed before disease onset. Similar therapeutic effects were obtained whether the BM was administered i.v. or i.r.

Hypertensive renal damage: insights from animal models and clinical relevance.

Investigations using chronic blood pressure (BP) radiotelemetry in conscious animals have provided substantial insights into the pathophysiology of hypertensive renal damage. Normal renal autoregulation protects the renal microvasculature from significant injury in most patients with primary hypertension, unless BP exceeds a certain threshold, when malignant nephrosclerosis develops. However, if autoregulation is impaired, as in chronic renal disease and/or diabetes models, the threshold for renal damage is lowered and glomerulosclerosis (GS) increases linearly with increasing BP. Modest BP reductions are predicted to prevent malignant nephrosclerosis, but prevention of GS in patients with diabetes and chronic renal disease requires that BP be lowered well into the normotensive range, as recognized in the currently recommended BP goals. When BP load is accurately assessed in these experimental models, renal protection is proportional to the achieved BP reductions, and there is little evidence of BP-independent protection, even with agents that block the renin-angiotensin system (RAS). Recent clinical data also suggest that achieving lower BP targets might be vastly more important than the choice of therapeutic regimens. Nevertheless, because aggressive diuretic use is usually necessary to achieve such BP goals, RAS blockade should be included as initial therapy both for antihypertensive synergy and to minimize the potassium and magnesium depletion associated with diuretics.

Continuing follow-up of malignant hypertension.

The history of accelerated (malignant) hypertension is reviewed, and unsolved problems related to the disease are illustrated, including its relationship to malignant nephrosclerosis, as well as terminology, current frequency and treatment. Over the past 25 years, out of a series of 131 patients, 53 were classified as suffering from essential malignant hypertension, the only suitable model on which the effects of pharmacological treatment on the disease can correctly be evaluated. In 2000, there were 24 survivors in our series and the maximum follow-up was 290 months. Multiple daily B.P. self-measurements allowed us to establish that pharmacological treatment was only able to approximate, to a varying degree, the conventional threshold of 140/90. Yet, despite this incomplete control over blood pressure levels, renal function was maintained in those patients whose initial creatininemia levels had not been higher than 2 mg/L. The renal protection effect of treatment was preserved even in patients who relapsed intoaccelerated disease phase one or more times over the study period.

Involvement of angiotensin II in cardiovascular and renal injury: effects of an AT1-receptor antagonist on gene expression and the cellular phenotype.

OBJECTIVES: We investigated the effects of an angiotensin II type 1 (AT1)-receptor antagonist on experimental cardiac hypertrophy, vascular thickening and nephrosclerosis, in order to determine the involvement of this receptor in the development of cardiovascular and renal damage. DESIGN: Accumulating evidence indicates that various growth-related genes, growth factors and extracellular matrix components play a central part in the pathogenesis and development of cardiovascular and renal diseases, either by regulating cell growth and migration or by promoting tissue fibrosis. MATERIALS AND METHODS: Stroke-prone spontaneously hypertensive rats were given candesartan cilexetil, a specific non-peptide AT1-receptor antagonist, for 10 weeks, and cardiac phenotypic and fibrosis-related gene expression and aortic and mesenteric arterial gene expressions were determined. Balloon-injured carotid arteries and deoxycorticosterone acetate (DOCA)-salt hypertensive rats were also similarly examined. RESULTS: Treatment of hypertensive rats with an AT1-receptor antagonist led to the regression of cardiac hypertrophy, suppression of cardiac phenotypic changes to a fetal phenotype and an increase in fibrosis-related gene expression in the hypertrophied heart. Balloon injury-induced neointima formation in the rat carotid artery was prevented by the AT1-receptor antagonist, which was associated with the inhibition of the induction of proto-oncogenes such as c-fos, c-jun and Egr-1 and of increased fibronectin gene expression. Furthermore, the AT1-receptor antagonist prevented either the phenotypic modulation of glomerular cells or an increase in transforming growth factor-beta 1 expression in an experimental model of nephrosclerosis. CONCLUSIONS: AT1-receptor antagonists in vivo potently inhibit the expression of the growth-related and extracellular matrix genes, as well as cellular phenotypic modulation. These molecular effects of the AT1-receptor antagonist may contribute to their protective effects on cardiovascular and renal diseases.

ACE inhibition prevents and reverses L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats.

Chronic nitric oxide inhibition exacerbates hypertension and nephrosclerosis in spontaneously hypertensive rats (SHRs). In this study, we determined whether angiotensin-converting enzyme (ACE) inhibition could prevent or reverse the systemic, renal, and glomerular hemodynamic alterations and the pathological changes of nephrosclerosis. Four groups of 20-week-old SHRs were studied: group 1, untreated controls; group 2, treated with N omega-nitro-L-arginine methyl ester (L-NAME, 50 mg/L for 3 weeks); group 3, L-NAME cotreated with quinapril (3 mg.kg-1.d-1 for 3 weeks); and group 4, L-NAME for 3 weeks followed by quinapril for 3 weeks (same doses). The results of this study demonstrated that both cotreatment (group 3) and posttreatment (group 4) with quinapril reduced mean arterial pressure (186 +/- 9 and 192 +/- 9 mm Hg, respectively, compared with group 2 SHRs, 221 +/- 5 mm Hg) and total peripheral resistance index associated with significant reductions in afferent and efferent arteriolar resistances; nephrosclerosis pathological scores; and urinary protein excretion (all at least P < .01). ACE inhibition also significantly increased stroke index, single-nephron glomerular filtration rate, and ultrafiltration coefficient compared with the L-NAME SHRs. Most notable were the findings that cotreatment with quinapril completely prevented the renal glomerular hemodynamic alterations with reduced glomerular capillary hydrostatic pressure and efferent arteriolar resistance compared with both the untreated and the L-NAME-treated SHRs (all at least P < .01). Posttreatment with quinapril also reversed the glomerular injury (subcapsular, -83%; juxtamedullary, -56%) and arteriolar (-87%) injury scores obtained from renal biopsy specimens (P < .005 and P < .0001, respectively). These changes were associated with decreased periarteriolar fibronectin and increased afferent arteriolar alpha-smooth muscle actin deposition (immunohistochemistry). These data, therefore, demonstrate that ACE inhibition not only prevents but also reverses L-NAME-exacerbated severe nephrosclerosis in SHRs, as indicated by improved systemic, renal, and glomerular hemodynamic changes, proteinuria, and histological alterations.

Effects of MPC-1304, a novel calcium antagonist, on stroke-prone spontaneously hypertensive rats.

The effects of MPC-1304, a newly developed 1,4-dihydropyridine derivative, on blood pressure and hypertensive complications in stroke-prone spontaneously hypertensive rats fed a high-salt diet (0.8% NaCl), were investigated. The antihypertensive effectiveness of nicardipine was used for the purpose of comparison. MPC-1304 and nicardipine were added to the diet, in doses of 0.01% (0.01% MPC-1304 diet), 0.03% (0.03% MPC-1304 diet) and 0.1% (0.1% nicardipine diet), respectively, throughout the experimental period (8 to 30 weeks of age). This chronic ingestion of MPC-1304 and nicardipine inhibited the development of hypertension and reduced the concentration of blood urea nitrogen, creatinine, triglyceride and total cholesterol in serum. Treatment with MPC-1304 inhibited the incidence of cerebral stroke, cardiac fibrosis, proliferative and fibrinoid arteriolitis and malignant nephrosclerosis. There was no significant difference in the antihypertensive effectiveness between 0.01% MPC-1304 and 0.1% nicardipine diets. Thus, MPC-1304 had antihypertensive effects in stroke-prone spontaneously hypertensive rats.

Nonpeptide angiotensin II type 1 receptor antagonist prevents nephrosclerosis in hypertensive rats.

Angiotensin II (AII) appears essential in remnant kidney models of renal injury in rats, and renal injury was reduced by angiotensin-converting enzyme inhibitor (ACEI). To determine whether this is due to AII blockade or other actions of ACEI, we studied a nonpeptide AII type 1 receptor antagonist and an ACEI in partially nephrectomised spontaneously hypertensive rats (SHR). Thirty SHR underwent surgery and were divided into three equal groups: Control, TCV (0.5 mg/kg/day TCV-116), and CAP (30 mg/kg/day captopril). All SHR received a 5%-NaCl diet. Systolic blood pressure (SBP) and urinary protein were measured at 2-week intervals. Serum total protein, albumin, urea nitrogen, and creatinine were determined at week 8. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured at weeks 4 and 8. Renal injury was evaluated histopathologically. TCV and CAP reduced SBP at week 2 and proteinuria at week 8. GFR and RBF fell in all groups, but decreases were not significant in treated SHR and histopathological changes were significantly ameliorated. All blockade by TCV or CAP reduces renal injury in salt-loaded SHR with partial renal ablation. AII is essential in remnant kidney models of renal injury, and AII blockade is essential in renal protection by ACEI.

[Antihypertensive effect of bopindolol on stroke-prone spontaneously hypertensive rats (SHRSP)].

The antihypertensive effect of bopindolol, a long-acting beta-adrenoceptor blocking agent, was investigated in stroke-prone spontaneously hypertensive rats (SHRSP). One group received tap water during the period of 8 to 32 weeks of age. The average dose of bopindolol administered was calculated from water intake to be approximately 1.4 mg/kg/day. The lowering effect in blood pressure of bopindolol was apparent at the age of 14 weeks, and this continued up to the end of the experiment. Bopindolol significantly reduced the heart rate. Plasma levels of urea nitrogen (BUN), triglyceride, and phospholipid of SHRSP treated with bopindolol were lower than those of the control SHRSP. One of the 8 control SHRSP died, and no rats treated with bopindolol died during the experiment. The histopathological study revealed that three of the control SHRSP had cerebral apoplexy, whereas there was no evidence of cerebral apoplexy in the treated SHRSP. Chronic treatment of bopindolol clearly alleviated myocardial fibrosis and hypertrophic changes in the left ventricular wall of the heart. Decreases in the incidence of proliferative arteritis and malignant nephrosclerosis in the kidney and necrotizing arteritis of the mesenteric arteries were observed in SHRSP treated with bopindolol. The data presented indicate that bopindolol is a powerful antihypertensive agent.