The effect of enalapril on the renal response to tilting in humans

Transcription

1 Br. J. lin. Pharma. (1989), 27, The effet of enalapril on the renal response to tilting in humans N. P. LWS & D. R. FRGUSON Department of Pharmaology, University of ambridge, Hills Road, ambridge 1 Seventeen normal subjets were tilted on a tilt table and hanges in blood pressure, heart rate and renal funtion were monitored in the absene of drug treatment; the same measurements were repeated during treatment with enalapril in eight of these subjets. 2 n the absene of drug, tilting of the whole body to the 45 head up position aused an antidiuresis, antinatriuresis and antikaliuresis; the antinatriuresis resulted from a transient fall in glomerular filtration and from a sustained inrease in the tubular reabsorption of sodium, as refleted by a prolonged fall in frational sodium eretion. 3 nalapril aused a redution in blood pressure in the upright position; there was no effet on heart rate. The antinatriuresis of tilt was signifiantly blunted by enalapril. This resulted from blunting of the transient fall in reatinine learane and of the inrease in tubular sodium reabsorption. Urinary potassium eretion during tilting was not altered by enalapril. 4 These findings are onsistent with a diret intrarenal ation of angiotensin, mediating some of the alterations in renal funtion apparent on assumption of the upright position. Keywords renin angiotensin system posture renal funtion enalapril ntrodution Studies performed in animals suggest that angiotensin has diret ations whih alter renal funtion. Angiotensin reeptors have been identified in glomeruli (Sraer et al., 1974) and in renal tubules (Brown & Douglas, 1982, 1983; o et al., 1984). nfusion of angiotensin into the renal artery has been shown to ause a fall in RBF and in GFR, and a redution in the urinary eretion of eletrolytes and water (Navar & Langford, 1974). n animals maintained on a low sodium intake, the administration of teprotide or aptopril to inhibit angiotensin formation (Kimbrough et al., 1977), or saralasin to blok angiotensin reeptors, auses an inrease in RBF, GFR and eletrolyte and water eretion (Trippodo etal., 1971), where the fall in systemi blood pressure is small. Diret intrarenal ation of angiotensin in humans has been suggested by the effet of aptopril on renal funtion in normal and hypertensive subjets fed a low sodium diet (Hollenberg et al., 1977, 1979), and by the renal effets of a subpressor infusion of angiotensin given into a peripheral vein (Dusing et al., 1985). n normal humans, transfer from the reumbent to the upright position is assoiated with a twofold rise in plasma renin ativity (Oparil et al., 197), an antidiuresis, antinatriuresis and antikaliuresis (Peare & Newman, 1954; Streeten & Speller, 1966; Surshin & White, 1956). To assess the degree to whih the renin angiotensin system auses hanges in renal funtion when body posture hanges, we have eamined the effets of the angiotensin onverting enzyme inhibitor enalapril on renal funtional hanges seen after tilting the whole body. Methods Subjets Seventeen normal volunteers (mean age 34 years, range 2262 years; three female) were studied orrespondene: Dr N. P. Lewis, Department of ardiology, University Hospital of Wales, ardiff F4 4XW 191

2 192 N. P. Lewis & D. R. Ferguson with informed onsent. The eperimental protool was approved by the ethis ommittee of Addenbrooke's Hospital, ambridge. ontrol eperiments were arried out on all 17 subjets; the eperiment was repeated in eight subjets (mean age 33 years, range 265 years; all male) after treatment with enalapril 5 mg orally 1 h prior to the eperiment. nalapril inhibits onverting enzyme; inhibition is maimal 4 h after oral dosing, and most of this effet is present within 1 h of oral dosing (Brunner et al., 1985). The remaining nine subjets were restudied after treatment with a 3adrenoeptor bloker. These two subsets were similar with respet to their age, blood pressure and renal responses to tilting in the absene of drug and seletion into the two subsets was randomised. Protool Pre and postdrug studies were arried out in eah subjet at the same time on onseutive days. The day on whih the drug was given was randomised. Subjets were asked to observe a similar dietary intake for 2 days prior to the study, and for the 2 days of the study; no attempt was made to feed the same diet to all subjets. Alohol, tea and offee and smoking were prohibited on the days of the eperiments. Prior to the eperiment, subjets emptied their bladder. Tap water 1 ml h was given to drink throughout the eperiment. Subjets were plaed in the 3 head down position on a tilting table for 12 min and voided immediately after tilt to the 45 head up position. Urine was subsequently voided in this position at 3 min intervals for a further 12 min. Urine volumes were measured from eah voiding period, and an aliquot taken for measurement of sodium, potassium and reatinine. Blood pressure was measured using a merury random zero sphygmomanometer; heart rate was measured by ounting the pulse for 1 min; these values were reorded after 6, 12 and 18 min. Blood samples were taken for measurement of sodium, potassium and reatinine at the midpoints of eah learane period. From these data, urine flow, total and frational sodium eretion, potassium eretion and reatinine learane were alulated. Biohemial measurements Urine and plasma sodium and potassium were measured by flame photometry, and reatinine by the manual alkaline pirate method. Analysis of results To standardise the results from different individuals, whih varied due to differenes in dietary eletrolyte intake, ontrol and postdrug omparisons were made after epressing all measurements as a perentage of the respetive value obtained during the 3 head down position for eah subjet. Statistial analysis of results was arried out by analysis of variane for repeated measures. Where a signifiant result was obtained overall, the differenes between individual means were ompared by ttest. P <.5 was taken as signifiant. Results Renal effets of tilting Tilting from the 3 headdown to the 45 headup position was assoiated with a signifiant fall in urine flow to approimately 25% of the value l1 r 1 D U) U). D t L u u 51 OL 1 r.v, 51 t f l! Titi ifi n A O 1 X td Figure 1 The effet of tilting on mean blood pressure and heart rate. The upper panel shows the hanges in blood pressure (histogram) and heart rate in all 17 subjets eamined in the absene of drug. The lower panel shows the hanges in heart rate and blood pressure in the subset of eight subjets eamined before and after enalapril. Results after enalapril are represented by the unhathed histogram, and by the square points. Values shown are means and s.e. mean, P<O.OOS. 5

3 Renal funtion after tilting 193 in the headdown position after 6 min of tilt (Figure 2); there was no signifiant hange in mean arterial pressure or in pulse rate (Figure 1). Tilting aused a fall in urinary sodium eretion to approimately 5% of the headdown value (Figure 3), and there was a similar redution in urinary potassium eretion (Figure 4). reatinine learane was redued by tilting to about 7% of the headdown value after 6 min. Over the final 6 min of observation reatinine learane inreased again toward the value observed in the headdown period (Figure 5). After 12 min in the headup position, reatinine learane was not signifiantly different from the value measured in the headdown position..r_ 6 ) ) z.2 r.1 F 4 1 ) 2 o 5 F._ 1 r L o _. ~~~~z._ Figure 3 The effet of tilting on urinary sodium eretion. The upper panel shows the hanges in urinary sodium eretion in all 17 subjets eamined in the absene of drug. The lower panel shows the hanges in urinary sodium eretion in the subset of eight subjets eamined before and after enalapril. Results after enalapril treatment are represented by the open irles. Values shown are means and s.e. mean. P <.5, P <.1, P <.1.._ ol 6 12 Figure 2 The effet of tilting on urine flow. The upper panel shows the hanges in urine flow in all 17 subjets eamined in the absene of drug. The lower panel shows the hanges in urine flow in the subset of eight subjets eamined before and after enalapril. Results after enalapril treatment are represented by the open irles. Values shown are means and s.e. mean. P <.1. Frational sodium eretion showed a sustained fall on tilting, indiating a sustained inrease in tubular sodium reabsorption (Figure 6). Reproduibility of the renal effets of tilting n five further subjets tilting was performed on onseutive days to assess the reproduibility of the renal response to tilting. The findings are shown in Table 1, demonstrating that the renal response to tilt was onsistent using the protool above.

4 194 N. P. Lewis & D. R. Ferguson 7 5 ).2 r.1. D f 15 r 75 F, 1 1 r.) J ) a1) (D._ 5 a._ a1) 4) a1).) Figure 4 The effet of tilting on urinary potassium eretion. The upper panel shows the hanges in urinary potassium eretion in all 17 subjets eamined in the absene of drug. The lower panel shows the hanges in urinary potassium eretion in the subset of eight subjets eamined before and after enalapril. Results after enalapril treatment are represented by the open irles. Values shown are means and s.e. mean. P <.1. ffet of enalapril on the renal response to tilt nalapril redued mean arterial blood pressure by 1 mmhg (P <.5) in the upright position; there was no hange in heart rate (Figure 1). Urine flow rates during tilt were not signifiantly affeted by treatment with enalapril (Figure 2). The fall in sodium eretion during tilting was signifiantly blunted by enalapril (Figure 3), but there was no signifiant effet on potassium eretion (Figure 4). The transient fall in reatinine learane and the fall in frational sodium eretion were both signifiantly blunted by enalapril (Figures 5 and 6). ' 6 12 Figure 5 The effet of tilting on reatinine learane. The upper panel shows the hanges in reatinine learane in all 17 subjets eamined in the absene of drug. The lower panel shows the hanges in reatinine learane in the subset of eight subjets eamined before and after enalapril. Results after enalapril treatment are represented by the open irles. Values shown are means and s.e. mean. P <.5, P <.1. Disussion Preliminary assessment in five subjets suggested that under the onditions of the eperiment, and in the absene of drug treatment, the renal response to tilting was onsistent within an individual on onseutive days (Table 1). The renal response to tilting desribed in these eperiments agrees well with previous reports (Peare & Newman, 1954; Streeten & Speller, 1966; Surshin & White, 1956) whih desribe an antidiuresis, antinatriuresis and antikaliuresis in

5 z 1o.) U 5 6._ ) ) z o _ 1 r 5 F _ 6 Renal funtion after tilting 195 suggesting that the antinatriuresis of tilting results both from a transient fall in GFR and from a sustained inrease in the tubular reabsorption of sodium. The possibility that these alterations in renal funtion ould result from inomplete bladder emptying should be onsidered. However, this seems unlikely as the hanges in reatinine learane and urine flow are dissoiated during tilting (Figures 2 and 5). A limitation of this study is that evidene of the inhibition of onverting enzyme by enalapril during eperiments is indiret, based on published data in normal subjets whih demonstrates inhibition of onverting enzyme by enalapril, at the dosage used, over the time ourse of these eperiments (Brunner et al., 1985). We found that enalapril signifiantly blunted postural antinatriuresis, by blunting the transient fall in GFR and the inrease in tubular sodium reabsorption (Figures 3, 5 and 6). nalapril had no signifiant effet on the urinary eretion of potassium during tilting. Our results largely agree with a previous report (Mimran & Deshodt, 1983) whih eamined the effet of aptopril on renal and hormonal funtion during whole body tilting; Mimran & Deshodt (1983) onluded that following inhibition of angiotensin synthesis by aptopril, the falls in GFR and sodium eretion on tilting were blunted but the fall in frational sodium 12 eretion was not affeted; however, in their eperiments, renal hanges were observed over Time (min) elapsed after hea id up tilt only 3 min of tilt. t an be seen from our results Figure 6 The effet of tilting on frationa1 that the hange in frational sodium eretion sodium had not reahed a signifiant level after 3 min of eretion. The upper panel shows the har frational sodium eretion in all 17 subjettgeseined tilt (Figure 6), and that any effet of onverting in the absene of drug. The lower panel shows the enzyme inhibition on this parameter would behe subset of ome apparent only after long periods of obser hanges in frational sodium eretion in t eight subjets eamined before and after enalapril. vations during tilting. Results after enalapril treatment are represented by onverting enzyme inhibitors may alter renal the open irles. Values shown are means and s.e. funtion via mehanisms other than the inhibimean. P <.5, P <.1, P <.11. tion of angiotensin synthesis. Kinin degradation by kininase is also inhibited, although not response to the upright position. Previ( ous studies onsistently in sodium replete subjets (Mimran have produed onfliting results regarding the & Deshodt, 1983; Hollenberg et al., 1981), ontribution of altered GFR and tiubular re raising the possibility that aumulation of kinins absorption to the antinatriuresis and anti may be responsible for some of the alteration in kaliuresis of tilting (dwards, 1974) >, possibly renal funtion found in these eperiments. on em verting enzyme inhibitors also ause a rise in the due to the different urine sampling pteriods ployed. amination of all the data presented prodution of the vasodilator prostaglandin 2 shows no lear orrelation between thle postural (Swartz et al., 198) whih may be impliated in hange in sodium eretion and the hange in some of the renal hanges noted in our study. GFR (dwards, 1974), suggesting thtat hanges Angiotensin is known to potentiate the effets in GFR alone do not wholly aount for the of noradrenaline (Khairallah, 1972) and inhibi demon tion of angiotensin synthesis by enalapril may altered eletrolyte eretion. Our data strate a transient fall in reatinine leatrane and affet renal funtion by modifiation of the effets a sustained fall in frational sodium eretion, of the sympatheti nervous system (Katholi,

6 196 N. P. Lewis & D. R. Ferguson Table 1 Urine flow, total urinary sodium and potassium eretion, reatinine learane and frational sodium eretion at 3 min intervals after tilting from the 3 head down to the 45 head up position in five subjets studied on onseutive days in the absene of drug treatment. All results are epressed as a perentage of the value obtained in the respetive ontrol period. Values shown are means (s.e. mean); no signifiant differene was noted between the 2 days Time (min) after tilting to head up position Urine flow (% ontrol) Day 1 62 (8.5) 27.7 (6.3) 2.2 (2.6) 17.2 (2) Day (12.1) 22.6 (2.7) 17 (2.5) 19.6 (2.2) Na eretion (% ontrol) Day (7.8) 59.7 (9.3) 6.9 (1.5) 5.3 (1.2) Day (9) 51.7 (16.1) 59.9 (128) 55.2 (12.6) K eretion (% ontrol) Day (1.9) 47.3 (7) 46.3 (7.6) 39.2 (7.5) Day (4.6) 5.6 (8.5) 43.7 (7.4) 44.3 (8.1) reatinine learane (% ontrol) Day 1 96(11.3) 71.4(4.4) 86(8.3) 88.5 (7.5) Day (14) 75.5 (8.3) 81.3 (8.9) 93.6 (8) Frational Na eretion (% ontrol) Day (9.8) 84.3 (13.1) 78.4 (15.2) 61.2 (13.4) Day (12.1) 77.6 (1.6) 73.8 (11.3) 57.6 (15.2) 1983) at the kidney. A reent report has suggested that inhibition of onverting enzyme with aptopril is assoiated with an inrease in resting plasma atrial natriureti peptide levels (Wilkins et al., 1987), raising the possibility that some of the renal effets demonstrated in our eperiments may result from altered atrial peptide metabolism. n summary, our data show that the postural hange in urinary sodium eretion in normal humans is due to a transient redution in GFR, and a sustained inrease in tubular sodium reabsorption. The effets of enalapril on the postural hange in renal funtion support the hypothesis that the antinatriuresis of the upright position results in part from the diret ation of angiotensin at the glomerulus ausing a transient fall in GFR, and in part from an inrease in tubular sodium reabsorption. Whether the inrease in tubular reabsorption is due to a diret effet of angiotensin on tubular mehanisms (Harris & Young, 1977) or to altered peritubular fores (Levens et al., 1981) annot be determined from our results in the absene of diret measurements of renal blood flow. The time ourse of the hange in tubular sodium reabsorption and the redution in potassium eretion on tilting suggest that aldosterone is not the primary effetor (Reid, 1984). Referenes Brown, G. P. & Douglas, J. G. (1982). Angiotensin binding sites on isolated rat renal brush border membranes. ndorinology, 111, Brown, G. P. & Douglas, J. G. (1983). Angiotensin binding sites in rat and primate isolated renal tubular basolateral membranes. ndorinology, 112, Brunner, H. R., Nussberger, J. & Waeber, B. (1985). The present moleules of onverting enzyme inhibitors. J. ardiovas. Pharma., 7, S2S11. o, H. M., Munday, K. A. & Poat, J. A. (1984). Loation of 125angiotensin reeptors on rat kidney orte epithelial ells. Br. J. Pharma., 82, Dusing, R., Morik, J, Glanzer, K. & Kramer, H. J. (1985). ffets of angiotensin and aptopril on renal tubular funtion in man. Br. J. lin. Pharma., 19, dwards,. M. (1974). diopathi oedema. M.D. Thesis, University of London.

7 Renal funtion after tilting 197 Harris, P. J. & Young, J. A. (1977). Dose dependent stimulation and inhibition of proimal tubular sodium reabsorption by angiotensin in the rat kidney. Pflugers Arh., 367, Hollenberg, N. K., Meggs, L. G., Williams, G. H., Garni, J., Garnsi, J. D. & Harrington, D. P. (1981). Sodium intake and renal responses to aptopril in normal man and in essential hypertension. Kidney nt., 2, Hollenberg, N. K., Swatz, S. L. & Passan, D. R. (1979). nreased GFR following onverting enzyme inhibition in essential hypertension. New ngl. J. Med., 31, 912. Hollenberg, N. K., Williams, G. H. & Taub, K. J. (1977). Renal vasular response to interruption of the renin angiotensin system in normal man. Kidney nt., 12, Katholi, R.. (1983). Renal nerves in the pathogenesis of hypertension in eperimental animals and humans. Am. J. Physiol., 245, F1F14. Khairallah, P. A. (1972). Ation of angiotensin on adrenergi nerve endings: inhibition of norepinephrine uptake. Fed. Pro., 31, Kimbrough, H. M. Jnr., Vaughan,. D. Jnr., arey, R. M. & Ayers,. R. (1977). ffet of intrarenal angiotensin blokade on renal funtion in onsious dogs. ir. Res., 4, Levens, N. R., Peah, M. J. & arey, R. M. (1981). Role of the intrarenal renin angiotensin system in ontrol of renal funtion. ir. Res., 48, Mimran, A. & Deshodt, G. (1983). The role of the renin angiotensin system in the hormonal and renal responses to tilt in normal man. Renal Physiol., 6, Navar, L. G. & Langford, H. G. (1974). n Angiotensin, eds Page,. H. & Bumpus, F. H., pp New York: Springer Verlag. Oparil, S. Vassau,., Sanders,. A. & Haber,. (197). Role of renin in aute postural homeostasis. irulation, 41, Peare, M. L. & Newman,. V. (1954). Some postural adjustments of salt and water eretion. J. lin. nvest., 33, Reid,. A. (1984). n dema, eds Staub, N.. & Taylor, A.., pp New York: Raven Press. Sraer, J. D., Sraer, J., Ardaillou, T. & Mimourne,. (1974). videne for renal glomerular reeptors for angiotensin. Kidney nt., 6, Streeten, D. H. & Speller, P. J. (1986). The role of aldosterone and ADH in the postural hanges in renal eretion in normal subjets and in patients with idiopathi oedema. Metabolism, 15, Surshin, A. & White, H. L. (1956). Postural effets on renal tubular ativity. J. lin. nvest., 35, Swartz, S. L., Williams, G. H., Hollenberg, N. K., Levine, L., Dluhy, R. G. & Moore, T. J. (198). aptopril indued hanges in prostaglandin prodution. Relationship to vasular responses in normal man. J. lin. nvest., 65, Trippodo, N. L., Hall, J.., Lohmeier, T.. & Guyton, A.. (1971). ntrarenal role of angiotensin in ontrolling sodium eretion during dehydration in dogs. lin. Si. mol. Med., 52, Wilkins, M. R., Lewis, H. M., West, M. J. & Lote,. J. (1987). aptopril redues the renal response to intravenous atrial natriureti peptide in normotensives. J. Human Hypertension, 1, (Reeived 16 June 1988, aepted 12 Otober 1988)