Salt blocks the renal benefits of ramipril in diabetic hypertensive rats.

Abstract

To establish if the benefit of angiotensin converting enzyme inhibitor therapy in retarding progressive diabetic renal injury is due to a specific intrarenal effect or the systemic hypotensive effect, we studied the effect of long-term ramipril treatment on blood pressure, glomerular filtration rate, and urinary protein excretion in streptozotocin-diabetic spontaneously hypertensive rats. The hypotensive effect of ramipril was prevented by a high salt diet, which did not alter the degree of renal angiotensin converting enzyme inhibition. Three weeks after uninephrectomy and induction of diabetes, rats were allocated to three groups. Groups 1 and 2 were given 1% NaCl, whereas group 3 was given water as drinking solution. One week later, groups 2 and 3 received 0.4 mg/kg/day ramipril in their drinking solution, which was continued over a 2-month period. Ramipril produced a blood pressure fall only in water-drinking rats (group 3) despite a similar reduction in plasma and renal angiotensin converting enzyme activity in groups 2 and 3. Salt-loaded rats had a progressive increase in urinary protein excretion over the duration of study. Ramipril treatment prevented an increase in protein excretion only in animals given water and with a reduced systolic blood pressure. Glomerular nitration rate was similar in all three groups. Ramipril treatment improved animal survival independently of a reduction in blood pressure or an effect on proteinuria. Although it is possible that angiotensin converting enzyme inhibitors have specific intrarenal effects reducing progression of diabetic proteinuria, concomitant control of systemic blood pressure appears to be necessary to demonstrate a benefit. (Hypertension 1991;17:497-503) U ncontrolled systemic hypertension is a wellknown cause of progressive renal injury in both humans and experimental animals. 1Hypertension is commonly associated with diabetic renal disease,'-3 and it has been shown to accelerate the rate of development of diabetic nephropathy both in humans 4 and in streptozotocin-diabetic rats. 13 or in other renal disorders. 1415 However, it is difficult to determine from these studies if the beneficial effect of ACE Received February 9, 1990; accepted in revised form November 29, 1990. inhibitors was due to a specific intrarenal effect of ACE inhibition or due to their systemic hypotensive effect.To evaluate this question further, we examined the effect of long-term administration of the ACE inhibitor ramipril on blood pressure, glomerular filtration rate, and proteinuria in streptozotocin diabetic uninephrectomized spontaneously hypertensive rats (SHR). To prevent the hypotensive effect of ACE inhibition, the rats were maintained on a high salt diet, which is known to oppose the blood pressurelowering action of ACE inhibitors. -17 Methods Study Protocol

Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus

“…4,5 Salt retention often found in diabetic patients not only attenuates the antihypertensive efficacy of ACE inhibition but may also interfere with the cardiac and renoprotective actions of ACE inhibitors. 39 This study has suggested an additional blood pressure-lowering effect of dual NEP/ACE inhibition in SHR with streptozotocin-induced diabetes and may therefore have an important bearing on treatment of hypertension in diabetic patients. However, one must be cautious in extrapolating the present findings in rodents to humans.…”

Combination treatment of enalapril with nitrendipine in rats with renovascular hypertension.

“…1 Clinical studies suggest that the combination of CCB and CEI may be superior in decreasing proteinuria compared with the respective monotherapy. 2 Despite the evidence for a beneficial effect of this combination on blood pressure 37 and proteinuria 2 in hypertensive patients, there are no data as to the effect of CCB plus randomly divided into seven groups: (1) untreated hypertensive rats (HC, n=18), (2) untreated normotensive rats (NC, n=10), (3) rats treated with enalapril (100 mg/L drinking water, n=9; Merck Sharp & Dohme, Munich, Germany), (4) rats treated with nitrendipine (1 mg/g diet, n=12; Bayer, Leverkusen, Germany), (5) rats treated with enalapril and nitrendipine (ENP+NIT) (same dosage as in monotherapy, n=12), (6) rats treated with enalapril and hydrochlorothiazide (ENP+HCTZ) (enalapril same dosage as in monotherapy; hydrochlorothiazide, 50 mg/L drinking water, n=12; Sigma, Deisenhofen, Germany), and (7) 7 days withdrawal of nitrendipine after 6 weeks therapy with nitrendipine (PNIT, n=9).…”

Sodium Intake, ACE Inhibition, and Progression to ESRD

“…1-3, 6 The efficacy of treatment, however, is heterogeneous and dependent on inborn 7 and environmental [8][9][10][11][12] factors. Data in experimental diabetes, 13,14 adriamycin nephrosis, 15 uninephrectomized rats, or in Munich Wistar rats with spontaneously reduced nephron numbers 16 uniformly show that expansion of the sodium pool, with glomerular hyperfiltration and activation of the renal RAS induced by enhanced sodium intake, all contribute to blunt the BP and proteinuria lowering effect of RAS inhibitors. 17 Consistently, observational studies in humans showed that increased dietary sodium intake increases proteinuria and accelerates renal disease progression.…”