Short and long term effects of antihypertensive therapy in the diabetic rat

Abstract

To compare the impact of differing antihypertensive regimens on the development of renal injury, studies were performed in three groups of moderately hyperglycemic diabetic rats, and one group of non-diabetic control (C) rats. One diabetic group (DM) received no therapy except insulin. The remaining diabetic groups received insulin and either the angiotensin I converting enzyme inhibitor captopril (CAP), or triple therapy (TRX) with reserpine, hydralazine and hydrochlorothiazide. CAP and TRX modestly and comparably lowered blood pressure. At 6 to 10 weeks, DM rats exhibited elevation of the single nephron glomerular filtration rate (SNGFR), due to elevations of the glomerular capillary plasma flow rate (QA) and the glomerular capillary hydraulic pressure (PGC). In both DM/CAP and DM/TRX rats, blood pressure reduction was associated with selective normalization of PGC, without change in SNGFR or QA. In long-term (70 weeks) studies, DM rats exhibited progressive albuminuria and marked glomerular sclerosis. CAP limited albuminuria and injury to values even lower than those in C rats, whereas TRX served only to delay, but not to prevent, the increase in albuminuria. TRX reduced glomerular sclerosis, but was less effective than CAP. At 70 weeks, CAP and TRX still reduced systemic blood pressure; PGC remained at normal levels with CAP but was no longer controlled with TRX. These results confirm the clinical observation that antihypertensive therapy slows diabetic glomerulopathy, but also suggest that CAP affords superior long-term protection as compared to the other antihypertensive drug regimen studied.

Glomerular hypertension as one cause of albuminuria in Type II diabetic patients

“…Results with inhibitors of ACE have, however, suggested that glomerular hypertension rather than glomerular hyperfiltration in itself accounts for most of the increased proteinuria and the progress of nephropathy in such rats [9,25]. It has been shown that inhibition of ACE prevents the progress of diabetic glomerulopathy in normotensive diabetic rats when such inhibition causes PGC to become normal and remain there without change in the raised GFR [9].…”

Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment

“…Treatment which successfully has reduced the progression in diabetic kidney disease both experimentally [8,9,25] and in clinical trials [12,13,16,17,26] has always been associated with a reduction in proteinuria during the intervention period. The association between albuminuria and progression of diabetic nephropathy, suggests that measurements of the initial antiproteinuric effect may provide a tool for rapid screening of the potential renoprotective effect of new drugs and non-pharmacological treatment regimens.…”

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

“…Other studies have shown the renoprotective effects of RAS inhibition in experimental diabetes [4], and these effects have been confirmed using both angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor antagonists in models of hypertensive and normotensive diabetic nephropathy [5,6,7,8]. However, blockade of the RAS alone, both experimentally and clinically, only retards but does not prevent or reverse diabetic nephropathy [6,9]. Furthermore, it has been postulated that the effects of blockade of the RAS could be limited by the salt and water retention often found in experimental and clinical diabetes [10,11].…”