Objective-To determine whether inhibition of angiotensin converting enzyme can reduce the rate of decline in kidney function more than reducing blood pressure with other antihypertensive treatment.Design-Prospective, open randomised study lasting a mean of 2*2 years in patients with diabetic nephropathy.Setting-Three outpatient nephrology clinics.Patients-40 patients with insulin dependent diabetes and diabetic nephropathy with reduced renal function.Intervention-Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide.Main outcome measure-Rate of decline in glomerular filtration rate measured as chromium-51 edetic acid clearance.Results-Glomerular filtration rate declined a mean of 2-0 (SD 3.2) ml/min/year in the group given enalapril and 5-6 (5.9) ml/min/year in the control group. The mean arterial blood pressure during the study was 102 (5) mm Hg in the patients given enalapril and 103 (5) mm Hg in the patients given metoprolol. Urinary albumin excretion during treatment with enalapril was 60% lower than during treatment with metoprolol.

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Objective-To assess whether angiotensin converting enzyme inhibition reduces proteinuria in diabetic nephropathy more than blood pressure reduction with other antihypertensive treatment.Design-Prospective, open randomised study lasting eight weeks in patients with diabetic nephropathy.Setting-Outpatient nephrology clinics.Patients-40 Patients with type I diabetes and diabetic nephropathy with reduced renal function.Intervention-Antihypertensive treatment with enalapril or metoprolol, usually combined with frusemide.Main outcome measures-Arterial blood pressure and urinary excretion of albumin and protein.Results-Arterial blood pressure after eight weeks was 135/82 (SD 13/7) mm Hg in the group given enalapril and 136/86 (16/12) mm Hg in the group given metoprolol. Proteinuria and albuminuria were similar in both groups before randomisation. After eight weeks' treatment, the geometric mean albumin excretion was 0-7 (95% confidence interval 0 5 to 1-2) g/24 h in the patients given enalapril and 1-6 (1-1 to 2 5) g/24 h in the patients given metoprolol (p<002). The proteinuria was 1-1 (0.7 to 1.7) and 2-4 (1-6 to 3.6) g/24 h respectively (p<002).Conclusions-Antihypertensive treatment with enalapril reduced proteinuria in patients with diabetic nephropathy more than an equally effective antihypertensive treatment with metoprolol. This points to a specific antiproteinuric effect of the angiotensin converting enzyme inhibitor independent ofthe effect on systemic blood pressure.

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Using OKT3 monoclonal antibody driven T-lymphocyte proliferation, we investigated the effects of plasma 10, 20 and 30% in cell cultures on the proliferation ex vivo after exposure to captopril or enalapril taken orally by healthy volunteers. We also studied the effects of captopril, angiotensin II and bradykinin in vitro. We observed a plasma dependent dual effect of ACE inhibition both ex vivo and in vitro and of bradykinin in vitro being a stimulated proliferation at low (10% plasma) and a suppression of proliferation at high (30% plasma). The suppression was shown to be PGE2 mediated but the nature of the stimulatory signal is unknown. Proliferation was also suppressed by angiotensin II mediated by PGE2, but angiotensin II had no stimulatory effect. The results indicate that the effects of ACE inhibition on OKT3 mAb driven T-lymphocyte proliferation is plasma dependent, class specific for ACE inhibitors and mediated by both the ACE inhibitor itself and by bradykinin. Furthermore, it was shown that indomethacin in combination with an ACE inhibitor or bradykinin converted a suppressive response into proliferation indicating an immunostimulatory activity by indomethacin.