Eur J Clin Pharmacol (1992) 43:1-5 lPhe s se@rleg g © Springer-Verlag 1992 Originals Lack of correlation between the acute haemodynamic response to intravenous captopril and plasma concentrations of angiotensin II in patients with chronic cardiac failure A. D. Fiapan, T. Ro D. Shaw, C. R. W. Edwards, M. Rademaker, E. Davies, and B. C. Williams Departments of Cardiology and Medicine, Western General Hospital, Edinburgh, UK Received: October 10,1991/Accepted in revised form: March 19,1992 Summary; We have given a series of incremental intrave- nous injections of captopril to ten patients with chronic cardiac failure. Small doses of captopril produced significant changes in pulmonary artery end-diastolic pressure and right atrial pressure, up to a total cumulative dose of captopril of 2.5 mg, after which further injections had no significant ef- fect. There were large changes in systemic vascular resis- tance and blood pressure up to a cumulative dose of cap- topril of 5.0 mg, after which the injection of larger doses caused no further significant changes. Small doses of intravenous captopril produced large in- creases in plasma renin activity and plasma angiotensin I concentrations up to a total cumulative dose of captopril of 1.25 mg, after which there were no significant further changes in either plasma renin activity or plasma an- giotensin ! concentration. However the plasma concen- tration of angiotensin II fell more slowly, no further change being recorded after a total cumulative dose of captopril of 10 rag. These results suggest that plasma renin activity is not the only determinant of plasma angiotensin II concentra- tions. Key words: Haemodynamic responses, Captopril, Car- diac failure; plasma renin activity; angiotensin II The acute haemodynamic response to angiotensin con- verting enzyme (ACE) inhibitors, which produce both ar- terial and venous dilatation in patients with cardiac failure, is well described [1]. However, in controlled clini- cal trials the dose of ACE inhibitor used has varied [2, 3, 4] and some authors have claimed that larger doses may be associated with increased inhibition of the converting enzyme and an improved clinical response [4]. The main target for ACE inhibitors was initially thought to be the circulating or endocrine renin-angiotensin system. How- ever, it is difficult to explain why ACE inhibitors are effec- tive in lowering the blood pressure in patients with normal or low plasma renin activity [5], or even in anephric sub- jects [6], and why the hypotensive response outlasts the duration of serum ACE inhibition [7]. In patients with chronic cardiac failure withdrawal of ACE inhibitor ther- apy does not lead to immaediate clinical deterioration [8], and beneficial haemodynamic responses are even seen in patients with normal plasma renin activity [9]. The activity of the renin-angiotensin-aldosterone sys- tem (RAAS) in patients with chronic cardiac failure may reflect their clinical state [10], and it increases after the in- troduction of diuretic therapy [11]. However, both the short- [12, 13] and long-term [14] haemodynamic effects of ACE inhibitors have not always correlated well with pre-treatment measurements of plasma renin activity, and sudden withdrawal of ACE inhibitors does not lead to im- maediate vasoconstriction, despite a rapid rise in plasma angiotensin II concentration [8]. Attention has recently been drawn to the peripheral tissues as a site of production of angiotensin II [15] and we have therefore examined the relation between haemody- namic responses and the circulating plasma angiotensin II concentration during a series of incremental doses of in- travenous captopril. Methods Patients We studied ten patients (8 m, 2 f) with chronic cardiac failure due to myocardial impairment. Their mean age was 61 (11) y. Myocardial impairment was documented by echocardiography and was due to ischaemic heart disease in seven and to a cardiomyopathy in three. The mean isotopicallydetermined ejection fraction was 10 % (range 6-26 %). All were in sinus rhythm. All remained symptomatic des- pite treatment with digoxin 0.25 mg daily and diuretics (mean daily dose of frusemide 106 mg, range 80-200 mg) and their clinical state had been stable for 4 weeks before the study. Haemodynamic measurements Haemod)~amic measurements were carried out followingan over- night fast, and all other medications were withheld on the day of the study. All other vasodilator drugs had been stopped at least 3 days before the study.