Proceedings of the British Pharmacological Society Clinical Pharmacology Section
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PROCEEDINGS OF THE BRITISH PHARMACOLOGICAL SOCIETY CLINICAL PHARMACOLOGY SECTION 9-11 September 1987 UNIVERSITY OF OXFORD For oral communications with more than one author, an asterisk(*) denotes the one who presented the work. 90P Proceedings of the BPS, 9-11 September 1987 COMMUNICATIONS Low dose angiotensin II enhances proximal min clearance period (CP). Urine was collected tubular sodium reabsorption in man for this and a further CP after the infusion. Absolute Na+ excretion (UNa + V) (,mol J. McMURRAY*, P. H. SEIDELIN & min-' ± s.e. mean) for the baseline preinfusion A. D. STRUTHERS CP, the infusion CP and post infusion recovery Department of Clinical Pharmacology, Ninewells CPwas: (a) 119 ± 15; 112 ± 14; 108 ± 14. (b) 108 Hospital and Medical School, Dundee DD1 9SY + 13; 82 + 10; 101 ± 14 (P < 0.01 vs control). Fractional Na+ excretion (FENa+) (% s.e. The renin-angiotensin-aldosterone system mean) for the equivalent CP was (a) 0.84 ± 0.1; (RAAS) is crucial in the maintenance of Na+ 0.75 ± 0.1; 0.72 ± 0.09 (b) 0.82 ± 0.09; 0.56 + balance in man. The role of aldosterone in Na+ 0.07; 0.69 ± 0.09 (P < 0.02 vs control). Fractional homeostasis is well known (Laragh, 1985). In Li+ excretion (FEL,-) (% + s.e. mean) was: (a) addition, however, there are now animal data to 31 ±2;30+2;34+3. (b)29±2;23±2;27±3. suggest that angiotensin II (All) plays a direct (P < 0.01 vs control). Distal Na+ reabsorption role, independent of aldosterone, in controlling (RDNa+) (% ± s.e. mean) was: (a) 34 ± 2; 34 + renal Na+ reabsorption. For example, studies in 3;38 ± 4.8. (b)28 ± 3;25 ± 3;28 ± 4. (P<0.05 experimental animals suggest that All itself has vs control). Aldosterone levels (pg ml-') were: potent effects of Na+ handling, mainly within (a) 168 ± 26; 189 ± 29; 171 ± 30. (b) 240 ± 36; the proximal tubule (PT). However, the effects 282 ± 47; 293 ± 35 (P < 0.01 vs control). HR and of physiological changes in All have been little BP did not change during either infusion. studied in man and evidence for a tubular site of All was potently antinatriuretic at the low action of All in man is lacking. To investigate dose used in this study. FENa+ also decreased these questions further, we have now studied the indicating a tubular site of action. Li+ is a specific effect of All on renal Na+ and Li' handling in marker for PT Na+ handling (Thomsen, 1984). salt replete normal volunteers. FEL`+ fell during All infusion indicating enhanced Six subjects were studied in the seated position PT Na+ reabsorption. AII also increased aldo- on two separate occasions. At 22.00 h the evening sterone secretion but the fall in RDNa+ suggests before the study each volunteer ingested 500 mg that aldosterone contributed little, if anything to of lithium carbonate. An initial water load of 15 the antinatriuresis caused by All. ml kg-1 of water was given at the start of the These results demonstrate for the first time in study. Urine was voided every 20 miii thereafter man, using Li+ as a specific marker, that physio- and the same volume of water drunk until a logical changes in All increase PT Na+ reabsorp- steady state diuresis was established. Aliquots of tion. This effect of AII may also be significant in urine were kept for later analysis. An infusion of disease states where the RAAS is activated. The either (a) 5%-D-glucose or (b) All 1 ng kg-' removal of the direct PT effect of All may also min-' was then administered for a further 20 be an important action of ACE inhibitors. Laragh, J. H. (1985). Newv Engl. J. Med., 313, 1330. Thomsen, K. (1984). Neplirotn, 37, 217. The renal effects ofatrial natriuretic peptide haloperidol or chlorpromazine) has been re- in man are not attenuated by D-sulpiride ported to inhibit or completely block these effects of ANP (Webb et al., 1986; Marin-Grez et al., S. FREESTONE*, T. M. MacDONALD, 1985). This was not confirmed in dogs using SCH R. F. JEFFREY & M. R. LEE 23390 (Murphy et al., 1986). We have therefore University Department of Clinical Pharmacology, The investigated the effect of dopamine receptor Royal Infirmary, Edinburgh, EH3 9YW blockade with D-sulpiride (S) on the effects of ANP in man. Infusion of oa-human atrial natriuretic peptide Eight healthy male volunteers (mean age 31.5 (ANP) causes a marked diuresis and natriuresis. range 24-42 years) were studied on two occasions, In rats, pre-treatment with dopamine (DA&)- at least 7 days apart. They took a normal diet and receptor antagonists (SCH 23390, D-sulpiride, for 2 days before each study day a supplement of Proceedings of the BPS, 9-11 September 1987 91P 100 mmol sodium (10 slow-sodium tablets), but Baseline urine flow rate and natriuresis were fasted on the morning of study. They were given similar on both days (Table 1), as were urine 500 ml of water by mouth and 200 ml every 30 dopamine excretion and blood pressure. D- min thereafter, plus an i.v. infusion of 0.9% sulpiride infusion did not alter these parameters saline (80 ml h-1). After 2 h subjects received D- significantly. Plasma concentrations of ANP sulpiride, a relatively selective DA1 antagonist, during infusion were not significantly different on one of the days (an i.v. bolus of 1.5 mg kg-l on both days (at the midpoint -431 ± 62 pg ml-1 over 5 min followed by an infusion of 1.5 mg kg-1 (ANP only) vs-451 ± 155 pg ml-' (ANP + S)). over 55 min then 1 mg kg-' hourly for 3 h). ANP at this dose level caused no change in blood This has been shown previously to attenuate the pressure or pulse rate. D-sulpiride did not signi- renal effects of the dopamine prodrug gludopa ficantly attenuate the effects of ANP (Table 1). (MacDonald et al., 1987). At 4 h, a 1 h infusion Under the conditions of this study DA1- of ANP 7.5 pmol kg-' min- was commenced. receptor blockade with D-sulpiride did not reduce Urine was collected hourly for 4 h during the run urine flow or natriuresis and did not attenuate in period, but at 30 min intervals during the ANP the renal effects of ANP. We conclude that the infusion. Blood pressure and pulse rate were renal effects of this peptide are not mediated by measured by a Dinamap recorder. dopaminergic (DA1) receptors in man. Table 1 Mean (s.d.) urine flow rate and natriuresis Baseline (0-2 h) After S (2-4 h) Peak (4.5-5 h) ANP ANP + S ANP ANP + S ANP ANP + S Urine flow rate 8.2 (3.3) 8.2 (3.2) 7.8 (1.7) 8.3 (2.1) 14.8 (3.3) 14.4 (4.8) (ml min-1) Natriuresis 0.29 (0.09) 0.27 (0.11) 0.27 (0.07) 0.28 (0.10) 0.58 (0.19) 0.53 (0.16) (mmol min'-) MacDonald, T. M. etal. (1987). Br. J. clin. Pharmac., Murphy, M. B. (1986). Clin. Res., 34, 712A. 23, 612P. Webb, R. L. et al. (1986). Life Sci., 38, 2319. Marin-Grez, M. et al. (1985). Life Sci., 36, 2171. Lithium attenuates the renal response to Seven healthy male volunteers aged 21-39 -y-L-glutamyl-L-dopa in man years were studied on two occasions under water loaded, salt-replete conditions. On each day R. F. JEFFREY*, T. M. MacDONALD & M. R. LEE normal saline (50 ml) was infused during a 90 Department of Clinical Pharmacology, The Royal min baseline period, followed by gludopa (25 ,g Infirmary, Edinburgh EH3 9YW kg-l min-1 in 50 ml normal saline) for 90 min, then a further 90 min recovery period with normal Analysis of the renal clearance of lithium has saline (50 ml). On one occasion, lithium carbonate been claimed to provide a marker for proximal (750 mg, Camcolit) was taken by mouth at 22.00 h tubular sodium reabsorption and the method has the previous evening. Subjects remained supine been used to identify the site of action in the except to void. Blood and urine samples were nephron of natriuretic agents (Thomsen, 1984). taken at 45 min intervals. Dopamine produces a natriuresis by increasing Gludopa alone increased urine dopamine ex- glomerular filtration rate and in addition, in cretion from 1.1 ± 0.1 to 854 ± 56 nmol min-' vitro studies have suggested a proximal tubular (mean ± s.e. mean P < 0.001), raised sodium action (Bello-Reus et al., 1982). -y-L-glutamyl- output from 0.18 ± 0.08 to 0.44 ± 0.08 mmol L-dopa (gludopa) is a highly efficient, renally min-' (P < 0.01), and suppressed plasma renin selective, dopamine prodrug in man (Worth et activity (PRA) from 1.40 ± 0.37 to 0.77 ± 0.15 al., 1985). We have assessed the effect of this ng Al ml-' h-', a 46% reduction (P < 0.05). dipeptide on renal salt handling and lithium Creatinine clearance and plasma atrial natriuretic clearance in man. peptide concentrations (ANP) were not signifi- 92P Proceedings of the BPS, 9-11 September 1987 cantly altered by gludopa. On the morning after not alter baseline dopamine levels or the dopa- lithium was taken, the plasma level was 0.29 + mine output after gludopa. Creatinine clearance 0.04 nmol I` at the start of the baseline period and plasma ANP were not different with lithium. and declined to 0.24 ± 0.04 mmol I` at the end A single dose of lithium, producing sub- of the study.