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. PAH ¼ p-aminohippurate. mean of three tests. Blood and urine collection was started after the period required to achieve stable plasma concentrations of inulin and PAH, at times after 30 min from the start of the continuous +75, +105 and +135 min (blood samples and blood infusion of inulin and PAH, with a Lifecare pressure measurement) and at times +90, +120 Microinfuser at the rate of 6 mg/kg/min; and +150 min (urine samples). The urinary volumes * after administration of the test drug during collected were replaced with an equal volume of oral amino-acid infusion. water to maintain the hydration state unchanged. Inulin and PAH were assayed with a colorimetric The four experimental conditions were investi- method using diphenylamine and ethylenediamine- gated in each patient at intervals of 48 h to restore N-1-naphthyl chlorhydrate, respectively.30 The RVR the starting haemodynamic conditions. Figure 1 and FF were calculated from the measurements of the shows a diagram of the study design. GFR and ERPF. The RVR was calculated, following Finally, from the day before the first clearance Gomez’s formula, as the ratio between mean blood session until the third day after conclusion of the pressure and effective renal blood flow (ERBF) study, antibacterial prophylaxis with 500 mg/day  80 000 and expressed in dyn s cmÀ5.ERBFwas ciprofloxacin was given to avoid the risk of urinary determined as ERPF/1-haematocrit. Finally, the FF infection from the bladder catheterization. Urine was obtained from the GFR/ERPF ratio. cultures performed on the 4th, 7th and 14th days after the end of the study gave negative results.

Study design In the four groups: ENA, NIF, NIT and AML, the Statistical analysis GFR, ERPF, RVR and FF were assessed in four All variables were normally distributed and data were different experimental conditions: expressed in the text as mean 7 standard deviation * before administration of the test drug; (s.d.). Statistical comparison between groups was * after administration of the antihypertensive test performed by paired t-test and one-way ANOVA. drug, to assess its effects of renal haemody- The data were analysed by SPSS Statistical Software. namics; the drug was administered at variable times before the clearance session according to its pharmocodynamic characteristics; as ENA Results reaches its peak serum concentration after 3–4 h it was administered (20 mg) 90 min before con- The mean values for the GFR are shown in Figure 2. tinuous infusion of inulin and PAH; NIF (20 mg) In baseline conditions (2a), the GFR (ml/min) and NIT (20 mg) reach their peak serum concen- was significantly reduced after administration of tration after 2–3 h,31,32 and were administered ENA (110.8 7 13.5 vs 79.8 7 22.2; P ¼ 0.0087), while 60 min before the session; AML (10 mg) was it significantly increased after NIF (78.1 7 25.2 administered 360 min before, as the peak is vs 106.2 7 27.9; P ¼ 0.003), NIT (76.8 7 24.4 vs reached after about 6 h;33 96.0 7 39.0; P ¼ 0.038) and AML (86.1 7 22.7 vs * during infusion of an amino-acid solution indu- 103.6 7 27.3; P ¼ 0.0001). Instead, in the glomerular cing glomerular hyperfiltration; the amino acids hyperfiltration conditions induced by amino-acid (Parentamin 10%, Pharmacia, a mixture of essen- infusion (2b), the reduction in the GFR produced tial and nonessential amino acids) were infused by AML (from 112.8 7 28.2 to 102.7 7 30.0;

Journal of Human Hypertension Calcium antagonist and glomerular pressure LF Morrone et al

490

Figure 3 Changes in ERPF induced by drug administration. Figure 2 Changes in GFR induced by drug administration. Baseline ¼ data obtained without drug and amino-acid adminis- Baseline ¼ data obtained without drug and amino-acid adminis- tration; drug ¼ data obtained after exposure to the tested drug; tration; drug ¼ data obtained after exposure to the tested drug; amino acids ¼ data obtained after amino-acid infusion; amino amino acids ¼ data obtained after amino-acid infusion; amino acids and drug ¼ data obtained after amino-acid infusion and acids and drug ¼ data obtained after amino-acid infusion and drug administration. ENA ¼ enalapril, NIF ¼ nifedipine, NIT ¼ drug administration. ENA ¼ enalapril, NIF ¼ nifedipine, NIT ¼ nitrendepine, AML ¼ amlodipine. nitrendepine, AML ¼ amlodipine. In all groups, a significant increase in GFR values was observed after amino-acid infusion (baseline vs amino acids GFR: Po0.001).

P ¼ 0.00003) and NIT (from 112.4 7 30.0 to 96.7 7 38.1; P ¼ 0.08 NS.) was similar to that of ENA (from 147.2 7 17.1 to 107.5 7 9.2; P ¼ 0.0003), while on the contrary NIF induced an increase in the GFR (from 107.9 7 20.0 to 129.9 7 32.7; P ¼ 0.04). The effect of the drugs studied on the ERPF (ml/ min) is shown in Figure 3, in baseline conditions (3a) and after amino-acid infusion (3b). All the drugs induced an increase in the ERPF: ENA in baseline conditions: from 344.7 7 67.9 to 409.6 7 121.1 (P ¼ 0.02); ENA after amino-acid infusion: from 451.2 7 104.6 to 525.7 7 144.5 (P ¼ 0.0088); NIF Figure 4 Changes in RVR induced by drug administration. 7 Baseline ¼ data obtained without drug and amino-acid adminis- in baseline conditions: from 340.4 106.4 to tration; drug ¼ data obtained after exposure to the tested drug; 389.4 7 128.7 (P ¼ 0.14 NS); NIF after amino acids: amino acid ¼ data obtained after amino-acid infusion; amino from 491.4 7 133.1 to 516.4 7 136.2 (P ¼ 0.48 NS); acids and drug ¼ data obtained after amino-acid infusion and NIT in baseline conditions: from 331.9 7 126.4 to drug administration. ENA ¼ enalapril, NIF ¼ nifedipine, NIT ¼ 488.4 7 166.1 (P ¼ 0.0006); NIT after amino acids: nitrendepine, AML ¼ amlodipine. from 461.6 7 192.6 to 462.9 7 152.5 (P ¼ 0.96 NS); AML in baseline conditions: from 291.1 7 86.2 to 10.1 7 3.4 to 7.7 7 2.3 (P ¼ 0.0016) after NIT, from 437.7 7 117.8 (P ¼ 0.0004); AML after amino acids: 15.6 7 5.3 to 12.0 7 3.0 (P ¼ 0.009) after AML. from 407.1 7 111.7 to 491.4 7 113.5 (P ¼ 0.0009). The FF was significantly reduced after adminis- However, the drug-induced increase in the ERPF tration of all the drugs except NIF, which induced an was less intense and not statistically significant for increase, albeit not significant, in this parameter NIF and NIT after amino-acid infusion. All the drugs both in baseline conditions and after amino-acid studied, with the exception of NIF, were able to infusion (Figure 5). In baseline conditions (5a), the provoke a significant decrease in the RVR FF went from 0.33 7 0.09 to 0.20 7 0.06 (P ¼ 0.007) (dyn  s  cmÀ5) (Figure 4). In baseline conditions after ENA, from 0.25 7 0.07 to 0.30 7 0.11 (P ¼ 0.19 (4a), the mean RVR dropped from 13.7 7 6.7 to NS) after NIF, from 0.24 7 0.05 to 0.20 7 0.04 11.4 7 5.5 (P ¼ 0.0025) after ENA, from 14.3 7 5.2 (P ¼ 0.021) after NIT, and from 0.30 7 0.06 to to 10.7 7 2.8 (P ¼ 0.054 NS) after NIF, from 14.4 7 0.24 7 0.02 (P ¼ 0.0058) after AML. After infusing 3.6 to 8.1 7 2.7 (P ¼ 0.00003) after NIT and from amino acids (5b) the FF went from 0.34 7 0.09 to 22.0 7 7.5 to 13.1 7 3.5 (P ¼ 0.0007) after AML. 0.22 7 0.07 (P ¼ 0.00006) after ENA, from A similar effect was obtained after amino-acid 0.23 7 0.07 to 0.26 7 0.06 (P ¼ 0.22 NS) after NIF, infusion (4b), and the RVR dropped from 10.9 7 5.7 from 0.26 7 0.05 to 0.21 7 0.04 (P ¼ 0.039) after NIT, to 9.4 7 5.3 (P ¼ 0.00009) after ENA, from 10.2 7 and from 0.28 7 0.06 to 0.21 7 0.03 (P ¼ 0.0003) 3.1 to 8.7 7 3.1 (P ¼ 0.18 NS) after NIF, from after AML. Notably, administration of all the drugs

Journal of Human Hypertension Calcium antagonist and glomerular pressure LF Morrone et al

491 contraction of the mesangium could trigger a dissociation between the GFR and the ERPF, to the advantage of the latter parameter, as a result of a reduction in the glomerular capillary surface as- signed to filtration. This does not occur with ACE inhibitors or calcium antagonists, as they tend on the contrary to induce relaxation of the mesangium and 34,35 an increase in the Kf. On the basis of this effect, they would tend to increase, rather than decrease, the FF. Thus, we believe that the reduction in the FF obtained with NIT, AML and ENA must be an expression of a vasodilatory effect on the postglo- merular resistances, since it occurs despite the Figure 5 Changes in FF induced by drug administration. Base- line ¼ data obtained without drug and amino-acid administration; increase in the Kf that these drugs could potentially drug ¼ data obtained after exposure to the tested drug; amino revoke. On the contrary, the increase in the FF acids ¼ data obtained after amino-acid infusion; amino-acids and observed with NIF, which might well have a causal drug ¼ data obtained after amino-acid infusion and drug admin- role in increasing the Kf, confirms that this drug can- istration. ENA ¼ enalapril, NIF ¼ nifedipine, NIT ¼ nitrendepine, not trigger vasodilation of the efferent arteriole.39–41 AML ¼ amlodipine. The fact that NIT and AML, unlike NIF, can reduce the glomerular hyperfiltration induced by amino- induced a moderate reduction in the mean blood acid infusion is another point in favour of the pressure in all the groups. This blood pressure hypothesis that these two calcium antagonists have reduction (delta mean blood pressure) was compar- a preferential effect on the postglomerular resis- able among groups both in baseline conditions tances, mimicking that of the ACE inhibitors. The (ENA ¼ 5.2 7 2.1 mmHg, NIF ¼ 4.6 7 1.8 mmHg, reduction in the GFR provoked by NIT and AML NIT ¼ 4.2 7 2.1 mmHg, AML ¼ 4.8 7 2.0 mmHg; after amino-acid infusion could be attributed to a ANOVA P ¼ NS) and under hyperfiltration (ENA ¼ vasodilatory effect on the efferent arterioles induced 4.7 7 2.0 mmHg, NIF ¼ 4.1 7 2.1 mmHg, NIT ¼ 3.9 7 by these second-generation dihydropyridinic drugs, 1.9 mmHg, AML ¼ 4.6 7 2.1 mmHg; ANOVA P ¼ NS) while the afferent arterioles, being already maxi- mally dilated by the infusion, could not undergo further drug-induced vasodilation. Discussion In conclusion, the renal haemodynamic effects induced by AML and NIT seem to be more similar Our findings suggest that the pharmacological effect to those of ACE inhibitors than to those of other of AML and NIT is exerted on the postglomerular calcium antagonists like NIF. These second-genera- arterial resistances, as demonstrated by the simulta- tion dihydropyridinic calcium antagonists seem neous reduction of the RVR and FF. This reduction to exert a vasodilatory effect prevalently on the in the FF, which is observed in both baseline and efferent arterioles, which is thus associated with a glomerular hyperfiltration conditions, reflects an reduction in the hydrostatic pressure in the glomer- imbalance between the GFR and ERPF that may be ular capillaries. considered typical of a condition of postglomerular vasodilation.34 This is supported by a similar haemodynamic effect observed after administration Acknowledgements of ENA, which is known to have a vasodilatory effect on the efferent arteriole.35–38 On the contrary, This study was partly supported by Grants (40%: vasodilatory drugs that do not reduce the postglo- 92.02039, 60%: 97.66633) from the Ministry of merular resistances, like NIF, in addition to reducing University and Scientific and Technological Re- the RVR, trigger an increase in the ERPF without search, Rome, Italy. Part of this work was presented reducing the FF.39–41 In fact, the increase in the ERPF at the European Dialysis Transplant Association is not proportionally greater than that of the GFR, so meeting, Geneva, Switzerland, 21–24 September, the FF does not diminish.42 These haemodynamic 1997. We thank Ms MVC Pragnell, BA, for her help changes cannot be attributed either to a hypotensive in revising the English text. effect of the drugs, in view of the increase in the ERPF, or to a potential effect on the mesangium, at least as regards ENA, AML and NIT. In fact, drugs that can contract the mesangium can induce a References reduction in the glomerular filtration capillary sur- 1 Raij L, Chiou XC, Owens R, Wrigley B. Therapeutic face and hence in the ultrafiltration coefficient implications of hypertension induced glomerular 43,44 (Kf). It is possible that drugs that reduce the Kf injury. Am J Med 1985; 79: 37–41. can decrease the FF regardless of any vasodilatory 2 Anderson S, Meyer TW, Rennke HG, Brenner BM. effect on the efferent arterioles. It could be that Control of glomerular hypertension limits glomerular

Journal of Human Hypertension Calcium antagonist and glomerular pressure LF Morrone et al

492 injury in rats with reduced renal mass. J Clin Invest nephropathy. Nephrol Dial Transplant 1998; 13: 1985; 76: 612–619. 3096–3102. 3 Meyer TW, Anderson S, Rennke HG, Brenner BM. 21 August P, Lenz T, Laragh JH. Comparative renal Reversing glomerular hypertension stabilizes estab- hemodynamic effects of lisinopril, verapamil, and lished glomerular injury. Kidney Int 1987; 31: 751–759. amlodipine in patients with chronic renal failure. 4 Anderson S. Antihypertensive therapy and the pro- Am J Hypertens 1993; 6: 148S–154S. gression of renal disease. J Hypertens 1989; 7 (Suppl): 22 Licata G et al. Effects of amlodipine on renal S39–S42. haemodynamics in mild to moderate hypertensive 5 Bedogna V et al. Effects of ACE inhibition in normo- patients. A randomized controlled study versus place- tensive patients with chronic glomerular disease bo. Eur J Clin Pharmacol 1993; 45: 307–311. and normal renal function. Kidney Int 1990; 38: 23 Loutzenhiser RD, Epstein M, Fischetti F, Horton C. 101–107. Effects of amlodipine on renal hemodynamics. Am J 6 Bauer JH, Reams GP, Lal SM. Renal protective effect of Cardiol 1989; 64: 122I–128I. strict blood pressure control with enalapril therapy. 24 Reams GP, Lau A, Hamory A, Bauer JH. Amlodipine Arch Intern Med 1987; 147: 1397–1400. therapy corrects renal abnormalities encountered in 7 Simons JL et al. Modulation of glomerular hyperten- the hypertensive state. Am J Kidney Dis 1987; 10: sion defines susceptibility to progressive glomerular 446–451. injury. Kidney Int 1994; 46: 396–404. 25 Viberti G et al. Effect of protein-restricted diets on 8 Vos PF, Boer P, Braam B, Koomans HA. Efficacy of renal response to a meat meal in humans. Am J Physiol intrarenal ACE-inhibition estimated from the renal (Renal, Fluid Electrol Physiol) 1987; 22: F388–F393. response to angiotensin I and II in humans. Kidney Int 26 Bergstrom J, Ahlberg M, Alvestrand A. Influence of 1995; 47: 274–281. protein intake on renal hemodynamics and plasma 9 Juncos LI et al. Abnormal renal vasodilation to an hormone concentrations in normal subjects. Acta Med amino acid infusion in congestive heart failure: Scand 1985; 217: 189–196. normalization by enalapril. Am J Kidney Dis 1999; 27 Jones MG, Lee K, Swaminathan R. The effect of dietary 33: 43–51. protein on glomerular filtration rate in normal sub- 10 Fridman K, Wysocki M, Friberg P, Andersson OK. jects. Clin Nephrol 1987; 27: 71–75. Candesartan cilexetil and renal hemodynamics in 28 Paller MS, Hostetter TH. Dietary protein increases hypertensive patients. Am J Hypertens 2000; 13: plasma renin and reduces pressor reactivity to angio- 1045–1048. tensin II. Am J Physiol (Renal, Fluid Electrol Physiol) 11 Buter H, Navis G, de Zeeuw D, de Jong PE. Renal 1986; 20: F34–F39. hemodynamic effects of candesartan in normal and 29 Liedtke RR, Duarte CG. Laboratory protocols and impaired renal function in humans. Kidney Int 1997; methods for the measurement of glomerular filtration 63 (Suppl): S185–S187. rate and renal plasma flow. In: Duarte CG (ed). Renal 12 Heller J, Horacek V. The effect of two different calcium Function Tests: Clinical Laboratory Procedures and antagonists on the glomerular haemodynamics in the Diagnosis. Little Brown Company: Boston, 1980, pp dog. Pflugers Arch 1990; 415: 751–755. 49–63. 13 Hayashi K et al. Disparate effects of calcium anta- 30 Walser M, Davidson DG, Orloff J. The renal clearance gonists on renal microcirculation. Hypertens Res 1996; of alkali-stable inulin. J Clin Invest 1955; 34: 19: 31–36. 1520–1523. 14 Ruggenenti P, Perna A, Benini R, Remuzzi G. Effects 31 Raemsch KD, Sommer J. Pharmacokinetics and meta- of dihydropyridine calcium channel blockers, angio- bolism of nifedipine. Hypertension 1983; 5 (Suppl II): tensin-converting enzyme inhibition, and blood II-18–II-24. pressure control on chronic, nondiabetic nephropa- 32 Dylewicz P et al. Bioavailability and elimination of thies. Gruppo Italiano di Studi epidemiologici in nitrendipine in liver disease. Eur J Clin Pharmacol Nefrologia (GISEN). J Am Soc Nephrol 1998; 9: 1987; 32: 563–568. 2096–2101. 33 Reid JL, Meredith PA, Donnelly R, Elliott HL. Pharma- 15 Kvam FI, Ofstad J, Iversen BM. Effects of antihyper- cokinetics of calcium antagonists. J Cardiovasc Phar- tensive drugs on autoregulation of RBF and glomerular macol 1988; 12 (Suppl 7): S22–S26. capillary pressure in SHR. Am J Physiol 1998; 275 34 Carmines PK, Perry MD, Hazelrig JB, Navar LG. Effects (4 Part 2): F576–F584. of preglomerular and postglomerular vascular resis- 16 Scaglione R et al. Antihypertensive efficacy and effects tance alterations on filtration fraction. Kidney Int 1987; of nitrendipine on cardiac and renal hemodynamics in 20 (Suppl): S229–S232. mild to moderate hypertensive patients: randomized 35 Hall JE et al. Control of glomerular filtration rate by controlled trial versus hydrochlorothiazide. Cardio- circulating angiotensin II. Am J Physiol 1981; 241: vasc Drugs Ther 1992; 6: 141–146. R190–R197. 17 Kloke HJ et al. Effects of nitrendipine and cilazapril on 36 Pelayo JC, Quan AH, Shanley PF. Angiotensin II con- renal hemodynamics and albuminuria in hypertensive trol of the renal microcirculation in rats with reduced patients with chronic renal failure. J Cardiovasc renal mass. Am J Physiol 1990; 258: F414–F422. Pharmacol 1990; 16: 924–930. 37 Steinhausen M et al. Angiotensin II control of the renal 18 Grossman E et al. Systemic and regional hemodynamic microcirculation: effect of blockade by saralasin. and humoral effects of nitrendipine in essential Kidney Int 1986; 30: 56–61. hypertension. Circulation 1988; 78: 1394–1400. 38 Navar LG, Rosivall L, Carmines PK, Oparil S. Effects of 19 Schmitz A. Acute renal effects of oral felodipine in locally formed angiotensin II on renal hemodynamics. normal man. Eur J Clin Pharmacol 1987; 32: 17–22. Fed Proc 1986; 45: 1448–1453. 20 Holdaas H et al. Renal effects of losartan and 39 Epstein M, Hayashi K, Loutzenhiser R. Nifedipine amlodipine in hypertensive patients with non-diabetic prevents pressure-induced afferent arteriolar vasocon-

Journal of Human Hypertension Calcium antagonist and glomerular pressure LF Morrone et al

493 striction in isolated perfused hydronephrotic kidneys 42 Ozawa Y et al. Renal afferent and efferent arteriolar from hypertensive rats. Kidney Int 1989; 35: 427. dilation by nilvadipine: studies in the isolated per- 40 Loutzenhiser RD, Epstein M. Renal hemodynamic fused hydronephrotic kidney. J Cardiovasc Pharmacol effects of calcium antagonists. J Cardiovasc Pharmacol 1999; 33: 243–247. 1988; 12 (Suppl 6): S48–S52. 43 ter Wee PM, Donker AJ. Pharmacologic manipulation 41 Fleming JT, Parekh N, Steinhausen M. Calcium of glomerular function. Kidney Int 1994; 45: 417–424. antagonists preferentially dilate preglomerular vessels 44 Dworkin LD, Ichikawa I, Brenner BM. Hormonal of hydronephrotic kidney. Am J Physiol 1987; 253: modulation of glomerular function. Am J Physiol F1157–F1163. 1983; 244: F95–F104.

Journal of Human Hypertension