Background: Angiotensin Converting Enzyme inhibitors reduce mortality in heart failure. One therapeutic mechanism is believed to be the reduction of circulating angiotensin II and aldosterone. However, the Renin᎐Angiotensin᎐Aldosterone axis Ž . RAAS is not uniformly suppressed during therapy for heart failure. This effect has been referred to as 'angiotensin II reactivation' and 'aldosterone escape' and their reactivation may herald clinical deterioration. In the CONSENSUS I trial, correlations were seen between mortality, and angiotensin II and aldosterone. Furthermore, mortality was lower in those with good angiotensin II suppression. Therefore, neurohormonal elevation despite adequate treatment may associate with a poorer prognosis. Aims: To follow chronic heart failure patients on ACE inhibitors for 18 months to assess whether or not angiotensin II and aldosterone reactivation are progressive with time, whether reactivation of both occurs simultaneously, and Ž whether different ACE inhibitors have different neurohormonal profiles. Methods and results: We studied 22 patients MrF . 19:3, 72.5" 7 years on stable ACE inhibitors. Five times, in 18 months, samples were taken for neurohormones and ACE activity. Mean levels of neurohormones were remarkably stable over time, although captopril takers had generally higher Ž . Ž . angiotensin II, but lower aldosterone and renin. Aldosterone 'escape' ) 80 pgrml occurred in 13r97 samples 13.5% , in Ž . Ž . Ž . 5r22 23% individuals. Angiotensin II was elevated G 10 pgrml in 8r102 samples 8% , in 6r22 27% individuals. Four subjects had isolated angiotensin II reactivation, and three had aldosterone escape alone. On regression analyses between Ž . neurohormones in captopril takers there were significant correlations between; renin and angiotensin II r s 0.62; P-0.02 ; Ž . Ž . angiotensin II and aldosterone r s 0.6; P-0.02 ; and renin and aldosterone r s 0.92; P-0.00001 . Conclusion: In stable heart failure patients un-suppressed levels of angiotensin II and aldosterone occur despite therapy, but they are not necessarily progressive, nor simultaneous. Furthermore, contemporaneous serum ACE activity makes it unlikely the data presented reflects poor compliance. The results suggest that captopril takers may have different neurohormonal profiles, i.e. higher angiotensin II, and also better correlations between RAAS components, compared to longer acting preparations, although the numbers are small. Our data supports that of Swedberg et al. who showed reductions in both aldosterone and angiotensin II due to ACE inhibitor therapy, but no correlation between ACE activity and angiotensin II and only a limited Ž . correlation r s 0.37 between angiotensin II and aldosterone. This suggests that the interaction between the components of the renin᎐angiotensin system is not simple and linear. The fact that each phenomenon appears to occur in isolation means that neurohormonal monitoring of individual could provide useful information to direct additional therapy. The RALES study ha...

Endothelial function is defective in hypercholesterolaemia, and animal models have suggested that angiotensin-converting enzyme inhibitors may prevent arterial damage. We studied the effect of 6 months treatment with lisinopril on endothelial function in a group of patients with hypercholesterolaemia. Forty patients were studied. Forearm blood flow responses to acetylcholine and sodium nitroprusside were assessed by venous occlusion plethysmography. Subjects were then randomized in a double-blind fashion to receive either lisinopril, 20 mg/day (n=20), or placebo (n=20) for 6 months. Plethysmography was then repeated. Baseline variables between groups were comparable. In the lisinopril group blood pressure fell significantly [systolic: 145+/-4 to 128+/-4 mmHg (P<0.001); diastolic: 84+/-2 to 74+/-2 mmHg (P<0.001)]. An improvement was found in the vasodilatory response (expressed as a ratio of the infused/control arm) to acetylcholine, e.g. 3.33+/-0.3 (pre) versus 4.45+/-0.48 (post) at 30 microg/ml (P<0.03), and also to nitroprusside, e.g. 3.0+/-0.2 (pre) versus 3.86+/-0.3 (post) at 3.2 microg/ml (P<0.01). In the placebo group vasodilatation did not change significantly in response to acetylcholine, and nitroprusside responses were unchanged. The data presented suggest that 6 months of lisinopril therapy have a beneficial effect on arterial function in subjects with hyperlipidaemia. Further work should now investigate whether angiotensin-converting enzyme inhibitors are beneficial in reducing mortality and morbidity in hypercholesterolaemia.

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N G -monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics. Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4 mg kgwith a front loaded bolus (4 mg kg −1 ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion (t 0 ) and after 4, 8, and 12 min (t 1 , t 2 and t 3 ).Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t 1 and persisted during the entire infusion period. Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.

Aims Oestrogens in women have been shown to cause vasodilation which may re¯ect alterations in the activity of vascular angiotensin converting enzyme (ACE) and/or sensitivity to angiotensin II. The aim of this study was to assess the effect of ovarian hormones on vascular tone, vascular ACE activity and vasoconstriction to angiotensin II in males. Methods Eight volunteers were randomised in a crossover design to oestradiol, medroxy-progesterone, and placebo. Vasoconstriction to angiotensin I and angiotensin II was assessed by forearm plethysmography. Results Although baseline forearm¯ow was increased with oestradiol, suggesting generalized vasodilation, there were no changes in the vasoconstrictor responses to angiotensin I or angiotensin II. Medroxy-progesterone affected neither baseline¯ow nor vasoconstrictor responses. The results expressed as percentage reduction in¯ow (mean t s.d.) were: angiotensin I 48 pmol ml x1 : placebo x48t14%; oestradiol x42t16%; medroxyprogesterone x43t8% and for angiotensin II 16 pmol ml x1 : placebo x42t10%; oestradiol x39t11%; medroxyprogesterone x46t13%. Conclusions Acute administration of oestradiol caused vasodilation in males, the effect was not due to alterations in vascular ACE activity or to altered sensitivity to angiotensin II.

Aims We wished to see if renin release in man was inhibited by nitric oxide blockade, suggesting a role for nitric oxide in renin release. Evidence from animal studies has shown variable effects on renin release depending on the model and stimulus used. Methods Ten normal male volunteers, received either l-NMMA as a front loaded infusion (4 mg kg −1 bolus, with 4 mg kg −1 infusion), or placebo, followed by an intravenous bolus of 5 mg frusemide to stimulate renin. To investigate whether any alteration in renin release was due to the pressor effect of the l-NMMA, the experiment was repeated using an equipressor dose of phenylephrine (0.5 mg kg −1 min −1 ). P<0.01). Phenylephrine 0.5 mg kg −1 min −1 produced very similar haemodynamic effects to l-NMMA, and also suppressed the renin response to frusemide (1.43±0.290 vs 2.67±0.342 ng mlConclusions In man, the renin inhibition seen with NO synthesis inhibition is similar to that seen with a standard pressor stimulus, hence inhibition of renin in man by l-NMMA, may be due to both direct effects on macula densa cells and indirect haemodynamic effects.Keywords: blood pressure, frusemide, nitric oxide, phenylephrine, renin juxtaglomerular cells [5]. Nitric oxide synthase has also Introduction been localized in a variety of other sites within the kidney including vascular and tubular elements [6]. Furthermore, There has recently been much experimental evidence to suggest that nitric oxide is important in control of the activation of nitric oxide synthase in the macula densa appears to occur under conditions which would be secretion of a variety of hormones, including pituitary secretion of growth hormone [1], insulin from pancreatic expected to increase renin secretion, e.g. frusemide stimulation [7]. In whole animal experiments, mainly in islet cells [2], and hypothalamic secretion of CRF [3]. This evidence would suggest that nitric oxide may be rats, nitric oxide antagonists can be shown to inhibit the release of renin in response to frusemide [8], which important as a signalling molecule in these situations, possibly working in a paracrine fashion. More recently, suggests a permissive role for nitric oxide in renin release [7, 9, 10]. However with regard to pressure-dependent experiments have been undertaken to examine the possibility that nitric oxide also mediates renin release.renin release the results are conflicting. Sigmon et al. [11] found that the inhibition of renin by nitric oxide This suggestion first arose when isoforms of nitric oxide synthase were found in the macula densa cells antagonists was due to their effects on renal perfusion pressure, and that if this was controlled, the inhibition of around the renal tubules [4], i.e. the same cells that are believed to control the secretion of renin from the renin could be reversed. suppressed by an equipressor dose of phenylephrine [7].