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Original Article Journal of Human Hypertension (2003) 17, 487–493 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Nitrendipine and amlodipine mimic the acute effects of enalapril on renal haemodynamics and reduce glomerular hyperfiltration in patients with chronic kidney disease LF Morrone, A Ramunni, E Fassianos, A Saracino, P Coratelli and G Passavanti Section of Nephrology, Department of Internal Medicine and Public Medicine, University of Bari, Polyclinic, Piazza G. Cesare, Bari, Italy Antihypertensive drugs may have an important effect on and NIT test dose reduced FF, as did ENA, but not NIF, glomerular haemodynamics. In chronic nephropathy in both baseline (AML: P ¼ 0.005; NIT: P ¼ 0.02; ENA: patients, we compared the effect on glomerular haemo- P ¼ 0.007) and glomerular hyperfiltration conditions dynamics of two second-generation dihydropyridinic (AML: P ¼ 0.0003; NIT: P ¼ 0.03; ENA: P ¼ 0.00006). In agents, nitrendipine and amlodipine, with a first genera- baseline conditions, only ENA resulted in a significant tion dihydropyridinic agent and an ACE-inhibitor, en- drop in the GFR (P ¼ 0.008), while NIF, NIT and AML alapril. In all, 32 patients (pts), divided into four groups, induced a significant increase (P ¼ 0.003, 0.03, 0.0001, received the different drugs: ENA (enalapril, eight pts), respectively). However, in hyperfiltration conditions, NIT NIF (nifedipine, eight pts), NIT (nitrendipine, eight pts) (0.08) and AML (0.00003) caused a decrease in the GFR, AML (amlodipine, eight pts). The study assessed the as did ENA (0.0003) but not NIF. In all the experimental effect on glomerular haemodynamics of a single admin- conditions, a RVR reduction and an ERPF increase were istration of the test drug in baseline conditions and in observed. Single dose of NIT and AML were effective in glomerular hyperfiltration experimentally induced by attenuating the effect of amino-acid infusion on glomer- amino-acid infusion. The glomerular filtration rate ular filtration, similar to ENA; this effect of NIT and AML (GFR, measured by inulin clearance), effective renal on the glomerular filtration rate is not observed under plasma flow (ERPF, measured by p-aminohippurate basal conditions. clearance), renal vascular resistances (RVR) and filtra- Journal of Human Hypertension (2003) 17, 487–493. tion fraction (FF) were assessed. Administration of AML doi:10.1038/sj.jhh.1001579 Keywords: ACE-inhibitors; dihydropyridinic calcium antagonists; glomerular haemodynamics Introduction glomerular hypertension has a fundamental role in the progression of renal injury justifies the continu- Reduced glomerular capillary pressure protects 1–3 ing search for treatment regimens that may succeed against the onset and progression of renal injury; in reducing this hypertension. Assuming that in it is well known that this pressure is affected by the humans with chronic kidney disease, the onset of afferent and efferent arteriolar resistances. Any glomerular hypertension in the nephrons of the substance that not only reduces systemic vascular residual renal parenchyma might predispose toward resistances, but also induces preferential dilatation progression of renal damage, antihypertensive drugs of the efferent arteriole, could thus cause a reduction could exert an important effect on the glomerular in glomerular capillary pressure and in the inci- 4,5 haemodynamics of nephrons spared by the initial dence of glomerular sclerosis. The theory that pathogenic noxae. It is well known that inhibitors of the angiotensin conversion enzymes (ACEi) such as enalapril (ENA) can slow the progression of the Correspondence: Dr LF Morrone, Department of Internal Medi- renal damage by reducing efferent arteriolar resis- cine and Public Medicine, Division of Nephrology, University of tances and intraglomerular pressure.6–9 The angio- Bari, Polyclinic, Piazza Giulio Cesare, 11 Bari 70124, Italy. tensin II receptor antagonists seem to share similar E-mail: [email protected] 10,15 Received 10 April 2002; revised 24 February 2003; accepted 19 renal protection effects with the ACEi. On the March 2003 contrary, first-generation dihydropyridinic calcium Calcium antagonist and glomerular pressure LF Morrone et al 488 antagonists like nifedipine (NIF) do not have any eight patients, and the patients in each group were marked vasodilatory effect on the efferent arteriole, administered a single dose of a different drug: do not reduce glomerular pressure and seem to have * ENA group (enalapril 20 mg os), less protective effects on the kidney than the * ACEi.12–15 Instead, there is some controversy as to NIF group (nifedipine R 20 mg os), * NIT group (nitrendipine 20 mg os), the intrarenal haemodynamic effects of second * generation dihydropyridinic calcium antagonists, AML group (amlodipine 10 mg os). as their vasodilatory effect on the efferent arteriole Patients assignment was random, but such as to may vary according to the drug used.16–24 In enable an equal distribution of the two kidney particular, the results of some studies suggest that diseases (four IgAN and four interstitial nephritis) amlodipine (AML) does not significantly reduce in each group. The patients in the four groups were postglomerular resistances,20,22–24 whereas others matched for sex, age, type of renal disease and have shown that amlodipine, nitrendipine (NIT) creatinine clearance. At least 2 weeks before and for and other second-generation dihydropyridinic the entire duration of the study, all other medica- calcium antagonists induce haemodynamic varia- tions were suspended and patients were given a tions suggesting a mainly efferent vasodilatory protein intake ranging between 1.0 and 1.3 g/kg b.w./ effect.16–19,21 Unfortunately, as the method is highly day and a sodium intake of 200 mmol/day. This complex, it has only been possible to carry out dietary restriction was adopted in order to exclude studies of the intrarenal haemodynamic effects any influence on renal haemodynamics of a differ- of antihypertensive drugs on relatively small patient ent protein and salt intake among patients. Com- samples, and the assumption that calcium antago- pliance to the dietary prescriptions was ascertained nists in general have only limited efficacy in reducing on the basis of their nitrogen intake and sodium glomerular hyperfiltration has remained strong. urinary excretion. The nitrogen intake was mea- In order to assess how effective second-generation sured by calculating the urinary urea nitrogen in dihydropyridinic calcium antagonists really are in 24 h urine collection and the estimated nonurea reducing glomerular hyperfiltration, we compared nitrogen excretion of 29 mg/kg N kgÀ1 on alternate the intrarenal haemodynamic effects of a single dose days, as follows: (urinary urea nitrogen+nonurinary of two such drugs, AML and NIT, with those of a urea nitrogen) Â 6.25.25 This policy was adopted to single dose of an ACEi, ENA and of a first generation ensure that the baseline value of the glomerular calcium antagonist, NIF. The comparison was con- filtration rate (GFR) would reflect the patients’ ducted in a group of patients with chronic renal constant dietary habits (the so-called ‘resting’ disease, mildly impaired renal function and mild-to- GFR).25–28 The patient characteristics of each group moderate arterial hypertension. The effects of the are listed in Table 1: there were no significant drugs on renal haemodynamics were assessed in differences among the four groups for any parameter baseline conditions and in transitory glomerular considered. The nature, purpose and potential risks hyperfiltration conditions experimentally induced of the study were explained to all subjects and by the infusion of amino acids. informed consent was obtained prior to enrolment. The procedures followed were in accordance with the principles of the Declaration of Helsinki. Patients and methods Patients Study of intrarenal haemodynamics A total of 32 patients (19 M and 13 F), mean age Four haemodynamic parameters were considered, 45.6 7 3.4 years, with chronic kidney disease (16 two of which were measured and two calculated. The patients with IgAN and 16 with interstitial nephritis) two measured were the GFR and the effective renal were studied. They were divided into four groups of plasma flow (ERPF); the two calculated were the Table 1 Patient characteristics and dietary compliance data related to daily protein content and salt intake ENA (N=8) NIF (N=8) NIT (N=8) AML (N=8) Age (years) 38.8 7 4.4 50.2 7 4.4 49.7 7 2.2 44.0 7 2.7 Creatinine clearance (ml/min) 95.4 7 10.1 83.7 7 11.1 88.8 7 8.8 83.2 7 6.1 Systolic blood pressure (mmHg) 150.1 7 6.6 147.3 7 6.1 151.7 7 1.5 154.0 7 3.8 Diastolic blood pressure (mmHg) 97.7 7 5.2 92.8 7 3.0 94.1 7 3.0 101.0 7 2.1 Mean blood pressure (mmHg) 115.2 7 5.5 111.0 7 3.8 113.3 7 2.4 118.6 7 2.4 Nitrogen intake (g/kg/day) 1.10 7 0.03 1.12 7 0.10 1.31 7 0.07 0.98 7 0.10 Urinary sodium (mmol/day) 194 7 7.0 215 7 5.6 202 7 9.9 190 7 8.1 All parameters were comparable in all the groups studied ENA=enalapril, NIF=nifedipine, NIT=nitrendepine, AML=amlodipine. Data are expressed as mean and standard error (s.e.). Journal of Human Hypertension Calcium antagonist and glomerular pressure LF Morrone et al 489 renal vascular resistances (RVR) and the filtration fraction (FF). The ERPF and GFR were measured on the basis of inulin and para-aminohippuric acid (PAH) clearance, respectively. The clearance sessions included: (a) bladder catheterization and oral water intake of 15 ml/kg b.w. to optimize the hydration state (at À30 min); (b) intravenous infusion of inulin and PAH, first in a bolus lasting 15 min then in continuous infusion from time zero; the quantity of bolus and continuous infusion of inulin and PAH (supplied by Jacopo Monico company, Mestre, Italy) were established using Duarte’s formulae29 and performed using a Lifecare microinfuser (Pump model 4, Abbott Laboratories, North Chicago, IL 60064, USA); (c) collection of blood and urine samples to determine three consecutive clearances for both inulin and PAH, each measured over 30 min, so that each parameter value was obtained from the Figure 1 Design study scheme.
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