Reduction of Sympathetic Hyperactivity by Enalapril in Patients with Chronic Renal Failure

Ligtenberg, Gerry; Blankestijn, Peter J.; Oey, P. L.; Klein, Inge H H T; Dijkhorst-Oei, Lioe-Ting; Boomsma, Frans; Wieneke, G.H.; Huffelen, Alexander C. van; Koomans, Hein A.

doi:10.1056/nejm199904293401704

Cited by 392 publications

(289 citation statements)

References 30 publications

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“…The role of the sympathetic nervous system is less clear. Our data show that in these patients the MSNA is often increased as well, confirming the limited available data on this issue in CRF patients (3,17). As a consequence of these findings, the logical treatment of these patients should be aimed at normalization of the fluid status and of the renin and sympathetic overactivity.…”

Section: Discussionsupporting

confidence: 87%

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Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure

Klein¹,

Ligtenberg²,

Oey³

et al. 2003

Journal of the American Society of Nephrology

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137

129

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Abstract. The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46 Ϯ 17 ml/min per 1.73 m 2 ), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33 Ϯ 10 to 27 Ϯ 13 and 27 Ϯ 13 bursts/min, respectively; P Ͻ 0.05) and average 24-h BP (from 141 Ϯ 8/93 Ϯ 8 to 124 Ϯ 9/79 Ϯ 8 and 127 Ϯ 8/81 Ϯ 9 mmHg; P Ͻ 0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (r ϭ 0.70 and r ϭ 0.63, respectively; both P Ͻ 0.05). Baroreceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients.Sympathetic hyperactivity in chronic renal failure (CRF) is caused by mechanisms arising in the failing kidneys (1). The renin system is often activated in hypertensive patients with CRF. There is clear evidence that high circulating angiotensin II (AngII) levels can stimulate central sympathetic outflow by a direct effect on the vasomotor center in the brain stem, which in humans can be quantified as increased muscle sympathetic nerve activity (MSNA) (2). We showed that MSNA is increased in patients with CRF and that this hyperactivity was reduced by chronic angiotensin-converting enzyme (ACE) inhibition (3). These findings support the idea that AngII is involved in the pathogenesis of the sympathetic hyperactivity. However, ACE inhibition did not completely normalize the MSNA in these patients. There is increasing evidence that sympathetic hyperactivity contributes to the cardiovascular risk profile, not only by its effect on BP, but also independent of this effect (4).The hypothesis in the present study was that AngII receptor blockade in an equally effective antihypertensive regimen more effectively reduces the sympathetic hyperactivity than ACE inhibition. AngII receptor blockers are well accepted as antihypertensive agents in patients with CRF (5-7). Their BP lowering effect is comparable to that of ACE inhibitors (7,8). However, although both classes of drugs primarily interf...

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Section: Discussionsupporting

confidence: 87%

“…Few studies have evaluated the effect of ACE inhibitors on MSNA. In essential hypertension, there was no effect (18), but MSNA was reduced when both renin and sympathetic activity were activated, such as in CRF or heart failure (3,19). The present study shows that an AngII receptor blocker also reduces MSNA in CRF patients.…”

Section: Discussionmentioning

confidence: 54%

Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure

Klein¹,

Ligtenberg²,

Oey³

et al. 2003

Journal of the American Society of Nephrology

Self Cite

137

129

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show abstract

“…Also, norepinephrine levels were higher in the patients with chronic renal insufficiency and norepinephrine levels were inversely correlated with renal function. Fromthese results, sympathetic activity was found to be a contributor to hypertension in chronic renal insufficiency as Ligtenberg et al recently confirmed (34). Similar findings were also reported by Baumgart et al (32), who demonstrated significantly lower differences in blood pressure between the awake and sleeping time in patients with chronic renal insufficiency compared to control subjects.…”

Section: Aggressive Blood Pressure Reduction In Patients With Chronicsupporting

confidence: 81%

“…These two variables of blood pressure give us valuable information on the highest levels of blood pressure and on the presence or absence of the morning surge. the study of Ligtenberg et al (34), enalapril controls hypertension and decreases sympathetic hyperactivity in patients with chronic renal insufficiency. In their study, they confirmed these effects in a short period.…”

Section: Aggressive Blood Pressure Reduction In Patients With Chronicmentioning

confidence: 95%

Treatment of Hypertension in Chronic Renal Insufficiency.

Suzuki

2000

Intern. Med.

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Hypertensionis the most common complication of chronic renal insufficiency (CRI) and it accelerates the rate of progression of most forms of CRI. Several large clinical trials have clearly demonstrated the efficacy of antihypertensive treatment for prevention of progression of renal failure. Angiotensin-converting enzyme (ACE) inhibitors may have therapeutic advantages. However, large scale trials include a variety of chronic renal diseases, and the origins of renal diseases are quite diverse. Moreover, the differences in sex, age, race have not been considered. Based on these trials, it was concluded that blood pressure control is the most effective meansfor the prevention of deterioration of renal dysfunction. Consistent with this view, our recent preliminary data provide evidence that aggressive blood pressure control using self-reported blood pressure values measured by a home blood pressure device is promising to arrest the progression of renal failure in Japanese patients with CRI.

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“…An influence of sympathetic drive as an underlying pathophysiological mechanism 21 is suggested by the positive association between heart rate at baseline and new-onset diabetes mellitus observed in both treatment arms and which was statistically significant in the valsartan group. The known increased sympathetic effect of amlodipine, 22 that is, treatment-heart rate interaction may contribute to the diminished effect of heart rate as a predictor in the patients treated with amlodipine (model 4).…”

Section: Discussionmentioning

confidence: 99%

Predictors of new-onset diabetes mellitus in hypertensive patients: the VALUE trial

et al. 2008

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Diabetes mellitus often develops in patients with hypertension. We investigated predictors of diabetes mellitus development in hypertensives at risk of developing the disease in the VALUE trial population. Among the 9995 non-diabetic hypertensive patients at baseline, 1298 patients developed diabetes mellitus during the average follow-up of 4.2 years. New-onset diabetes mellitus was defined from adverse event reports, information about new antidiabetic medication and/or a fasting glucose X7.0 mmol l À1 at the end of trial. Twentyfive potential baseline predictors of new-onset diabetes mellitus were analysed by univariate logistic regression and 14 of 25 predictors were found to be statistically significant with a P-value o0.05. The predictors were in order of decreasing significance; glucose, body mass index (BMI), age, uric acid, non-Caucasian race, haemoglobin, heart rate, randomized study treatment, history of coronary heart disease (CHD), gender, total cholesterol, proteinuria, potassium and creatinine. Multivariate stepwise logistic regression analyses were used and potential baseline predictors of new-onset diabetes mellitus were considered significant by four different models (P-value o0.001). The final multivariate model selected included all patients, but not treatment group as a potential predictor, and the six significant predictors identified from this model were glucose, BMI, non-Caucasian race, age, heart rate and history of CHD. In conclusion, glucose and BMI were the most important predictors of new-onset diabetes mellitus in hypertensive patients at high cardiovascular risk, and easily accessible clinical characteristics strongly predict patients at risk of developing diabetes mellitus.

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Reduction of Sympathetic Hyperactivity by Enalapril in Patients with Chronic Renal Failure

Abstract: Increased sympathetic activity contributes to hypertension in patients with chronic renal disease. ACE inhibition controls hypertension and decreases sympathetic hyperactivity.

Cited by 392 publications

References 30 publications

Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure

Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure

Treatment of Hypertension in Chronic Renal Insufficiency.

Predictors of new-onset diabetes mellitus in hypertensive patients: the VALUE trial

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