Renal protection and angiotensin converting enzyme inhibition in microalbuminuric type I and type II diabetic patients

BACKGROUND: Many studies have emphasized the role of antihypertensive drugs and in particular angiotension converting enzyme (ACE) inhibitors in the retardation of diabetic nephropathy. Although these studies have focused predominantly on patients with overt proteinuria, more recently a number of investigators have explored the role of ACE inhibitors in both type I and type II diabetic patients with an earlier phase of diabetic renal disease known as microalbuminuria. These agents are now being considered as renoprotective agents not only in hypertensive patients but also in those with 'normal' blood pressure. Initially, studies in type I diabetic patients showed that ACE inhibition was effective in retarding the increase in albuminuria which was observed in placebo treated groups. More recently, several multi-centre placebo controlled studies have been performed suggesting that prolonged treatment not only reduced albuminuria but also preserved renal function. The role of ACE inhibition in microalbuminuric type II diabetic patients is less well characterised although several studies have recently described beneficial effects of ACE inhibition on albuminuria and possibly on renal function. REVIEW: Although ACE inhibitors have been clearly shown to reduce urinary albumin excretion in diabetic patients, the issue as to whether they confer a specific benefit over other classes of antihypertensive agents remains controversial. Several meta-analyses have suggested that ACE inhibitors are more potent at decreasing albuminuria or proteinuria than other antihypertensive agents, for a given reduction in blood pressure. The Melbourne Diabetic Nephropathy Study Group has instituted a study which is placebo-controlled and is confined to normotensive type I and type II diabetic patients. The ACE inhibitor perindopril has been compared not only with placebo but also with the dihydropyridine calcium channel blocker, nifedipine. Preliminary analysis reveals that after 12 and 24 months of treatment, perindopril is more effective in reducing albuminuria than placebo or nifedipine. CONCLUSION: ACE inhibitors are a promising class of antihypertensive agents in diabetic patients with microalbuminuria. These drugs should be considered as first line agents in such patients, even in the absence of systemic hypertension.     

The effects of perindopril on vascular smooth muscle polyploidy in stroke-prone spontaneously hypertensive rats

OBJECTIVE: To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters. DESIGN: The following experimental groups were used: young (age < 20 weeks) and old (age > 20 weeks) untreated WKY rats and untreated SHRSP; SHRSP treated with perindopril, and age- and sex-matched control SHRSP; and SHRSP treated with hydralazine and hydrochlorothiazide and age- and sex-matched control SHRSP. The effects of treatment of the SHRSP with perindopril for 30 days on vascular smooth muscle polyploidy and growth kinetics were measured and compared with the effects of equivalent antihypertensive doses of hydralazine and hydrochlorothiazide. METHODS: Vascular smooth muscle polyploidy was measured using flow-cytometry DNA analysis of freshly harvested cells. Growth curves were performed on cultured aortic cells. Plasma renin activity was measured by an antibody-trapping method, plasma angiotensin II (Ang II) by radioimmunoassay and plasma ACE activity by a colorimetric method. Cardiac hypertrophy was evaluated by measuring the heart weight:body weight and left ventricle + septum weight:body weight ratios. RESULTS: The SHRSP had markedly and significantly elevated G2 + M phase of the cell cycle. Treatment with perindopril resulted in a significant reduction in polyploidy in the SHRSP, whereas treatment with hydralazine and hydrochlorothiazide had no effect on the percentage of cells in the G2 + M phase of the cell cycle. The regression of polyploidy after treatment with perindopril was associated with a significant reduction in the concentration of Ang II and ACE activity, and with a significant regression of cardiac hypertrophy. Increased mitogenesis of cultured vascular smooth muscle cells from the SHRSP was not altered by treatment with perindopril. CONCLUSIONS: ACE inhibition reduces vascular smooth muscle polyploidy in large conduit arteries. This type of vascular protection is mediated by the reduced Ang II and possibly by increased kinins level, rather than by the hypotensive effect alone.     

Antihypertensive therapy and diabetic microvascular disease

Hypertension is commonly associated with diabetes and may represent either a manifestation or a cause of diabetic vascular injury. The following series of studies have explored the role of hypertension in accelerating diabetic microvascular injury. In addition, the role of various classes of antihypertensive agents in preventing or reversing diabetic vascular abnormalities in the presence and absence of systemic hypertension was assessed in both the experimental and clinical context. The induction of streptozotocin diabetes in SHR leads to accelerated development of nephropathy as assessed by both functional and structural parameters. ACE inhibitors but not dihydropyridine calcium channel blockers favourably influence the progression of experimental diabetic nephropathy even in the setting of a normal blood pressure. More recent studies have shown that the trophic changes in the mesenteric arteries from diabetic rats are also attenuated by ACE inhibition. Preliminary results from the Melbourne Diabetic Nephropathy Study Group suggest that the ACE inhibitor, perindopril, is more effective than the dihydropyridine calcium channel blocker, nifedipine, in retarding the rise in urinary albumin excretion in normotensive insulin and noninsulin dependent diabetic patients with microalbuminuria. In conclusion, ACE inhibitors appear to be the drugs of choice in prevention and treatment of diabetic renal disease and may also act as protective agents at other sites of vascular injury.     

Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation

Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.     

Angiotensin converting enzyme inhibition reduces the expression of transforming growth factor-beta1 and type IV collagen in diabetic vasculopathy

OBJECTIVE: The purpose of this study was to assess the role of transforming growth factor (TGF)-beta1 in the development of diabetes-associated mesenteric vascular hypertrophy and in the antitrophic effect of angiotensin converting enzyme inhibitors. DESIGN AND METHODS: Streptozotocin-induced diabetic and control Sprague-Dawley rats were randomly allocated to treatment with the angiotensin converting enzyme inhibitor ramipril or to no treatment and were killed 1 or 3 weeks after the streptozotocin injection. Blood was collected and mesenteric vessels removed. Mesenteric vascular weight was measured and TGF-beta1 and alpha1 (type IV) collagen messenger (m)RNA levels were analysed by Northern analysis. Immunohistochemical analyses for TGF-beta1 and type IV collagen were also performed. RESULTS: The diabetic rats had increased mesenteric vessel weight at 3 weeks but not at 1 week and a concomitant rise in mesenteric TGF-beta1 and in alpha1 (type IV) collagen mRNA levels. Ramipril treatment attenuated mesenteric vessel hypertrophy and prevented the increase in TGF-beta1 and alpha1 (type IV) collagen mRNA levels after 3 weeks of diabetes. The immunohistochemical analysis revealed that diabetes was associated with increased TGF-beta1 and type IV collagen protein and extracellular matrix accumulation in mesenteric vessels, and this increase was reduced by ramipril treatment. CONCLUSIONS: These results support the concept that TGF-beta is involved in the changes associated with diabetic vascular disease, and suggest a mechanism by which angiotensin converting enzyme inhibitors exert their antitrophic effects.     

Heparin inhibits mesenteric vascular hypertrophy in angiotensin II-infusion hypertension in rats

OBJECTIVE: Chronic infusion with angiotensin II increases blood pressure and activates growth mechanisms to produce hypertrophy of the heart and vessels. In order to better understand mechanisms of angiotensin II induced vascular hypertrophy, this study aimed to determine whether heparin, a potent inhibitor of smooth muscle proliferation mechanisms, was able to inhibit vascular hypertrophy. METHODS: Angiotensin II (100, 200 or 300 ng/min/kg s.c.) or a saline vehicle control were infused into rats for 14 days. A separate group of animals were co-infused with heparin (0.3 mg/h/kg i.v.) and angiotensin II (200 ng/min/kg s.c.) to test whether hypertension or hypertrophy were antagonized. Blood pressure was measured by tail cuff method and vessel media cross sectional area was measured by morphometry in aorta and mesenteric arteries. RESULTS: Blood pressure elevation and cardiovascular hypertrophy produced by angiotensin II were strongly dose-dependent. Hypertrophy responses at 14 days of treatment also appeared to be influenced partly by local factors as medial cross sectional area was increased more in mesenteric arteries than in thoracic aorta, and left ventricle weight was least affected. Heparin treatment did not influence the increase of blood pressure in angiotensin II infused animals, but the mesenteric vascular hypertrophy response due to angiotensin II was inhibited by approximately 50%. Inhibition of a modest cardiac hypertrophy and aortic medial hypertrophy did not reach significance. CONCLUSIONS: Angiotensin II infusion produced vascular medial hypertrophy and increased blood pressure, however the inhibitory effect of heparin on hypertrophy in mesenteric arteries was not mediated through angiotensin II induced vasoconstriction or blood pressure elevation. These data suggest that heparin interferes directly with the hypertrophy mechanism in mesenteric arteries, and that heparin-sensitive growth mechanisms are important in mediating angiotensin induced mesenteric vascular hypertrophy.     

Effects of angiotensin converting enzyme inhibition on vascular remodelling of resistance vessels in hypertensive patients

BACKGROUND: Essential hypertension is known to be associated with a decrease in the lumen diameter and an increase in the wall thickness-to-lumen diameter ratio of the resistance vessels. Recently, it has been clarified that this alteration does not necessarily involve vascular growth, but could be due to a rearrangement of the same amount of material, a phenomenon now termed 'eutrophic remodelling'. OBJECTIVES: This review summarizes work aimed at determining the extent to which angiotensin converting enzyme (ACE) inhibitor treatment is able to normalize these abnormalities, and whether this is desirable. RESULTS: In essential hypertension, the changes seen in subcutaneous resistance vessels appear to be mainly due to eutrophic remodelling and only a small portion to growth. In addition, rat studies indicate that eutrophic remodelling, rather than growth, is found in all vascular beds. Antihypertensive treatment of hypertensive rats with ACE inhibitors causes a dose-dependent regression of the media: lumen ratio. Clinical studies have now confirmed these findings, showing that when previously untreated essential hypertensive patients are treated with the ACE inhibitor perindopril the abnormal structure of resistance vessels regresses towards normal values; in contrast, treatment with a beta-blocker does not affect the abnormal vascular structure. CONCLUSION: The available evidence indicates that ACE inhibitors are able to normalize the abnormal resistance vessel structure seen in essential hypertension, and suggests that this effect may not only be dependent on their ability to reduce blood pressure.     

Therapeutic interventions for nephropathy in type I diabetes mellitus

Diabetic nephropathy is the single most common cause of end-stage renal disease in the United States. Recently, several major therapeutic interventions have been developed and shown to slow or halt the progression of renal failure in patients with diabetes and diabetic kidney disease. Studies have shown that in patients with insulin-dependent diabetes and proteinuria, lowering systemic blood pressure slows the rate of decline in renal function and improves patients' survival. In the recently completed trial of angiotensin converting enzyme (ACE) inhibition in diabetic nephropathy, ACE inhibitors were specifically shown to decrease dramatically the risk of doubling of serum creatinine or reaching a combined outcome of end-stage renal disease or death independent of their effect on systemic blood pressure. In studies with small numbers of patients, dietary protein restriction has also been shown to slow the rate of decline of renal function. New potential interventions currently undergoing study include treatment with aldose reductase inhibitors, treatment with inhibitors of the formation of advanced glycosylation end-products, treatment of dyslipidemia, and a variety of other less well-studied interventions.     

Morphogenesis of the lateral nasal wall from 6 to 36 weeks

Salt intake, and the sensitivity of blood pressure (BP) to excessive salt intake is thought to contribute to the pathogenesis of essential hypertension in some patients. This study was designed to ascertain whether salt sensitivity of BP is a determinant of BP and renal vascular responsiveness to angiotensin converting enzyme (ACE) inhibition. In 24 patients with essential hypertension, ranging in age from 30 to 68 years, renin status, renal hemodynamics, and sensitivity of BP to steady state changes in salt intake were assessed. Twenty-four hour ambulatory BP monitoring (ABPM) was employed to measure baseline BP and BP response to 4 weeks' treatment with benazepril at 20 or 40 mg/day. Benazepril induced a highly-significant reduction in BP (P < .001) and increase in renal plasma flow (530 +/- 17 to 580 +/- 19 mL/min/1.73 m2; P < .001). Systolic BP fell from 143 +/- 2 to 129 +/- 2 mm Hg (P < .001), and diastolic BP fell from 91 +/- 1.6 to 80 +/- 2 mm Hg (P < .001). The magnitude of the BP and renal vascular response to ACE inhibition was not influenced by the sensitivity of BP to salt intake. In a multivariate analysis neither body mass index nor age influenced the BP response to ACE inhibition or the relationships between salt intake and a BP response to ACE inhibition. We conclude that the factors that influence sensitivity of BP to salt intake do not influence the systemic or renal hemodynamic response to ACE inhibition.     

Angiotensin converting enzyme inhibition and chronic cyclosporine-induced renal dysfunction in type 1 diabetes

AIM: This study was designed to evaluate whether the angiotensin converting enzyme inhibitor enalapril could prevent cyclosporine-induced renal dysfunction in diabetic patients treated with CsA in monotherapy. DESIGN: Twenty-four recent onset insulin-dependent diabetic patients without prior renal involvement were randomized to receive a 3 month course of either cyclosporine (CsA) alone (7.5 mg/kg. b.i.d. in olive oil) or CsA+enalapril (20mg p.o. oad.). END POINTS: were mean arterial pressure, plasma creatinine, GFR, renal plasma flow, renal vascular resistance, sodium and lithium clearances measured before and after 3 months of treatment. RESULTS: Baseline values were identical in both groups except for mean arterial pressure which was slightly higher in the subjects subsequently receiving CsA + enalapril. Three month treatment with CsA increased significantly mean arterial pressure and renal vascular resistance by 9 and 24% respectively, while decreasing significantly glomerular filtration rate and renal plasma flow by 17 and 14% respectively. Enalapril was able to prevent the decline in GFR and the increase in blood pressure induced by CsA. This effect was demonstrated despite a similar increase in renal vascular resistance suggesting a dissociation between changes in glomerular filtration rate and renal vascular resistance during angiotensin converting-enzyme inhibition. CONCLUSION: Chronic angiotensin converting-enzyme inhibition could afford some degree of protection against CsA-induced renal dysfunction. Whether these results can be extrapolated to transplant recipients in whom CsA is usually associated to treatment by glucocorticosteroids deserves further evaluation.     

Perindopril treatment prevents the loss of endothelial nitric oxide function and development of neo-intima in rabbits

An atheroma-like neo-intima was produced by positioning a flexible collar around the common carotid arteries of normocholesterolaemic rabbits. Vessel segments taken from the mid-region of the collared and control region of the same artery were studied 7 days after surgery. Placebo rabbits were provided ab libitum with regular tap water, and treated animals were supplied with water containing perindopril (0.3 mg/kg/day) for 14 days. Perindopril treatment reduced plasma angiotensin converting enzyme (ACE) activity by 88%, but did not significantly alter arterial blood pressure or heart rate. In control rings from placebo rabbits perindoprilat in vitro (0.1-1.0 microM) reduced the sensitivity to angiotension I up to 20-fold but did not affect that of angiotensin II. In placebo rabbits, the collared arterial segments were approximately five-fold more sensitive to the vasoconstrictor action of 5-HT (P < 0.05) than the corresponding control segments. Perindopril treatment did not prevent the supersensitivity of the collared vessels to 5-HT. Development of the lesion in placebo or perindopril-treated rabbits did not alter the vascular sensitivity to either angiotensin I (10(-9)-10(-5)M) or angiotensin II (10(-10)-10(-6)M). The vasorelaxant action of sodium nitroprusside was similar in collared and control rings, whereas the maximum endothelium-dependent vasorelaxant response to acetylcholine was reduced from 68 +/- 5% in control rings, to 44 +/- 8% (mean +/- S.E.M., n = 9, P < 0.05) in collared rings of placebo-treated rabbits. In the perindopril-treated animals, this impairment of relaxation was restored in collared vessels and was no longer significantly different from the control sections. In contrast, perindoprilat in vitro (1.0 microM) did not alter the vasorelaxant response to acetylcholine in control or collared rings in a separate series of placebo rabbits. Morphologically, vessel segments taken from the centre of the collared artery of all placebo rabbits showed a thickened intima filled with cells that had the appearance of synthetic-state smooth muscle. The intimal/medial cross-sectional area ratio was reduced from 0.11 +/- 0.02 (n = 10) in placebo rabbits to 0.05 +/- 0.01 (n = 9) in perindopril-treated rabbits, whereas cross-sectional area of media of the collared vessels was similar in the two groups. Thus ACE may have important roles in the initiation and progression of atheroma-like lesions. Inhibition of ACE with perindopril reduces intimal thickening and restores the defective vasodilatation induced by the endothelial-dependent vasodilator, acetylcholine.     

Nephroprotection by long-term ACE inhibition with ramipril in spontaneously hypertensive stroke prone rats

BACKGROUND: The effect of life-long treatment with the ACE inhibitor ramipril on hypertension-induced histological changes in the kidney was tested in stroke-prone spontaneously hypertensive rats (SHR-SP). METHODS: One-month-old pre-hypertensive SHR-SP were randomized into three groups of 45 animals each, and exposed via drinking water for their lifetime to a dose of: 1 mg.kg-1.d-1 ramipril (antihypertensive dose, HRA); 10 micrograms.kg-1.d-1 slight dose of ramipril (non-antihypertensive dose, LRA); or placebo. Histological and biochemical assessments were conducted after 15 months in ten rats each, when about 80% of the placebo group had died. RESULTS: Kidneys from placebo treated SHR-SP showed pronounced arterial wall hypertrophy and sclerosis, arterial fibrinoid necrosis, glomerulopathy and tubular interstitial injury that were, in concert with normalized blood pressure, completely prevented by HRA treatment. LRA treatment did not affect any blood pressure increase, and also attenuated the development of arterial wall hypertrophy, sclerosis and arterial fibrinoid necrosis, though to a minor extent only, but did not change glomerular and tubulointerstitial degeneration. These effects of ramipril were associated with a dose-dependent inhibition of plasma and renal tissue ACE activities as well as lower serum concentrations of creatinine, but there were no changes in serum potassium. CONCLUSIONS: Life-long HRA-induced ACE inhibition protects against hypertension-induced renal damages in SHR-SP. This is associated with a doubling of the lifespan in these animals.     

The placement of central venous catheters in infants with cardiac shunts: safety measures and false alarms

We report a case of RVT, diagnosed at 34 weeks' gestation in a case of fetal distress occurring four days after an acute maternal gastroenteritis. The typical ultrasonic pattern included renal enlargement, with parenchymal hyperechogenicity and venous echoic streaks, loss of the cortico-medullary boundary and lack of definition of renal sinus echoes. Color Doppler velocimetry confirmed the absence of venous flow with an increased vascular resistance in the renal artery. After delivery by an emergency caesarean section the infant had a full anatomical and functional recovery of his affected kidney at the seventh day of life.     

A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR)

BACKGROUND: The tissue renin-angiotensin system (RAS) may modulate the structural and functional changes that occur in the diabetic kidney. METHODS: Hypertensive transgenic (mREN-2)27 rat (TGR) that exhibit increased tissue renin expression were administered streptozotocin (STZ, diabetic) or citrate buffer (non-diabetic) at six weeks of age, and sacrificed 4 and 12 weeks later. Further groups were treated for 12 weeks post-STZ or vehicle with the angiotensin converting enzyme inhibitor, perindopril. Comparisons were made with 18-week-old non-diabetic and diabetic spontaneously hypertensive rats (SHR). RESULTS: In diabetic TGR, the most florid lesion was seen after 12 weeks of STZ, with kidneys exhibiting vacuolated tubules, hylanized arterioles, medullary fibrosis and necrosis and severe glomerulosclerosis. In contrast, only mild glomerulosclerosis was seen in non-diabetic TGR and diabetic SHR. Glomerular filtration rate was increased after four weeks of diabetes in TGR and 12 weeks of diabetes in SHR, but declined by greater than 50% after 12 weeks of diabetes in TGR. In both TGR and SHR, diabetes increased albuminuria but did not modify systolic blood pressure. Renal renin content increased progressively in diabetic TGR, and this was associated with increased renin immunolabeling in the juxtaglomerular apparatus (JGA) and the appearance of renin in proximal convoluted tubules. In contrast, renal renin content and JGA renin immunolabeling were unchanged in diabetic SHR. Perindopril attenuated renal pathology, improved renal function and abolished proximal tubular renin immunolabeling in diabetic TGR. CONCLUSIONS: This is the first report of a diabetic rodent model developing rapid onset renal impairment. Furthermore, this study suggests a role for an activated renal RAS in the acceleration of diabetic renal disease and confirms the benefit of drugs that inhibit this system.     

ACE inhibitors and proteinuria

This review discusses the clinical consequences of urinary protein loss and the effects of inhibitors of the angiotensin converting enzyme (ACE) on this clinical finding. Proteinuria appears to be an important risk factor for renal function deterioration and for cardiovascular mortality. ACE inhibitors have been shown to reduce proteinuria more effectively than other antihypertensives. Their antiproteinuric effect seems to be independent of the underlying renal disease, and is mediated by a specific, not yet fully elucidated mechanism. Urinary protein loss related phenomena, such as hypoalbuminemia and aberrant lipoprotein profile, tend to improve also during ACE inhibitor treatment. Furthermore, ACE inhibition has been shown to prevent the renal function deterioration that is frequently observed in patients with renal disease. Interestingly, it has recently been shown that in proteinuric patients with renal disease the initial proteinuria lowering response to ACE inhibition predicts long-term renal function outcome during this treatment the more proteinuna is lowered during the first months, the better renal function will be preserved over the following years. Because of these favorable effects ACE inhibitors have become a widely used class of agents in nephrology. They are not only prescribed for lowering blood pressure in the hypertensive renal patient, but also as symptomatic treatment of patients with proteinuria, and to prevent renal function loss in patients with both diabetic and non-diabetic renal disease.     

Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension

OBJECTIVE: Nitric oxide is a vasodilating and blood pressure lowering substance. To investigate whether calcium antagonists or angiotensin-converting enzyme (ACE) inhibitors increase vascular nitric oxide activity, we assessed systemic and renal vascular sensitivity to nitric oxide synthase inhibition in hypertensives on and off medication. METHODS: Ten essential hypertensive patients, aged 22-51 years, were studied 3 times: > or = 4 weeks off medication, after 3 weeks treatment with enalapril 20 mg twice a day and after 3 weeks nifedipine 60 mg/day. Each time, 24-h blood pressure registration was performed, followed by a clearance study to obtain a 3-h dose-response curve for intravenously infused NG-monomethyl-L-arginine (L-NMMA, respectively 0.75, 1.5 and 3.0 mg/kg/h). RESULTS: L-NMMA dose-dependently increased mean arterial pressure with 5 +/- 2 mmHg and systemic vascular resistance with 24 +/- 5% at maximum dose, whereas cardiac output decreased (all P < 0.001). Enalapril and nifedipine treatment decreased blood pressure, while the L-NMMA-induced increase in systemic vascular resistance was potentiated (enalapril: 45 +/- 7% and nifedipine: 46 +/- 8%; both P < 0.01). L-NMMA also dose-dependently decreased renal blood flow by 58 +/- 8% at maximum dose (P < 0.001), but neither drug potentiated these effects. CONCLUSION: These results indicate that, in essential hypertensives, antihypertensive therapy with enalapril or nifedipine increases nitric oxide dependency of systemic vascular tone, which may play a role in the blood pressure lowering effect of these drugs. However, this phenomenon cannot be observed in the renal circulation, suggesting a different regulation of endothelium-dependent vasomotion in the hypertensive kidney.     

Inhibition of angiotensin converting enzyme from sheep tissues by captopril, lisinopril and enalapril

Inhibition of angiotensin converting enzyme(EC 3.4,15.1, ACE) in presence of captopril, lisinopril and enalapril were investigated in kidney, lung and serum of sheep using Hip-His-Leu(HHL) as substrate. The activity in kidney, lung and serum was inhibited at HHL concentration above 5 mM. The inhibitory constants (IC50) ranged between 5.6 nM for serum ACE with lisinopril and 70000 nM for renal ACE with enalapril while Ki ranged from 1.0 nM for serum ACE with lisinopril to 12000 nM for kidney ACE with enalapril. Differences in inhibition observed in different tissues suggest that the inhibitors may block function(s) of ACE to varying degrees in each tissue.     

Trandolapril's protective effects in stroke-prone spontaneously hypertensive rats persist long after treatment withdrawal

The effects of long-term oral administration of the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.01 mg/kg [T0.01] and 1 mg/kg [T1]) on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats during the treatment period (5-20 weeks of age) and up to 8 weeks thereafter. During the treatment period T1, but not T0.01, limited the increase in blood pressure. However, both doses of trandolapril prevented stroke and mortality and strongly opposed (T0.01) or abolished (T1) the increases in saline intake, diuresis, and proteinuria observed in control animals. Simultaneously, trandolapril markedly prevented (T0.01) or abolished (T1) vascular fibrinoid necrosis formation in the brain, kidney, and heart. Finally, trandolapril dose-dependently reduced arterial thickening and glomerular and tubulointerstitial lesions in the kidney, as well as arterial thickening, infarction, and fibrosis in the myocardium. At 8 weeks after treatment withdrawal, the antihypertensive effect of T1 had disappeared, but stroke-related mortality and fibrinoid necrosis remained completely suppressed. Further, no additional cerebral, renal, or cardiac lesions developed, and no increase in proteinuria occurred. In the T0.01 group, 17% of the animals died, fibrinoid necrosis tended to develop, organ lesions worsened, and proteinuria strongly increased. We conclude that (1) early ACE inhibition with trandolapril affords a long-lasting protection versus stroke and mortality both during and after the treatment period; and (2) that this beneficial effect is due to the suppression of fibrinoid necrosis formation and not to the drug's antihypertensive action. In contrast, both properties appear to contribute to trandolapril's renal and cardiac protective effects.     

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice

Angiotensin-converting enzyme (ACE) generates the vasoconstrictor angiotensin II, which plays a critical role in maintenance of blood pressure in mammals. Although significant ACE activity is found in plasma, the majority of the enzyme is bound to tissues such as the vascular endothelium. We used targeted homologous recombination to create mice expressing a form of ACE that lacks the COOH-terminal half of the molecule. This modified ACE protein is catalytically active but entirely secreted from cells. Mice that express only this modified ACE have significant plasma ACE activity but no tissue-bound enzyme. These animals have low blood pressure, renal vascular thickening, and a urine concentrating defect. The phenotype is very similar to that of completely ACE-deficient mice previously reported, except that the renal pathology is less severe. These studies strongly support the concept that the tissue-bound ACE is essential to the control of blood pressure and the structure and function of the kidney.