Effects Of Angiotensin-converting Enzyme Inhibitors Research Articles

Lessons from large interventional trials on antihypertensive therapy in chronic renal disease.

Studies in animal models have shown a convincing role for hypertension in the progression of renal disease. However, in clinical studies, the relationship between hypertension and progression is difficult to demonstrate owing to confounding factors such as age, gender, race, difficulty in identifying blood pressure (BP) parameters that correlate with progression, abnormal circadian BP pattern, and many non-haemodynamic factors of progression. A recent meta-analysis of several studies has shown that pharmacological agents that reduce both BP and proteinuria (U(P)), particularly angiotensin-converting-enzyme (ACE) inhibitors, significantly slow the rate of progression of chronic kidney disease. In these studies, lower achieved BP in patients both with and without U(P) was associated with slower decline in renal function. ACE inhibitors are effective BP-lowering agents and are associated with improved preservation of renal function compared with antihypertensive regimens without ACE inhibitors. The protective effect of ACE inhibition is additional to the effect of reducing BP and U(P).

P-35 Effect of angiotensin-converting enzyme inhibition on gene expression in vascular smooth muscle cell

P-35 Effect of angiotensin-converting enzyme inhibition on gene expression in vascular smooth muscle cell

Metabolic effects of angiotensin-converting enzyme inhibition: the role of bradykinin

Angiotensin-converting enzyme (ACE) inhibitors exert several general systemic and tissue-specific actions attributable to partial elimination of angiotensin II and to potentiation of bradykinin. This article briefly reviews the metabolic effects of ACE inhibition on insulin-dependent glucose transport and utilization, which are believed to be kinin-mediated and are enhanced by activation of the B2 type receptor of bradykinin. Studies using selective B1 or B2 receptor antagonists or genetically engineered mice with deleted B2 receptor gene have elucidated to a large extent which effects of bradykinin are mediated by each type of receptor. The data suggest that with physiologic conditions, most hemodynamic and metabolic actions of bradykinin are attributable to the B2 receptor. However, the hemodynamic (vasodilatory) actions are indirect, as they are mediated via activation of various locally generated tissue autacoids, such as prostaglandins and NO; in the absence of the B2 receptor, there is marked compensatory upregulation of the B1 receptor, which is also capable of activating these downstream mediators and thus maintaining the hemodynamic effects. On the contrary, the metabolic properties of bradykinin, ie, enhancement of insulin-mediated glucose transport across cell membranes and utilization of glucose, seem to be direct actions of the B2 receptor on insulin receptor and glucose transporter; in the absence of an intact B2 receptor, those metabolic actions are not taken over by the overexpressed B1 receptor.

AT(1)-receptor blockade and the kidney: importance of non-ACE pathways in health and disease.

Large-scale trials with angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT(1))-receptor blockers have clearly shown that blockade of the renin-angiotensin system reduces the deterioration in renal function associated with diabetes. AT(1)-receptor blockers represent a more rational approach to blockade of this system than ACE inhibitors, due to the presence of non-ACE pathways of angiotensin II formation. Studies in healthy volunteers maintained on a low-salt diet indicate that such pathways account for approximately 30-40% of total angiotensin II formation, and this figure increases to 60-70% in individuals maintained on a high-salt diet (resembling the situation in most human populations). Activation of the renin-angiotensin system is increased in diabetic patients, and comparison of the renal vascular responses to captopril and candesartan shows a strong correlation between the effects of ACE inhibition and AT(1)-receptor blockade, indicating that the deleterious effects of renin-angiotensin system activation in diabetes are mediated largely through angiotensin II. The presence of multiple risk factors, such as genetic predisposition, hyperglycaemia, obesity and tissue damage, places diabetic patients at high risk of disease related to activation of the renin-angiotensin system. Effective and early blockade of this system is therefore an important aspect of management.

Modification of Myosin Gene Expression by Imidapril in Failing Heart due to Myocardial Infarction

J. Wang, X. Liu, B. Ren, H. Rupp, N. Takeda and N. S. Dhalla. Modification of Myosin Gene Expression by Imidapril in Failing Heart due to Myocardial Infarction. Journal of Molecular and Cellular Cardiology (2002) 34, 847–857. The beneficial effects of imidapril, an angiotensin converting enzyme (ACE) inhibitor were investigated on changes in myofibrillar ATPase as well as myosin heavy chain (MHC) content and gene expression due to myocardial infarction (MI). Three weeks after occluding the left coronary artery, rats were treated with or without imidapril (1mg/kg/day), for 4 weeks. The infarcted hearts exhibited depressed rates of left ventricular (LV) pressure development (57±2.4% reduction) and pressure decay (55.5±1.6% reduction). LV myofibrillar Ca2+ ATPase activity, unlike that in the right ventricle (RV), was decreased in the infarcted animals compared with controls (6.8±0.4 vs 10.3±0.6μmol Pi/mg/hr). MHC α-isoform contents were decreased by 47 and 41% whereas those of MHC β-isoform were increased by 823 and 1200% in the LV and RV due to MI, respectively. MHC α-isoform mRNA levels were decreased by 55 and 35% whereas those for MHC β-isoform were increased by 50 and 30% in the infarcted LV and RV, respectively. Imidapril treatment partially prevented the changes due to MI in LV function (rate of pressure development, 24±2.3% reduction and rate of pressure decay, 14±1.8% reduction), myofibrillar Ca2+ ATPase activity (8.2±0.7μmol Pi/mg/hr), MHC protein content (α-MHC, 24% reduction and β-MHC, 525% increase) and MHC gene expression (α-MHC, 18% reduction and β-MHC, 15% increase). The results suggest that the beneficial effects of ACE inhibition on the failing heart are associated with improvements in myofibrillar ATPase activities as well as prevention of changes in MHC isozyme protein contents and their gene expression. Copyright 2002 Elsevier Science Ltd. All rights reserved.

Oestrogen action on the myocardium in vivo: specific and permissive for angiotensin-converting enzyme inhibition.

In contrast to the vasculature, it remains unclear whether oestrogens also directly affect the myocardium. In this study, we addressed basic questions regarding oestrogen effects on the myocardium, including specificity, pathophysiological relevance and potential clinical implications, with a special focus on interactions between oestrogen and angiotensin-converting enzyme (ACE) inhibitors in an established in-vivo model of cardiac hypertrophy. Female spontaneously hypertensive rats (SHR) were ovarectomized (OVX) or sham-operated and treated with 17beta-oestradiol (2 microg/kg per day subcutaneously), the oestrogen receptor antagonist ZM-182780 (250 microg/kg per day subcutaneously) and the ACE-inhibitor moexipril (10 mg/kg per day orally) alone or in combination for 3 months. Hormone replacement restored physiological oestradiol serum levels and prevented uterus atrophy. Whereas moexipril alone was ineffective in OVX rats, substitution of oestradiol restored the beneficial effect of moexipril on systolic blood pressure (-30 +/- 5 mmHg) and relative heart weight (-11 +/- 3%) in OVX rats. Oestradiol upregulated alpha-myosin heavy chain (MHC) mRNA (+37 +/- 7%) and protein expression (+43 +/- 6%) in spite of increased blood pressure in OVX rats. Simultaneous treatment with oestradiol plus moexipril most effectively shifted the ratio of alpha-/beta-MHC mRNA and protein expression towards alpha-MHC in OVX animals. Oestradiol (10 nmol/l) also upregulated alpha-MHC mRNA and protein in cultured cardiac myocytes. The oestrogen receptor antagonist ZM-182780 significantly inhibited the observed oestrogen effects. Oestrogen replacement is permissive for the beneficial effects of ACE-inhibition in female SHR rats. Oestrogen effects on the myocardium in vivo are specific (i.e. oestrogen receptor mediated) because they are inhibited by a pure oestrogen receptor antagonist and occur at physiological hormone levels.

Ventricular remodeling after myocardial infarction and effects of ACE inhibition on hemodynamics and scar formation in SHR

The effect of ACE inhibition after myocardial infarction (MI) on MI healing and remodeling in the presence of hypertension is not exactly known. Therefore, the effect of quinapril on scar formation, remodeling and hemodynamics was studied in spontaneously hypertensive rats (SHR). Nine weeks after moderate and large MI, left ventricular end-diastolic pressure (LVEDP) and passive pressure–volume relations were similar in 28-week-old hypertensive and normotensive rats. Chronic therapy with quinapril (6 mg/kg/day, started 30 min post-MI) reduced LVEDP and LV to body weight ratio, yet did not affect pressure–volume relations. Quinapril increased MI size and reduced the content and brightness of collagen fibers in the scar examined by polarized light microscopy. In conclusion, ventricular dilatation after MI was not accelerated in SHR, probably due to LV hypertrophy. Quinapril produced beneficial hemodynamic effects similar to that observed in the normotensive rat model. The significance and timing of ACE inhibitor-induced impairment of scar formation need further evaluation.

Blockade of endothelial enzymes: new therapeutic targets.

Nitric oxide (NO) is the principal vasoactive substance produced by the vascular endothelium with antitrombotic, antiatherogenic and vasodilator actions. The loss of these functions is now known as endothelial dysfunction (ED) and it has been proposed that it is the final common pathway in cardiovascular disease. At the moment there is an important body of evidence that supports the proposal that ED is a consequence of an imbalance between the free radicals, NO, superoxide (O(-)(2)) and peroxynitrate (ONOO(-)). This imbalance is the result of the actions of well known risk factors associated with an inappropriate diet and infection-inflammation. Angiotensin-converting enzyme (ACE) inhibitors are highly effective against a variety of cardiovascular disorders. Experimental and clinical studies have demonstrated a beneficial effect of ACE inhibition on endothelial function. This action is mainly due to an increase in the concentration of bradykinin, which stimulates NO production. ACE inhibitors also block the formation of angiotensin II that results in a lower production of O(-)(2). These effects lead to improve the imbalance between NO and O(-)(2) observed in cardiovascular disease. This proposal is supported by different clinical trials that have shown that the ACE inhibitors with higher affinity by the tissular ACE, such as quinapril, are the most effective in reversing ED principally by accumulating bradykinin. Recently, the HOPE study conducted in patients at a high risk of cardiovascular events, showed how ramipril, an ACE inhibitor with high affinity by tissular ACE, decreased the mortality rate due to cardiovascular disease independently of changes in blood pressure.

Induction of functional bradykinin b(1)-receptors in normotensive rats and mice under chronic Angiotensin-converting enzyme inhibitor treatment.

The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B(1)- and B(2)-receptor expression, which are the molecular entities responsible for the biological effects of kinins. Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT(1)-receptor antagonist, and B(1)- and B(2)-receptor antagonists. Chronic ACE inhibition induced both renal and vascular B(1)-receptor expression, whereas B(2)-receptor expression was not modified. Furthermore, with B(1)-receptor antagonists, it was shown that B(1)-receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B(1)-receptors in all segments. ACE-inhibitor-induced B(1)-receptor induction involved homologous upregulation, because it was prevented by B(1)-receptor antagonist treatment. Finally, using B(2)-receptor knockout mice, we showed that ACE-inhibitor-induced B(1)-receptor expression was B(2)-receptor independent. This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B(1)-receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B(1)-receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.

Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases

Extracellular matrix accumulation is thought to be involved in the pathogenesis of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting, have not been fully explored. Furthermore, the effect of renoprotective therapies on matrix accumulation through these pathways has not been examined. We investigated the degradative pathway of type IV collagen and the effects of ACE inhibition in experimental diabetic nephropathy. Diabetes was induced in 16 rats by administrating streptozocin; 8 of the diabetic rats were allocated at random to receive the ACE inhibitor perindopril (2 mg/l) in their drinking water and 8 age and weight matched rats served as controls. Gene expression of matrix metalloproteinase ( MMP) and tissue inhibitor of metalloproteinase ( TIMP) was measured by RT-PCR and type IV collagen content by immunohistochemistry. MMP activities were determined by degradation of a radiolabelled substrate and by zymography. Six months of diabetes was associated with a decrease in mRNA and enzymatic activity of MMP-9 (21 % and 51 % respectively, p < 0.05 vs control) and a 51 % increase in TIMP-1 mRNA ( p < 0.05 vs control). By contrast, MMP-2 mRNA was increased but its activity decreased (43 % and 43 % respectively, p < 0.05 vs control). Total degradative capacity of kidney tissue from diabetic rats was also lower (Control: 48 +/- 7 %, Diabetic: 33 +/- 6 %, p < 0.05). Activation of latent MMPs with amino-phenylmercuric acetate increased matrix degradation by two-fold. However the relative decrease associated with experimental diabetes still remained. All diabetes-associated changes in MMP and TIMP mRNA and activities were attenuated by perindopril treatment in association with reduced type IV collagen accumulation. These results indicate that the impairment of matrix degradation contributes to matrix accumulation in diabetic nephropathy and that the beneficial effects of ACE inhibition could in part be mediated by modulation of changes in matrix degradative pathways.

Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease.

Angiotensin-converting enzyme inhibitors (ACEi) reduce cardiovascular morbidity and mortality by improving coronary perfusion, reducing ventricular hypertrophy and remodeling, and preventing progression of coronary atherosclerosis. However, the cellular mechanisms underlying the beneficial effects of ACEi are not fully understood. We studied the in vivo effects of ACE inhibition with perindopril on cellular expression of ACE, AT(1) receptors and 2 nitric oxide synthase (NOS) isoforms, endothelial (eNOS) and inducible NOS (iNOS), in human blood vessels using quantitative in vitro autoradiography and immunocytochemistry. Seven patients with ischemic heart disease were treated with perindopril (4 mg/d) for up to 5 weeks before elective coronary bypass surgery, whereas controls did not receive the ACEi (n=7). Perindopril decreased plasma ACE by 70% and the plasma angiotensin II to angiotensin I ratio by 57% and reduced vascular ACE to approximately 65% of control levels in both endothelium and adventitia. By contrast, AT(1) receptor binding in vascular smooth muscle cells was increased by 80% in patients treated with perindopril as confirmed by immunocytochemistry. eNOS was expressed primarily in endothelial cells, whereas little iNOS expression occurred in vascular smooth muscle cells of untreated patients. Both eNOS and iNOS expression seemed to increase during perindopril treatment. These results suggest that suppression of angiotensin II formation in the vascular wall and increased expression of eNOS and iNOS during ACE inhibition may be beneficial in reversing endothelial dysfunction in patients with cardiovascular disease. Because vascular AT(1) receptor expression is increased during chronic ACE inhibition, more clinical studies are required to determine whether it is necessary to combine ACE inhibitors and AT(1) receptor antagonists in clinical management of heart failure, coronary heart disease, and hypertension

Myocardial blood flow after chronic cardiac decentralization in anesthetized dogs: effects of ACE-inhibition

Coronary blood flow regulation was studied in dogs with an intact or chronically decentralized intrinsic cardiac nervous system. We also examined the effect of angiotensin-converting enzyme inhibition (ACEI) on coronary autoregulatory pressure–flow relations and distribution of blood flow since the renin–angiotensin system may play a critical role in vasoregulation. Myocardial oxygen demand was reduced in the chronic decentralized dogs compared to the control dogs. The lower pressure limit of the autoregulatory pressure–flow relation was similar for the control and chronic decentralized dogs (47±2 and 44±7 mm Hg, respectively; p=NS). After ACEI, the lower pressure limit shifted leftward to 40 mm Hg ( p=0.001) in both groups. Concomitant blockade of cyclooxygenase, bradykinin catabolism and nitric oxide synthase had no further effect on the lower pressure limit. Total myocardial blood flow was lower ( p=0.001) in the chronic decentralized dogs compared to the control dogs, while transmural distribution of blood flow was preserved in both groups. The results show that even though myocardial oxygen requirements are lower in the chronically decentralized heart compared to controls, coronary autoregulation is maintained at levels observed in normally innervated hearts. The present findings indicate that intrinsic cardiac neurons contribute to coronary autoregulatory control and myocardial blood flow distribution even in the absence of cardiac connections to the central nervous system. In addition, in the chronic decentralized dog, ACEI allows the heart to work at lower coronary perfusion pressures while myocardial blood flow distribution is preserved.

Beneficial Effects of Angiotensin-Converting Enzyme Inhibition in Adriamycin-Induced Cardiomyopathy in Hamsters

This study was performed to determine whether angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase might contribute to the development of adriamycin-induced cardiomyopathy in hamsters. Hamsters were administered adriamycin (2.0 mg/kg per day, i.p.) three times weekly for 2 weeks. In the ACE inhibitor-treated group, the hamsters received lisinopril (20 mg/kg per day, p.o.) for 2 weeks after the last injection of adriamycin. The 4-week mortality rates of the vehicle- and ACE inhibitor-treated hamsters were 44% and 12%, respectively. In comparison to the age-matched hamsters used as the control hamsters, a significant decrease in cardiac function and a significant increase in the ratio of the heart weight to the body weight were observed in the vehicle hamsters. Cardiac ACE activity, but not the chymase activity, in the vehicle hamsters was significantly increased in comparison to that in the control hamsters. In the ACE inhibitor-treated group, the increased ACE activity was reduced significantly, and the cardiac hypertrophy and dysfunction were improved significantly. In adriamycin-induced cardiomyopathic hamsters, cardiac ACE activity was increased and ACE inhibition significantly improved cardiac function and survival rate, indicating that cardiac ACE, but not the chymase, plays the pivotal role in the development of the adriamycin-induced cardiomyopathy.

ICATIBANT BLOCKS BUT DOES NOT REVERSE ACE INHIBITOR RENAL EFFECT IN GOLDBLATT RABBIT

This study examined the proposition that kinins are involved in the renal hemodynamic effect of an ACE inhibitor in Goldblatt (GB) hypertension. The effects of the ACE inhibitor enalaprilat were compared in two groups of anesthetized two-kidney one-clip GB rabbits. One group (n=11) was given enalaprilat (10 mg/kg, iv) while a second group (n=10) received the kinin B2 receptor antagonist, icatibant (2.5–5 µg/kg/min, iv) prior to enalaprilat. Enalaprilat caused a 40% rise in renal blood flow and 11 mm Hg decrease in blood pressure in the untreated, but no significant renal effect in the icatibant-treated group. Blood pressure was reduced to the same degree in both groups. The results indicate that kinins play a major role in the renal hemodynamic, but not the blood pressure effect of ACE inhibition in the GB rabbit.

Angiotensin‐converting enzyme inhibition attenuates renal platelet‐derived growth factor gene expression and cell proliferation in subtotal nephrectomy

SUMMARY:Cell proliferation, matrix accumulation and cell infiltration are characteristic features of progressive glomerulosclerosis and tubulointerstitial fibrosis. Platelet‐derived growth factor (PDGF), a cytokine which has proliferative, prosclerotic and chemokine properties, has been shown to be upregulated in the rat remnant kidney model. Inhibition of the renin–angiotensin system by angiotensin‐converting enzyme (ACE) inhibitors has a beneficial effect on renal function and morphology, but the effect of ACE inhibition on PDGF gene expression and PDGF‐mediated cellular proliferation in subtotal nephrectomy has not been studied in detail. Twelve rats were subtotally nephrectomized (STNx) and received either the ACE inhibitor perindopril or a placebo for 12 weeks. Five sham‐operated rats served as controls. Subtotal nephrectomy was associated with hypertension, proteinuria, elevated plasma creatinine and increased kidney weight. After 12 weeks, PDGF B‐chain mRNA was significantly upregulated in the glomeruli and tubulointerstitium of subtotally nephrectomized rats. ACE inhibition attenuated PDGF mRNA expression in association with a reduction in tubular and glomerular proliferation, as assessed by staining for proliferating cell nuclear antigen. In the context of the known in vitro and in vivo effects of PDGF, it is postulated that the renoprotective action of ACE inhibitors may be partially related to PDGF‐mediated antiproliferative mechanisms.

Effect of angiotensin type I–receptor blockade on left ventricular remodeling in pressure overload hypertrophy

Background: The renin-angiotensin system is involved in cardiac remodeling. In contrast to the well-recognized salutary effects of angiotensin-converting enzyme inhibition, the value of angiotensin II type I (AT1)-receptor blockade on left ventricular (LV) hypertrophy and dysfunction is controversial. Methods and Results: Descending thoracic aorta–banded and sham-operated guinea pigs were given either losartan (30 mg · kg−1 · day−1 intraperitoneally) or vehicle for 8 weeks (n = 7 in each group). LV end-diastolic and end-systolic dimensions and wall thicknesses were measured echocardiographically, and LV fractional shortening, relative wall thickness, and LV mass normalized by body weight were calculated. Isolated heart function (Langendorff perfusion) was studied 8 weeks after surgery, and LV performance was assessed by maximum LV pressure and ±dP/dt normalized by LV mass. Eight weeks after banding guinea pigs developed concentric LV hypertrophy and had decreased maximum LV pressure and ±dP/dt normalized by LV mass; LV end-diastolic dimension and LV fractional shortening were unchanged. In band-operated guinea pigs treatment with losartan had no significant effects on any of these measurements. Conclusions: In guinea pigs with descending aortic banding, treatment with losartan for 8 weeks neither attenuates progression of pressure overload hypertrophy nor significantly improves impaired mass-normalized pressure-derived indices of LV contraction and relaxation.

Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure.

Atrial structural remodeling creates a substrate for atrial fibrillation (AF), but the underlying signal transduction mechanisms are unknown. This study assessed the effects of ACE inhibition on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF). Dogs were subjected to various durations of ventricular tachypacing (VTP, 220 to 240 bpm) in the presence or absence of oral enalapril 2 mg. kg(-1). d(-1). VTP for 5 weeks induced CHF, local atrial conduction slowing, and interstitial fibrosis and prolonged atrial burst pacing-induced AF. Atrial angiotensin II concentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38-kinase. Enalapril significantly reduced tachypacing-induced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1+/-0.4 to 1.9+/-0.2 ms/mm, P<0.05), atrial fibrosis (from 11.9+/-1.1% to 7.5+/-0.4%, P<0.01), and mean AF duration (from 651+/-164 to 218+/-75 seconds, P<0.05). Vasodilator therapy of a separate group of VTP dogs with hydralazine and isosorbide mononitrate did not alter CHF-induced fibrosis or AF promotion. CHF-induced increases in angiotensin II content and MAPK activation contribute to arrhythmogenic atrial structural remodeling. ACE inhibition interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.

Effect of angiotensin-converting enzyme inhibition on renal filtration surface area in hypertensive rats

Angiotensin-converting enzyme (ACE) inhibitor treatment leads to protective effects on the cellular structure of the glomerulus and the kidney. The aim of this study was to determine whether ACE inhibition increases renal filtration surface area in the spontaneously hypertensive rat (SHR). SHR were treated with the ACE inhibitor perindopril at a high dose (3 mg/kg/day) or a low dose (0.1 mg/kg/day) during the period of hypertension development, from 7 to 14 weeks of age. Some animals were treated concomitantly with the bradykinin B2 receptor antagonist, S16118. Tail-cuff systolic blood pressure and body weights were measured twice weekly. At termination of treatment, glomerular number and volume, length, and surface area of glomerular capillaries and renal filtration surface area were estimated using unbiased stereological techniques. There were significant dose-related reductions in blood pressure with high- and low-dose perindopril treatment. Neither low- nor high-dose perindopril treatment had any effect on glomerular number or size or glomerular capillary length and surface area. Hence, there was no significant difference in total renal filtration surface area between any of the experimental groups (8721 +/- 610 mm2 in untreated SHR and 7879 +/- 338 mm2 and 8767 +/- 437 mm2 in the low and high dose perindopril-treated groups, respectively). Coadministration of the bradykinin antagonist did not affect any of the glomerular parameters. ACE inhibition during the period of hypertension development does not lead to an enhanced glomerular capillary growth or increases in total renal filtration surface area in this model.

Prevention, protection, and the intrarenal renin-angiotensin systems.

The use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, or aldosterone antagonists can have important beneficial effects on the progression of renal disease associated with glomerular and interstitial fibrosis, especially if the adverse side effects (eg, hyperkalemia) can be minimized. Because it appears that chronic renal insufficiency and proteinuria may well be cardiovascular risk factors, it is exciting to note that recent large scale epidemiologic studies (Heart Outcomes and Prevention Evaluation [HOPE]) have shown both cardioprotective and renoprotective effects of ACE inhibition. It appears paradoxic that such renoprotective effects are clearly evident in diabetes mellitus in which the plasma renin activity may be suppressed. Even in this setting, it appears that there is activation of the renal angiotensin system(s), and inhibitions of these intrarenal systems are involved in the renoprotective effects of these agents. Recent studies have identified nearly all of the components needed to generate angiotensin II in the renal luminal compartment, and suggest that there may be a direct effect through AT(1) receptors on NaCl transport in the distal nephron. The possibility that the components of this intraluminal renin-angiotensin system may be acutely regulated by variations in dietary salt intake provides an opportunity to better understand the normal maintenance of salt balance. Whether or not inhibition of these pathways is involved in the renoprotective effects of ACE inhibitors and angiotensin receptor antagonists is an important issue to be addressed.

The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study

The renoprotective effect of ACE inhibition in chronic renal disease is well established but the studies on effects of calcium antagonists on progression of renal disease and on proteinuria have given varying results. We conducted an open long-term randomized prospective multi-centre study comparing the combination of ramipril and felodipine ER (F) with either drug alone in non-diabetic renal disease. Included were patients with uncontrolled hypertension (diastolic blood pressure (DBP)) > or =95 mmHg on treatment with a diuretic and a beta-blocker. Fifty-one patients received the combination of R and F, 54 patients R, and 53 patients F. The treatment goal was a DBP <90 mmHg and a similar BP reduction in the three groups. Mean doses at the last visit were 5+5, 10 and 9 mg, respectively, after a mean treatment time of nearly 2 years. The progression of renal impairment was studied by serial measurements of serum creatinine, iohexol clearance, and albuminuria. The reduction in supine systolic (S) BP and DBP expressed as median values were -19.0/-14.5,-14.3/-15.0 and -13.5/-13.3 mmHg in the R+F, R, and F groups, respectively. There was no significant difference between the groups. When correction for the acute drug effect was performed the R+F group had a slower progression rate of the renal disease (loss of glomerular filtration rate (GFR) ml/min/year) compared with the F group (P<0.05) but not to the R group (P>0.20). There was a rise in albuminuria after 2 years in the F group (P<0.05), but no significant change was found in the other groups. In patients with non-diabetic renal disease the combination of an ACE inhibitor and a calcium antagonist in reduced doses used in addition to baseline therapy with beta-blockers and diuretics, tended to cause a better BP reduction as each drug per se. The R+F treatment also caused a slower progression of the renal disease compared with F alone. The combination treatment seems to afford better BP control and appears to be a favourable therapeutic option in patients with renal disease and hypertension.