Expression of laminin alpha2 chain during normal and pathological growth of myocardium in rat and human.

OBJECTIVES: Fibrosis is a classical feature of cardiac hypertrophy. To date changes within the basal lamina during normal and pathological cardiac growth have been poorly investigated. The goal of the present study was to determine if the expression of the muscle specific subunit of merosin (laminin alpha2 chain) together with that of fibronectin (FN) is modified in the diseased human heart. Laminin alpha2 chain expression was also investigated during physiological and pathological cardiac growth in the rat. METHODS: In ten normal human hearts and ten hearts with idiopathic dilated cardiomyopathy (IDCM), the laminin-alpha2 and FN mRNA levels were quantified by slot-blot using total RNA and the protein distribution was analysed using an immunofluorescence approach. In Wistar rats, laminin alpha2 and FN mRNA expression was analyzed using RNase protection assay (RPA) and slot-blot assays. RESULTS: The amount of laminin alpha2 mRNA did not vary in normal and pathological human hearts whereas it was significantly decreased in renovascular hypertensive rats (-20%) P<0.05 versus normal tissue). The amount of fibronectin mRNA increased in IDMC patients (x2, P<0.05 versus normal tissue), but was unchanged in hypertensive rats. A negative correlation was found between the cardiac laminin-alpha2 level and the age of the patients whatever the cardiac status. During postnatal development in the rat, a similar decrease in cardiac laminin-alpha2 level was observed between 3 and 30 weeks of age. Finally, the immunofluorescent approach failed to detect any alteration in laminin alpha2 distribution within the human myocardium. CONCLUSION: These data indicate that an imbalance between myocyte hypertrophy and the level of laminin-alpha2 might contribute to alterations in sarcolemmal properties, which occur during the development of cardiac hypertrophy and its transition to cardiac failure.

Trandolapril treatment at low dose improves mechanical and functional properties in perfused coronary arteries of spontaneously hypertensive rat.

The ex-vivo effects of a 1-month treatment period with trandolapril at a low dose (0.3 mg/kg/day) were assessed on the mechanical and functional alterations observed in SHR coronary arteries. The in-vitro intrinsic elastic properties of the wall in treated SHR coronary arteries were determined in comparison to those of SHR rats. In preconstricted preparations, agonist- and flow-induced dilatations were investigated in arteries of both groups. Arterial segments were cannulated at both ends using an arteriograph system. Internal diameter and wall thickness were continuously monitored while intraluminal pressure and flow were controlled. Wall thickness was reduced in arteries of treated rats compared to those in control SHR (mm): 52 +/- 2 vs. 41 +/- 2, P < 0.001, respectively. Arterial stiffness, expressed by the incremental elastic modulus-stress relationship, was significantly lower in arteries of treated compared to control SHRs. In preconstricted preparations, dilatations induced by bradykinin were significantly greater in treated SHR compared to control SHR arteries whereas dilatations induced by acetylcholine were slightly but not significantly increased. On the other hand, starting flow at the plateau of 5-HT-induced constriction led to dilatations which were not significantly different in the treated compared to the control group. The maximal dilatation induced by flow in arteries of treated rats was obtained for the same value of shear stress compared to that determined in preparations of control SHRs: (dyn/cm2) 63 +/- 3 vs. 61 +/- 2, respectively, NS. These results show that together with hypertrophy, the abnormal mechanical properties observed in the coronary arterial wall of SHR were improved by a low dose of trandolapril treatment. However, differential effects of trandolapril treatment were observed on agonist and flow-induced dilatations. Although flow-induced dilatation seemed to remain unaffected, acetylcholine-induced dilatation was slightly improved and bradykinin-induced dilatation was markedly increased by trandolapril treatment.

The use of hydroxyapatite-coated implants in revision surgery for acetubular component loosening.

Since 1989,the authors have used the Hydroxyapatite (HA)-coated ABG prosthesis for both primary and revision hip replacement. Hydroxyapatite is osteoconductive, and therefore speeds up bone formation and ensures a direct contact between the implant and the host bone, without any interposed fibrous tissue. The cup can thus be firmly fixed in the bony acetabulum, with eventual osseointegration into the host bone. The quality of the results achieved, at primary hip replacement, with bioactively coated devices has been highlighted in a large number of publications.

HR 720, a novel angiotensin receptor antagonist inhibits the angiotensin II-induced trophic effects, fibronectin release and fibronectin-EIIIA+ expression in rat aortic vascular smooth muscle cells in vitro.

The aim of this study was to evaluate the direct trophic effects of angiotensin II (AII) on rat vascular smooth muscle cells obtained from a single cellular isolate. Cell volume, protein synthesis, fibronectin (FN) release and FN-EIIIA+ mRNA isoform expression were analyzed in parallel. The effects of HR 720, a novel AT1 angiotensin receptor antagonist with some AT2 receptor affinity, were compared with those of selective AT1 antagonist EXP 3174. Both HR 720 and EXP 3174 inhibited in a concentration-dependent manner the maximum increase in cell volume induced by 10(-9) M Sar1-All (IC50 = 0.49 x 10(-9) M and 0.79 x 10(-9) M, respectively). Maximum [3H]leucine incorporation was also achieved at 10(-9) M All. HR 720 blocked the increase in protein synthesis with potency similar to EXP 3174; the respective IC50 values were 1.04 x 10(-9) M and 1.36 x 10(-9) M. All dose-dependently increased FN release, which was also equally inhibited by about 50% with both compounds at 10(-6) M. Furthermore, All enhanced FN-EIIIA+ mRNA in rat vascular smooth muscle cells (VSMC), which indicated a modulation of FN isoform expression which was inhibited by angiotensin II antagonists. In conclusion, All induced parallel and concentration-dependent increases in cell volume, protein synthesis, FN release and FN-EIIIA+ mRNA expression in vascular smooth muscle cells. These effects appeared to be essentially mediated by AT1 receptor stimulation as indicated by the equal inhibitory effects of HR 720 and EXP 3174.

Effect of growth hormone replacement on wound healing in healthy older men.

The secretion of growth hormone, an important anabolic agent, declines with aging. We hypothesize that growth hormone levels (measured as insulin-like growth factor-1) correlate with postoperative tissue repair in otherwise healthy, elderly persons. The goal was to determine whether growth hormone supplementation can improve wound healing in this circumstance. We conducted a randomized controlled double-blind trial of 6 months of growth hormone replacement or placebo in 28 healthy older men (>69 years of age) with low baseline plasma insulin-like growth factor-1. Growth hormone doses were adjusted to elevate insulin-like growth factor-1 to levels expected in younger adults. Wound healing was tested by implanting 10 cm expanded polytetrafluoroethylene porous tubes for 10 days, then measuring the content of collagen (as hydroxyproline), DNA, and total protein. Hydroxyproline content was 15% greater in the wounds of the growth hormone group (n = 13) compared with the placebo group (n = 15), (4.52 +/- 0.94 versus 3.92 +/- 0.78 microg/cm; p = 0.04). Therefore, healthy older men who took growth hormone had enhanced reparative collagen deposition during the wound healing process. This action may be clinically useful after selected surgery or trauma in the elderly.

Renal and haemodynamic responses to a novel kappa opioid receptor agonist, niravoline (RU 51,599), in rats with cirrhosis.

Because renal water retention is a complication of cirrhosis, niravoline (RU 51,599), a novel kappa (kappa) opioid receptor agonist which is known to cause a water diuresis under normal conditions, may be useful in the therapy of chronic liver diseases. Thus, the present study examined the effects of niravoline on renal function in rats with cirrhosis. Urine was collected during the 2 h period following the administration of vehicle (saline) in one groups of animals or niravoline (3 mg/kg, i.v.) in another group. Urinary and plasma osmolality were measured prior to and 2 h after niravoline in a third group of animals. Urine flow and natraemia were significantly higher after niravoline (147 +/- 12 microL/min and 153 +/- 2 mmol/L, respectively) than after vehicle (27 +/- 7 microL/min and 146 +/- 1 mmol/L, respectively). Niravoline significantly decreased urinary osmolality and significantly increased plasma osmolality and free water clearance. This substance did not significantly change urinary sodium excretion. In conclusion, this study shows that niravoline, a kappa opioid receptor agonist, induced a water diuresis in rats with cirrhosis.

Renal enlargement and insulin-like growth factor-1 accumulation in the Wistar rat model of experimental diabetes is not prevented by angiotensin converting enzyme inhibition.

Experimental diabetes is associated with renal enlargement and glomerular hyperfiltration. Possible mechanisms for these changes could be the direct effects of growth factors such as insulin-like growth factor-1 and angiotensin II. We investigated whether treatment with trandolapril, an angiotensin converting enzyme inhibitor, prevented renal enlargement in streptozotocin-diabetic rats. Seven groups of male Wistar rats were studied: C (control + placebo); CL (control + low-dose trandolapril, 0.01 mg.kg-1.day-1); CH (control + high-dose trandolapril, 0.5 mg.kg-1.day-1; DP (diabetic + placebo); DI (diabetic, insulin-treated); DL (diabetic + low-dose trandolapril); DH (diabetic + high-dose trandolapril) and DI (diabetic + insulin). From day 2 glucose concentrations and body weight were similar in the non-diabetic and diabetic animals treated with insulin. Diabetic animals treated with placebo and low-dose trandolapril weighed significantly less compared to the control group. The diabetic groups, not treated with insulin, showed marked hyperglycaemia throughout the study. Kidney weight was greater in the diabetic, non insulin-treated groups compared with the control and insulin-treated groups. After 24 h of diabetes, kidney insulin-like growth factor-1 content was significantly increased from baseline levels in groups DP, DL and DH but by 48 h these levels had returned to normal. Renal tissue angiotensin converting enzyme activity was similar in groups C and DI but significantly reduced in all trandolapril-treated animals. Despite inhibiting renal angiotensin converting enzyme activity renal enlargement with increased tissue insulin-like growth factor-1 still occurred. This suggests that neither angiotensin II nor glomerular hyperfiltration, with raised intraglomerular pressure, play a role in the initial renal enlargement seen in experimental diabetes. Renal accumulation of insulin-like growth factor-1 appears to be an important factor in early renal hypertrophy and its effects are not modulated by angiotensin converting enzyme or angiotensin II.

The arterial wall: a new pharmacological and therapeutic target.

In recent years, two key concepts having numerous interrelationships were advanced for the understanding of various cardiovascular diseases: the "endothelial dysfunction" and the "arterial remodelling". Both endothelial dysfunction and arterial remodelling occur in various pathologies including essential hypertension, heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extra-cellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extra-cellular matrix.

Effect of chronic treatment with trandolapril or enalapril on brain ACE activity in spontaneously hypertensive rats.

The aim of the present study was to determine whether the new ACE inhibitor trandolapril was able to inhibit brain ACE activity in spontaneously hypertensive rats (SHRs). Therefore, we have measured ex vivo ACE activity in discrete brain areas of SHRs after a 2-week oral treatment with trandolapril (0.001, 0.01, 0.1 and 1 mg/kg/day). The effects of trandolapril were compared to those of enalapril (10 mg/kg/day), used as a reference compound. Enalapril induced a decrease in ACE activity in brain areas not protected by the blood brain barrier (subfornical organ and median eminence) and in cerebral cortex. Conversely, trandolapril at a dose of 0.01 mg/kg/day and above induced a dose-dependent inhibition of ACE activity in all brain areas assayed, including the supraoptic and paraventricular hypothalamic nuclei, septum, amygdala, hippocampus, cerebellar and cerebral cortex, nucleus of the tractus solitary and caudate nucleus. The inhibition was roughly similar in all brain areas studied. These data suggest that after chronic oral administration in SHRs, trandolapril or its metabolite, in contrast to enalapril or enalaprilat, was able to reach all brain areas of SHRs, including those protected by the blood brain barrier.

Trandolapril decreases prevalence of ventricular ectopic activity in middle-aged SHR.

BACKGROUND: Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease. METHODS AND RESULTS: Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy. CONCLUSIONS: After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.

Morphometric detection of incipient glomerular lesions in diabetic nephropathy in rats. Protective effects of ACE inhibition.

BACKGROUND: Glomerulosclerosis is the main renal lesion complicating diabetes in humans and in experimental models. Angiotensin I-converting enzyme (ACE) inhibitors are effective in preventing the development of diabetic nephropathy. Incipient glomerular lesions were explored in streptozotocin-diabetic rats at a stage when glomerulosclerosis was not yet established. The modulation of such early glomerular lesions by a new ACE inhibitor (Trandolapril (T) at high or low doses was assessed. EXPERIMENTAL DESIGN: Five groups of rats were designed as follows: (a) nondiabetic control rats, (b) diabetic rats, (c) diabetic rats treated with 0.1 mg/kg/day of T, (d) diabetic rats treated with 1 mg/kg/day of T, and (e) nondiabetic rats treated with 1 mg/kg/day of T. The rats were killed at 1, 3, and 6 months after the beginning of the treatment. The kidneys were studied using a powerful morphometric technique at optical microscopic level with an image analyzer to measure the following glomerular parameters to assess the development of incipient glomerular lesions: (a) total glomerular surface area, (b) glomerular tuft surface area, (c) mesangial surface area, (d) ratio of the mesangial surface area to the glomerular tuft surface area, and (e) mean thickness of the Bowman's capsule. In parallel, albuminuria was measured. RESULTS: The results showed the development of glomerular hypertrophy in parallel with the increase in glomerular mesangial domain and in albuminuria with diabetes. They also demonstrated that ACE inhibitor given at a high dose is significantly effective in reducing glomerular hypertrophy and the expansion of the mesangial domain. ACE inhibitor given at a low dose tended to reduce glomerular hypertrophy and the expansion of the mesangial domain. Furthermore, ACE inhibitor at both doses completely abolished the albuminuria increase, maintaining the levels of albuminuria within the range of young nondiabetic rats. CONCLUSIONS: Using morphometric image analysis, incipient glomerular changes can be detected before glomerulosclerosis is patent in experimental diabetes. Moreover, they can be easily and reliably quantified by this technique, allowing comparison among experimental groups. These changes can be prevented by ACE inhibition.

[Arterial wall: a new pharmacological and therapeutic target?]. / La paroi artérielle: une nouvelle cible pharmacologique et thérapeutique?

In recent years, endothelial dysfunction and arterial remodelling in various cardiovascular diseases have emerged as two key concepts, with numerous interrelationships. Both endothelial dysfunction and arterial remodelling occur in various pathologies including heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extracellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extracellular matrix.

Sulfonylureas and sulfonylcarbamates as new non-tetrazole angiotensin II receptor antagonists. Discovery of a highly potent orally active (imidazolylbiphenylyl)sulfonylurea (HR 720).

The synthesis and pharmacological activity of new potent nonpeptide non-tetrazole angiotensin II (AII) receptor antagonists are described. These compounds are 4-thioimidazole derivatives linked on N1 to a biphenylsulfonyl fragment by a methylene spacer. Different acidic sulfonamides such as sulfonylureas 12, sulfonylcarbamates 15, sulfonylamides 16, and sulfonylsulfonamides 17 have been investigated as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activity were evaluated by AII receptor binding assay as well as by in vivo (i.v. and po) assays such as inhibition of the AII-induced pressor response in pithed rats. Most of the synthesized sulfonyl derivatives showed nanomolar affinity for the AT1 receptor subtype. The N-propylsulfonylurea 12d and the ethyl sulfonylcarbamate 15b as representative members of this series exhibited high oral activity in the pithed rat model with ID50 values of 0.38 and 0.4 mg/kg, respectively. Structure-activity relationships on the imidazole ring linked to the methylbiphenyl N-propylsulfonylurea fragment demonstrated similar features to those found in the corresponding tetrazole series. For both class of compounds, the linear butyl chain in position 2 and a carboxylic acid in position 5 were important for high in vitro and in vivo activity. In most cases, replacement of the carboxylic acid was detrimental to in vivo activity while maintaining the in vitro binding affinity. Introduction of a methylthio group in position 4 was found to enhance oral activity compared to compounds with chloro or other alkylthio, (polyfluoroalkyl)thio, and arylthio groups. 2-Butyl-4-(methylthio)-1-[[2'- [[[(propylamino)carbonyl]amino[sulfonyl](1,1'-biphenyl)-4- yl]methyl]-1-H-imidazole-5-carboxylic acid (12d) as the most promising example of the series was synthesized as its dipotassium salt (50, HR 720). This compound 50 inhibited the specific binding of [125I]-AII to rat liver membranes with an IC50 value of 0.48 nM. In vivo, 50 dose-dependently inhibited the AII-induced pressor response in normotensive pithed rats (ID50 = 0.11 mg/kg i.v. and 0.7 mg/kg po). In addition, this compound produced a marked and long-lasting decrease in blood pressure in high renin animal models and proved to be superior to the corresponding tetrazole 45 as well as to DuP 753 or its active metabolite EXP 3174. Compound 50 has been selected for in-depth investigations and is currently undergoing phase II clinical trials.

Transforming growth factor-beta 1 lowers the CD14 content of monocytes.

Marked elevation of transforming growth factor-beta 1 (TGF-beta 1) has been demonstrated clinically following injury and in sepsis. While alterations in the monocyte binding site (CD14) for the lipopolysaccharide (LPS)-lipopolysaccharide binding protein (LBP) complex have been noted with exposure to LPS, immune complexes, gamma-interferon, and IL-4, it is not known whether TGF-beta 1 can alter CD14 expression. To study the effect of TGF-beta 1 on monocyte CD14 expression, human leukocytes were isolated from healthy donors with discontinuous gradient centrifugation and incubated at 37 degrees C for 2 and 24 hr with increasing doses of purified human platelet TGF-beta 1. Monocytes were immunofluorescently stained with monoclonal antibodies recognizing CD14 and CD16. The cells were analyzed by flow cytometry. At 2 hr, 50 ng/ml TGF-beta 1 significantly lowered CD14 expression (51%, P = 0.043). At 24 hr, there was no significant difference between cells stimulated by TGF-beta 1 and control cells. To confirm that TGF-beta 1 was active at 24 hr, we examined levels of CD16. CD16 expression was increased by 10 ng/ml of TGF-beta 1. These observations suggest that high physiologic concentrations of TGF-beta 1 cause early monocyte suppression of CD14. Thus, CD14 may be marker for the transition of monocytes to macrophages and TGF-beta 1 may be responsible for the down-regulation of CD14 expression observed in monocytes obtained from septic patients.

Compared properties of trandolapril, enalapril, and their diacid metabolites.

The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. To understand the reasons for such discrepancies between ex vivo effects of ACE inhibitors and in vitro actions of their diacid metabolites, we measured the lipophilicities of the compounds and investigated the possibility that trandolapril could display an ACE inhibitory effect by itself. Trandolaprilat was found to be far more lipophilic than enalaprilat, as shown by reverse-phase high-performance liquid chromatography studies performed at pH 7.4 (log kw7.4 = 1.487 vs. 0.108). In addition, trandolapril was practically as active in vitro as its diacid metabolite (IC50 = 2.5 vs. 1.35 nM) in inhibiting ACE activity in the aorta, whereas enalapril was practically devoid of any effect (IC50 = 240 nM). Measurements of relative affinities of inhibitors or metabolites for purified human renal ACE showed that trandolapril displayed about 20% of the affinity of its diacid metabolite (IC50 = 15 vs. 3.2 nM); enalaprilat affinity (34 nM) was within the same range as those of trandolapril and trandolaprilat, whereas enalapril displayed a very low affinity for the purified enzyme (IC50 = 50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Trandolapril dose-response in spontaneously hypertensive rats: effects on ACE activity, blood pressure, and cardiac hypertrophy.

The dose-related effects of trandolapril on serum angiotensin-converting enzyme (ACE) activity, blood pressure and cardiac hypertrophy were studied after 2-week oral treatment in adult spontaneously hypertensive rats. Trandolapril caused a dose-dependent decrease in mean blood pressure at doses of 0.03-3 mg/kg. Inhibition of serum ACE was demonstrated by even the lowest dose (-9% at 0.003 mg/kg), was about 40% at 0.03 mg/kg, and rose to 84% at 3 mg/kg. Regression of cardiac hypertrophy (heart:body weight) was seen at doses of trandolapril as low as 0.03 mg/kg (-5.1%), which was also the minimal effective antihypertensive dose. Clear dose-response curves were observed for trandolapril from 0.03 mg/kg upwards with respect to hypotensive effect and regression of cardiac hypertrophy, which were not seen with enalapril. Enalapril had no significant effect on plasma ACE activity except at the highest dose (10 mg/kg), despite demonstrating hypotensive effects with smaller doses. These results indicate that trandolapril is a more potent (by a factor of about 30) inhibitor of ACE than enalapril (only 34% inhibition at 10 mg/kg) and causes a greater degree of regression of cardiac hypertrophy.

Effect of chronic converting-enzyme inhibition on kidney function of senescent hypertensive rats.

The age-related changes in the structure and the function of the kidney and the effect of chronic inhibition of angiotensin-converting enzyme (ACE) activity on these alterations were assessed in senescent, genetically hypertensive rats. Mean blood pressure was unchanged between 6 and 21 months, being 136 +/- 10 and 135 +/- 21 mm Hg, respectively. Hypertrophy of the glomeruli with a high incidence of glomerulosclerosis was reported in the 21-month-old animals. Renal blood flow, glomerular filtration rate, and filtration fraction were reduced between 6 and 21 months, whereas albuminuria and cGMP excretion were markedly enhanced with aging. Chronic ACE inhibition by administration of 0.3 mg/kg/day trandolapril from 18-21 months increased the life expectancy of the animals without affecting their mean blood pressure. The incidence of glomerular lesions and the excretion of enzymes that reflected the integrity of tubular and glomerular cells were not altered by ACE inhibition. On the other hand, the filtration fraction was restored in the 21-month-old treated animals, and the age-related albuminuria and rise in cGMP excretion were prevented by ACE inhibition. These results indicated that ACE inhibitor administered at the end of the life of senescent hypertensive rats was able to prevent some of the age-related changes in kidney function when glomerulosclerosis was already present.

Effects of 4 weeks of treatment with trandolapril on renal hypertension and cardiac and vascular hypertrophy in the rat.

The effects of the angiotensin-converting enzyme inhibitor trandolapril were studied using a Goldblatt (two-kidney, one-clip) rat model of renovascular hypertension after 4 weeks of oral treatment at 0.3 or 1 mg/kg/day. The effects of trandolapril on blood pressure and on cardiac and vascular hypertrophy were analyzed in comparison with the control group. Trandolapril produced a rapid, dose-dependent decrease in blood pressure, which plateaued after 2 weeks of treatment. Complete normalization of blood pressure was observed at a daily dose of 1 mg/kg. Dose-dependent inhibition of cardiac hypertrophy was also observed, heart:body weight ratio being decreased by 17 and 30% at 0.3 and 1 mg/kg, respectively, leading to a normalization of this parameter at the higher dose compared with normotensive controls. Similarly, trandolapril produced a marked decrease in vascular wall hypertrophy in both the mesenteric artery and the aorta. Indeed, complete normalization of media thickness was observed, compared with the normotensive control group, at 1 mg/kg of trandolapril. These results show that short-term treatment with trandolapril can induce complete regression of cardiac and vascular hypertrophy, which is associated with the development of renal hypertension.

Effects of subchronic treatment with trandolapril and enalapril on cardiovascular morphologic alterations in the aged spontaneously hypertensive rat with heart failure.

The effects of a 3-month treatment period with the angiotensin-converting enzyme (ACE) inhibitors trandolapril (0.3 mg/kg/day, p.o.) and enalapril (10 mg/kg/day, p.o.) on hemodynamics, cardiac hypertrophy, and vascular structures were examined in old spontaneously hypertensive rats (SHRs) (24 months at the end of treatment) presenting with congestive heart failure. During the course of treatment, the mortality rate was lower in the two treated groups than in the control group. At the end of treatment, serum ACE activity was inhibited by 63 and 33% by trandolapril and enalapril, respectively, but the decrease in blood pressure they induced was not significant. The atrial natriuretic factor(ANF) plasma levels and cyclic GMP urine excretion were about 10-fold and 3-fold higher, respectively, in old SHRs than in old Wistar rats. These values were markedly decreased by both ACE inhibitors. The ventricular hypertrophy was greatly decreased by both compounds (-24% by trandolapril and -26% by enalapril). In the aorta, the media hypertrophy was significantly decreased and nuclear density increased to a similar extent by both ACE inhibitors. In the mesenteric artery, trandolapril treatment induced a complete regression of the media hypertrophy and a marked decrease in extracellular matrix surface. In addition, the collagen network appeared less dissociated in the treated animals. Similarly the nuclear density was increased and the surface of cell nuclei was decreased by trandolapril. Enalapril appeared much less potent on these parameters. These data demonstrate that treatment with trandolapril of aged SHRs presenting with heart failure results in an increase in survival of the animals and a marked regression of cardiac and vascular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)