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

Abstract

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...

Sympathetic Nerve Activity Is Inappropriately Increased in Chronic Renal Disease

“…Indeed, the patients of this study had increased PRA. Previously, we demonstrated that an ACE inhibitor and an angiotensin II receptor antagonist reduce sympathetic overactivity, strongly suggesting that angiotensin II importantly contributes in the pathogenesis of the sympathetic hyperactivity (5,23).…”

Sympathetic Overdrive and Cardiovascular Risk in the Metabolic Syndrome

“…They include, for example, angiotensin II, which 1) enhances neuroadrenergic cardiovascular drive through stimulation of receptors located within the hypothalamus (paraventricular nucleus) (38), 2) interacts with the nitric oxide system to potentiate sympathetic function (38, 39) and 3) affects norepinephrine turnover at the level of peripheral nerve endings (40). This hypothesis appears to be confirmed also in humans by the evidence that in obese hypertensive patients, patients with renal insufficiency, or patients with left ventricular failure (i.e., in conditions characterized by a marked sympathetic and reninangiotensin activation), administration of angiotensin II receptor blockers results in a clearcut sympathoinhibition (41)(42)(43). A further hormonal substance is leptin, which acts at the level of the hypothalamus to increase blood pressure via its central sympathoexcitatory effects (44,45).…”

Persistent Sympathetic Activation During Chronic Antihypertensive Therapy

“…A recent study showed that the combination of losartan and hydrochlorothiazide provided greater reductions in clinic and ambulatory BP than hydrochlorothiazide or losartan monotherapy. 13 It was reported recently that losartan decreased MSNA in hypertensive patients with chronic renal failure, 14 whereas administration of hydrochlorothiazide alone for 12 weeks did not affect MSNA in obese hypertensive individuals. 11 We thereby reasoned that administration of Hyzaar may decrease MSNA in hypertensive patients, which would suggest resetting of sympathetic baroreflex function associated with control of BP.…”