The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events

Effect of antihypertensive treatment on progression of renal insufficiency in non-diabetics patients. (Espiral trial)

A three year randomized, multicenter, prospective, open trial, will be developed with the aim of studying the influence of antihypertensive therapy on chronic renal failure progression in non-diabetics patients. The study will compare the effects of an angiotensin converting enzyme inhibitor, fosinopril, with a slow release calcium antagonist, nifedipine slow release. Two hundred and fifty patients, with progressively fallug renal function, shom by an increase of serum creatinine (SCr) of at least 25 % in the 2 years preceding entry to the study, and SCr levels between 1.5 and 4.0 mg/dl, will be included. The primary end point of the trial will be the rate of change of SCr (mg/dl/month) and of the reciprocal of serum creatinine concentration (1/SCr) over time. The secondary end point will be the percentage of patients with a doubling of SCr, progreswith to dialytic therapy, or deah during the study. Patients with nephrotic syndrome (serum albumin concentration < 3 g %), systemic disease (including diabetes), severe cardiac or hepatic dysfunction, malignant or renovascular hypertension, obstructive nephropathy, initial serum potassium concentration > 5.8 mmol/l and initial serum total cholesterol level ³ 270 mg/dl, will be excluded. After a «wash out» period of four weeks, patients with arterial blood pressure ³ 140/90 will be assigned either to fosinopril (10-30 mg/day) or nifedipine slow release (30-60 mg/day). In case of insufficient blood pressure control, furosemide (20- 100 mg/d) will be added as a first step and then atenolol (25-100 mg/d) and/or doxazosine (1-12 mg/d) in order to maintain arterial blood pressure control under 140/90. All patients will receive a diet with 4-5 g/day salt content and a protein content of 0.8-1 g/kg body weight. At the begining of the study, at 2, 4 and 8 weeks, and every 4 months, the following parameters will be measured: supine blood pressure after 5 minutes rest, body weight, SCr, 1/SCr, serum albumin, electrolytes and lipid pattern; urinary protein and urea concentrations and creatinine clearange. The relation between the progression chronic renal failure and ambulatory blood presure during 24 hours will be studied in some patients

Effect of antihypertensive treatment on progression of renal insufficiency in non-diabetics patients. (Espiral trial)

A three year randomized, multicenter, prospective, open trial, will be developed with the aim of studying the influence of antihypertensive therapy on chronic renal failure progression in non-diabetics patients. The study will compare the effects of an angiotensin converting enzyme inhibitor, fosinopril, with a slow release calcium antagonist, nifedipine slow release. Two hundred and fifty patients, with progressively fallug renal function, shom by an increase of serum creatinine (SCr) of at least 25 % in the 2 years preceding entry to the study, and SCr levels between 1.5 and 4.0 mg/dl, will be included. The primary end point of the trial will be the rate of change of SCr (mg/dl/month) and of the reciprocal of serum creatinine concentration (1/SCr) over time. The secondary end point will be the percentage of patients with a doubling of SCr, progreswith to dialytic therapy, or deah during the study. Patients with nephrotic syndrome (serum albumin concentration < 3 g %), systemic disease (including diabetes), severe cardiac or hepatic dysfunction, malignant or renovascular hypertension, obstructive nephropathy, initial serum potassium concentration > 5.8 mmol/l and initial serum total cholesterol level ³ 270 mg/dl, will be excluded. After a «wash out» period of four weeks, patients with arterial blood pressure ³ 140/90 will be assigned either to fosinopril (10-30 mg/day) or nifedipine slow release (30-60 mg/day). In case of insufficient blood pressure control, furosemide (20- 100 mg/d) will be added as a first step and then atenolol (25-100 mg/d) and/or doxazosine (1-12 mg/d) in order to maintain arterial blood pressure control under 140/90. All patients will receive a diet with 4-5 g/day salt content and a protein content of 0.8-1 g/kg body weight. At the begining of the study, at 2, 4 and 8 weeks, and every 4 months, the following parameters will be measured: supine blood pressure after 5 minutes rest, body weight, SCr, 1/SCr, serum albumin, electrolytes and lipid pattern; urinary protein and urea concentrations and creatinine clearange. The relation between the progression chronic renal failure and ambulatory blood presure during 24 hours will be studied in some patients

A random comparison of fosinopril and nifedipine GITS in patients with primary renal disease

OBJECTIVE: To investigate in a random comparison the capacity of an angiotensin converting enzyme inhibitor (fosinopril), and that of a long-acting dihydropiridine (nifedipine GITS) to modify the decay in renal function in patients with primary renal disease, exhibiting a progressive increase in serum creatinine during the previous 2 years. METHODS: A randomized, open-label, multicenter study with a minimum follow-up of 3 years. A total of 241 patients were included in the study. All of them were hypertensive and had a 25% or at least 0.5 mg/dl increase in the value of serum creatinine during the 24 months prior to entering the study. Initial doses of fosinopril and nifedipine GITS were 10 and 30 mg respectively, and titration to 30 and 60 mg was performed if needed to obtain the expected blood pressure goal (< 140/90 mmHg). Furosemide, atenolol, and doxazosin were added as second, third, and fourth drugs if necessary, for blood pressure control. The primary end-point of the study was the appearance of double the serum creatinine values and/or the need to enter a dialysis programme. Secondary end-points were cardiovascular events, death, changes in 24 h proteinuria, and the evolution of serum creatinine. Data reflect the analysis performed by intention to treat. RESULTS: Mean age of the group was 54 +/- 14, and 59% were males. Primary glomerulonephritis (31%), nephrosclerosis (26%) and polycystic kidney disease (19%) were the three most frequent diagnostic findings. After 3 years of follow-up, 21% (27/127) of patients treated with fosinopril, and 36% (40/112) of those receiving nifedipine GITS presented a primary end-point, (OR 0.47, 95% confidence intervals 0.26-0.84, P = 0.01). Renal survival was significantly better when fosinopril constituted the first step therapy (P = 0.002). These results did not seem to be influenced by the type of primary renal disease. Proteinuria decreased at the end of the study by a mean of 57% in the fosinopril group and increased by 7% in the group receiving dihydropiridine. Blood pressure control did not differ among groups for diastolic values. During follow-up, however, the patients receiving ACEi showed systolic blood pressure values 4-6 mmHg lower. CONCLUSION: In patients with chronic renal failure and hypertension due to primary renal disease, fosinopril significantly differed from nifedipine GITS by its capacity to slow the progressive decay in renal function. The drugs also differed by their capacity to lower blood pressure. The better control, in particular of systolic blood pressure, in the fosinopril arm could have contributed in a relevant manner to the attainment of a better outcome when the ACEi was employed

Pathophysiologic and therapeutic importance of tissue ACE: a consensus report

Angiotensin-converting enzyme (ACE) activation and the de novo production of angiotensin II contribute to cardiovascular disease through direct pathological tissue effects, including vascular remodeling and inflammation, as well as indirect action on nitric oxide bioavailability and its consequences. The endothelium plays a pivotal role in both vascular function and structure; thus, the predominant localization of ACE to the endothelium has implications for the pathobiology of vascular disease, such as coronary artery disease. Numerous experimental studies and clinical trials support the emerging realization that tissue ACE is a vital therapeutic target, and that its inhibition may restore endothelial function or prevent endothelial dysfunction. These effects exceed those attributable to blood pressure reduction alone; hence, ACE inhibitors may exert an important part of their effects through direct tissue action. Pharmacologic studies show that while ACE inhibitors may differ according to their binding affinity for tissue ACE the clinical significance remains to be determined

Pathophysiologic and therapeutic importance of tissue ACE: a consensus report

Angiotensin-converting enzyme (ACE) activation and the de novo production of angiotensin II contribute to cardiovascular disease through direct pathological tissue effects, including vascular remodeling and inflammation, as well as indirect action on nitric oxide bioavailability and its consequences. The endothelium plays a pivotal role in both vascular function and structure; thus, the predominant localization of ACE to the endothelium has implications for the pathobiology of vascular disease, such as coronary artery disease. Numerous experimental studies and clinical trials support the emerging realization that tissue ACE is a vital therapeutic target, and that its inhibition may restore endothelial function or prevent endothelial dysfunction. These effects exceed those attributable to blood pressure reduction alone; hence, ACE inhibitors may exert an important part of their effects through direct tissue action. Pharmacologic studies show that while ACE inhibitors may differ according to their binding affinity for tissue ACE the clinical significance remains to be determined