TY - JOUR
AU - McMurray, John, J.V
AB - Abstract Objective: The relative importance of ETA and ETB receptors in mediating the constrictor effects of endogenous endothelin-1 in patients with chronic heart failure is not known. The primary purpose of this study was to compare the acute effects of selective ETA and ETB receptor antagonists in vivo in healthy subjects and patients with chronic heart failure. Our secondary aim was to examine more closely the effect of chronic heart failure on endothelin biosynthesis. Methods: We studied the effects of BQ-123 (a selective ETA antagonist) and BQ-788 (a selective ETB antagonist) in ten healthy subjects and ten patients with chronic heart failure. Locally active doses of each antagonist were infused into the non-dominant brachial artery for 90 min on separate days at least 1 week apart. Changes in forearm blood flow were measured by venous occlusion plethysmography. Venous blood samples were obtained prior to antagonist infusion for assay of total endothelin, big endothelin-1 and C-terminal fragment immunoreactivity. Results: BQ-123 (100 nmol/min) increased blood flow by 54±10% (P<0.001) and 30±5% (P<0.001) in controls and heart failure patients, respectively. BQ-788 (1 nmol/min) reduced blood flow by 15±5% (P=0.036) and 9±4% (P=0.001) in controls and heart failure patients, respectively. Total endothelin immunoreactivity was non significantly greater in heart failure patients than controls (6.8±1.4 vs. 4.6±0.5 pM; P=0.13). Big endothelin-1 (2.6±0.4 vs. 1.7±0.1 pM; P=0.04) and C-terminal fragment immunoreactivity (2.1±0.3 vs. 0.6±0.1 pM; P<0.0001) were each significantly greater in heart failure patients than controls. Conclusions: Selective ETA receptor antagonism caused vasodilatation in the peripheral circulation of healthy subjects and patients with chronic heart failure while selective ETB receptor antagonism caused vasoconstriction in each group. ETB receptor antagonism may therefore cause potentially deleterious vasoconstriction in chronic heart failure. Chronic heart failure is associated with a significant increase in plasma big endothelin-1 and C-terminal fragment immunoreactivity. Endothelins, Heart failure, Receptors, Vasoconstriction/dilation Time for primary review 25 days. 1 Introduction Endothelin-1 (ET-1) has potent vasoconstrictor and mitogenic properties which are important in the pathophysiology of chronic heart failure (CHF) [1]. Acute and chronic administration of drugs which block the generation or actions of endogenous ET-1 have favourable haemodynamic effects in both experimental [2–4] and human forms of CHF [5–7]. Encouragingly, chronic treatment with either an ETA selective [3] or mixed ETA/ETB endothelin receptor antagonist [4] substantially reduces mortality in rats with CHF following myocardial infarction. Anti-ET drugs would truly represent an important development in heart failure therapeutics if they can be shown to have a similarly beneficial effect on mortality in patients with CHF. Two subtypes of ET receptor, designated ETA and ETB, mediate the effects of ET-1 in human blood vessels [8–11]. Both ETA and ETB receptor subtypes are expressed on vascular smooth muscle cells where their activation results in vasoconstriction [10,11]. ETB receptors are also expressed on vascular endothelial cells where their activation triggers the release of endothelium-derived vasodilators [12]. Agonist based studies in healthy subjects [11] and patients with CHF [5,13] suggest that both ETA and ETB receptors can mediate vasoconstriction in human resistance and capacitance vessels in vivo. However, much has still to be learned about the functional importance of each receptor subtype in mediating the effects of endogenous ET-1 in human physiology and pathophysiology. Knowledge of the contribution of ETA and ETB receptor subtypes to vasoconstriction in CHF has obvious implications for the therapeutic use of ET receptor antagonists in this disease. Currently, it is unclear whether a non-selective or mixed ETA/ETB antagonist would have the more favourable haemodynamic profile in CHF. Acute administration of a selective ETA receptor antagonist causes substantial vasodilatation in healthy subjects [14,15] and patients with CHF [5]. This suggests an important role for ETA receptors in regulating basal vascular tone and possibly the increased vascular resistance characteristic of CHF. Brachial artery infusion of a selective ETB receptor antagonist causes vasoconstriction in healthy individuals suggesting that the action of endogenous ET-1 at endothelial ETB receptors contributes importantly to basal vascular tone [15]. ETB receptor mediated vasoconstriction may be increased in CHF [5,16] but the effect of selective ETB receptor blockade in patients with CHF is not known. It has been shown, however, that systemic administration of a selective ETB antagonist to dogs with CHF induced by rapid ventricular pacing causes vasoconstriction and a fall in cardiac output [17]. The primary purpose of this study, therefore, was to compare the effects of selective ETA and selective ETB receptor antagonists in patients with CHF. We studied the acute haemodynamic effects of BQ-123, a selective ETA receptor antagonist [18], and BQ-788, a selective ETB receptor antagonist [19], in the forearm circulation of CHF patients and compared responses with those in age-matched healthy control subjects. Our secondary aim was to examine more closely the effect of CHF on ET biosynthesis. Previous studies have suggested that CHF is associated with a predominant increase in plasma big ET-1 [20,21], the precursor peptide cleaved by endothelin converting enzyme (ECE) to generate mature ET-1 and a biologically inert C-terminal fragment (CTF) [22]. The effect of CHF on plasma CTF immunoreactivity has not been studied previously. We therefore measured plasma ET, big ET-1 and CTF immunoreactivity in CHF patients and age-matched control subjects. 2 Methods 2.1 Subjects Studies were conducted with the approval of the local ethics committee and conformed with the principles outlined in the Declaration of Helsinki (Cardiovascular Research 1997;35:2–3). Ten men with CHF stable for at least the previous 3 months were recruited together with ten age-matched healthy male controls. Nine CHF patients had underlying ischaemic heart disease (one had coexisting aortic stenosis) and one had idiopathic dilated cardiomyopathy. No CHF patient had concomitant hypertension, diabetes mellitus or chronic renal failure and each was receiving maintenance treatment with a diuretic and angiotensin converting enzyme inhibitor (either captopril 50 mg three times daily, enalapril 10 mg twice daily or lisinopril 10 mg once daily). Medication was continued as usual before and during the day of studies because we wished to evaluate the effects of ETA and ETB receptor blockade in patients already receiving conventional medical therapy for CHF. All control subjects were asymptomatic with no clinical, electrocardiographic or echocardiographic evidence of cardiovascular disease. Patient and control subject characteristics are summarised in Table 1. Table 1 Subject characteristics . CHF patients . Control subjects . Age (years) 67±4 60±6 NYHAa clinical class II 3 – III 7 – Mean ejection fractionb (%) 21±2 65±3 Baseline forearm blood flowcd (ml/min/100 ml) 3.4±0.2 3.7±0.2 Cholesterold (mmol/l) 4.5±0.2 5.0±0.2 Mean arterial pressured (mmHg) 91±4 93±2 Mean heart rated (beats/min) 70±5 66±2 Drug therapy ACE inhibitor 10 – Diuretic 10 – Aspirin 9 – Digoxin 7 – Beta-blocker 2 – Oral nitrate 2 – Calcium channel antagonist 0 – . CHF patients . Control subjects . Age (years) 67±4 60±6 NYHAa clinical class II 3 – III 7 – Mean ejection fractionb (%) 21±2 65±3 Baseline forearm blood flowcd (ml/min/100 ml) 3.4±0.2 3.7±0.2 Cholesterold (mmol/l) 4.5±0.2 5.0±0.2 Mean arterial pressured (mmHg) 91±4 93±2 Mean heart rated (beats/min) 70±5 66±2 Drug therapy ACE inhibitor 10 – Diuretic 10 – Aspirin 9 – Digoxin 7 – Beta-blocker 2 – Oral nitrate 2 – Calcium channel antagonist 0 – a NYHA, New York Heart Association. b Calculated from M-mode echocardiogram at mitral leaflet tips. c Expressed as mean of infused and non-infused arms. d Baseline differences in cholesterol, forearm blood flow, mean arterial pressure and heart rate were not statistically significantly different between patients and controls. Open in new tab Table 1 Subject characteristics . CHF patients . Control subjects . Age (years) 67±4 60±6 NYHAa clinical class II 3 – III 7 – Mean ejection fractionb (%) 21±2 65±3 Baseline forearm blood flowcd (ml/min/100 ml) 3.4±0.2 3.7±0.2 Cholesterold (mmol/l) 4.5±0.2 5.0±0.2 Mean arterial pressured (mmHg) 91±4 93±2 Mean heart rated (beats/min) 70±5 66±2 Drug therapy ACE inhibitor 10 – Diuretic 10 – Aspirin 9 – Digoxin 7 – Beta-blocker 2 – Oral nitrate 2 – Calcium channel antagonist 0 – . CHF patients . Control subjects . Age (years) 67±4 60±6 NYHAa clinical class II 3 – III 7 – Mean ejection fractionb (%) 21±2 65±3 Baseline forearm blood flowcd (ml/min/100 ml) 3.4±0.2 3.7±0.2 Cholesterold (mmol/l) 4.5±0.2 5.0±0.2 Mean arterial pressured (mmHg) 91±4 93±2 Mean heart rated (beats/min) 70±5 66±2 Drug therapy ACE inhibitor 10 – Diuretic 10 – Aspirin 9 – Digoxin 7 – Beta-blocker 2 – Oral nitrate 2 – Calcium channel antagonist 0 – a NYHA, New York Heart Association. b Calculated from M-mode echocardiogram at mitral leaflet tips. c Expressed as mean of infused and non-infused arms. d Baseline differences in cholesterol, forearm blood flow, mean arterial pressure and heart rate were not statistically significantly different between patients and controls. Open in new tab Subjects were asked to abstain from caffeine containing drinks, alcohol and cigarette smoking on study days and to fast for at least 2 h before studies commenced. Studies were performed in a quiet clinical laboratory maintained between 23 and 25°C. Each CHF patient and control subject attended on two separate occasions at least 1 week apart for plasma sampling and separate, single-blind infusions of BQ-123 and BQ-788. 2.2 Plasma sampling Ante-cubital venous cannulae (23 Gauge) were sited in both arms using 1% lignocaine (Astra Pharmaceuticals Ltd.) for local anaesthesia. Blood samples (10 ml) were withdrawn from each arm into chilled plastic tubes containing EDTA after at least 30 min of supine rest and immediately before infusion of BQ-123 and BQ-788. Samples were centrifuged at 3000 rpm for 15 min at 4°C and separated immediately. Plasma was stored at −70°C until the time of assay. 2.3 Drug administration An unmounted 27-standard wire gauge steel cannula (Cooper's Needle Works) was inserted in the brachial artery of the non-dominant arm using 1% lignocaine for local anaesthesia and connected to a Welmed P1000 infusion pump (Welmed Clinical Care Systems) via a 16-Gauge epidural catheter (Portex Ltd.). Physiological saline (0.9%; Baxter Healthcare Ltd.) was infused intra-arterially at 1 ml/min for an equilibration period of at least 30 min prior to drug infusion. Locally active doses of BQ-123 and BQ-788 were dissolved in physiological saline and administered intra-arterially at 1 ml/min for 90 min. BQ-123 (Clinalfa AG) was infused at 100 nmol/min for 90 min, a dose previously shown to cause progressive forearm vasodilatation in healthy subjects [14,15] and patients with CHF [5]. BQ-788 (Clinalfa AG) was infused at 1 nmol/min for 90 min, a dose shown previously to inhibit in vivo venoconstriction caused by the selective ETB receptor agonist sarafotoxin S6c [23] and also to cause progressive forearm vasoconstriction in healthy subjects [15]. 2.4 Forearm blood flow measurement Forearm blood flow was measured by venous occlusion plethysmography as described previously using indium and gallium-in-silastic strain gauges applied to the widest aspect of each forearm [24]. The hand circulation was excluded during periods of blood flow measurement by inflation of wrist cuffs to 220 mmHg. Upper arm cuffs were inflated to 40 mmHg for 10 in every 15 s to prevent venous outflow and obtain plethysmographic recordings. Voltage output from a Vasculab SPG 16 strain gauge plethysmograph (Medasonics Inc.) was transferred to an Apple Macintosh computer (LC III; Apple Computer Inc.) for analysis using a MacLab analog-digital converter and Chart software (v. 3.2.8; both from AD Instruments). Blood flow was measured in both forearms at 10-min intervals during saline equilibration and at 5-min intervals during drug infusion. The last five measurements of forearm blood flow during each 3-min recording period were averaged and the mean percentage change from baseline in the ratio of flow between the infused and non-infused arms calculated. In this way the non-infused arm acts as an in-built control to ensure that the effects of infused drugs are distinguished from any external influences on blood flow. Blood pressure and heart rate were recorded in the non-infused arm at 10-min intervals throughout all studies using a well validated semi-automated sphygmomanometer (Takeda UA-751; Takeda Medical Inc.). 2.5 Measurement of plasma ET immunoreactivity After thawing, acidified plasma samples were subjected to selective solid-phase extraction in order to separate the CTF from ET and big ET-1. Each peptide was measured by radioimmunoassay as previously described [25,26]. 2.6 Data analyses All results are expressed as mean values with 95% confidence intervals (CI) in the text and standard errors in figures. Statistical significance was taken at the 5% level. The significance of the effect of BQ-123 and BQ-788 on forearm blood flow was examined using Statview 4.02 software (Abacus Concepts Inc.) for the Apple Macintosh computer to perform repeated measures analysis of variance (ANOVA). Unpaired t-testing was performed to test whether the peak effect of each antagonist on forearm blood flow was significantly different between patients and controls. Mean ET, big ET-1 and CTF immunoreactivities were determined for each subject from the four plasma samples obtained prior to antagonist infusion. Overall mean values for each group were then calculated from the sum of these individual means and unpaired t-testing employed to test the significance of differences observed between patients and controls. 3 Results Heart rate, blood pressure and forearm blood flow in the non-infused arm did not change significantly in any study confirming that BQ-123 and BQ-788 had no systemic haemodynamic effects. 3.1 Effects of BQ-123 and BQ-788 in control subjects BQ-123 caused progressive vasodilatation in control subjects, increasing forearm blood flow by 54±10% (CI: 33–73%; ANOVA vs. baseline: P<0.001) after 90 min of infusion (Fig. 1). BQ-788 caused progressive vasoconstriction in control subjects, reducing forearm blood flow by 15±5% (CI: 5–24%; ANOVA vs. baseline: P=0.04) after 90 min of infusion (Fig. 1). Fig. 1 Open in new tabDownload slide Brachial artery infusion of BQ-123 and BQ-788 in healthy male subjects (n=10). BQ-123 (100 nmol/min; □) caused progressive vasodilatation and a peak increase in forearm blood flow of 54±10% (P<0.001) after 90 min of infusion. BQ-788 (1 nmol/min; ●) caused progressive vasoconstriction and a peak reduction in forearm blood flow of 15±5% (P=0.036) after 90 min of infusion. Fig. 1 Open in new tabDownload slide Brachial artery infusion of BQ-123 and BQ-788 in healthy male subjects (n=10). BQ-123 (100 nmol/min; □) caused progressive vasodilatation and a peak increase in forearm blood flow of 54±10% (P<0.001) after 90 min of infusion. BQ-788 (1 nmol/min; ●) caused progressive vasoconstriction and a peak reduction in forearm blood flow of 15±5% (P=0.036) after 90 min of infusion. 3.2 Effects of BQ-123 and BQ-788 in CHF patients BQ-123 caused progressive vasodilatation in CHF patients, increasing forearm blood flow by 30±5% (CI: 20–42%; ANOVA vs. baseline: P<0.002) after 90 min of infusion (Fig. 2). Peak vasodilatation to BQ-123 was significantly blunted in CHF patients compared to controls (CHF vs. controls P<0.05). BQ-788 caused progressive vasoconstriction in CHF patients, reducing forearm blood flow by 9±4% (CI: 2–17%; ANOVA vs. baseline: P=0.0006) after 90 min of infusion (Fig. 2). The effect of BQ-788 was not significantly different between CHF patients and controls. Fig. 2 Open in new tabDownload slide Brachial artery infusion of BQ-123 and BQ-788 in patients with CHF (n=10). BQ-123 (100 nmol/min; □) caused progressive vasodilatation and a peak increase in forearm blood flow of 30±5% (P<0.001) after 90 min of infusion. BQ-788 (1 nmol/min; ●) caused progressive vasoconstriction and a peak reduction in forearm blood flow of 9±4% (P=0.001) after 90 min of infusion. Fig. 2 Open in new tabDownload slide Brachial artery infusion of BQ-123 and BQ-788 in patients with CHF (n=10). BQ-123 (100 nmol/min; □) caused progressive vasodilatation and a peak increase in forearm blood flow of 30±5% (P<0.001) after 90 min of infusion. BQ-788 (1 nmol/min; ●) caused progressive vasoconstriction and a peak reduction in forearm blood flow of 9±4% (P=0.001) after 90 min of infusion. 3.3 Plasma ET, big ET-1 and CTF immunoreactivity Total ET immunoreactivity was non-significantly greater in CHF patients (6.8±1.4 pM) than control subjects (4.6±0.5 pM; CHF vs. controls P=0.13; Fig. 3). Big ET-1 (2.6±0.4 vs. 1.7±0.1 pM; CHF vs. controls P=0.04) and CTF immunoreactivity (2.1±0.3 vs. 0.6±0.1 pM; CHF vs. controls P<0.0001) were both significantly greater in CHF patients than control subjects (Fig. 3). Fig. 3 Open in new tabDownload slide Comparison of plasma CTF, big ET-1 and total mature ET immunoreactivity in CHF patients and age-matched healthy controls (both n=10). Plasma ET tended to be higher in CHF patients (CHF vs. controls P=0.13) while CTF and big ET-1 immunoreactivity were both significantly greater in CHF patients than controls (CHF vs. controls P<0.0001 and P=0.04, respectively). Fig. 3 Open in new tabDownload slide Comparison of plasma CTF, big ET-1 and total mature ET immunoreactivity in CHF patients and age-matched healthy controls (both n=10). Plasma ET tended to be higher in CHF patients (CHF vs. controls P=0.13) while CTF and big ET-1 immunoreactivity were both significantly greater in CHF patients than controls (CHF vs. controls P<0.0001 and P=0.04, respectively). The mean CTF:big ET-1 ratio, a putative novel index of ECE activity, was significantly greater in CHF patients than in control subjects (0.9±0.1 vs. 0.4±0.1; P=0.006). 4 Discussion Morbidity and mortality from CHF remain high despite the impact of ACE inhibitors and, more recently, beta-blockers. Novel treatment strategies capable of further improving symptoms and reducing mortality are needed. Preliminary evidence suggests that anti-ET drugs, in particular ET receptor antagonists, might have a role to play in this regard [2–7]. However, the relative functional importance of ETA and ETB receptors in mediating the effects of endogenous ET-1 in patients with CHF is not known. We have, therefore, undertaken the first comparison of the vascular actions of ETA and ETB receptor selective antagonists in patients with CHF. Our key finding was that administration of a selective ETB receptor antagonist to CHF patients treated with ACE inhibitors caused arteriolar vasoconstriction, with a similar effect seen in age-matched healthy controls. Agonist based studies have confirmed the presence of contractile ETB receptors in healthy subjects [11] and patients with CHF [5,13,27], but antagonist studies tell us more about the role of endothelin receptors in mediating the effects of endogenous ET-1. Our current studies with BQ-788 indicate that the dominant action of endogenous ET-1 at ETB receptors is at the dilator endothelial rather than constrictor smooth muscle ETB receptor. Similar findings have been seen following systemic administration of BQ-788 in healthy subjects [28]. Consequently, as has been seen in a canine model of CHF, ETB receptor antagonism may cause potentially deleterious vasoconstriction in patients with CHF [17]. It is important to acknowledge that the vasoconstrictor effect of BQ-788 may simply reflect better access of the antagonist to dilator endothelial than constrictor smooth muscle ETB receptors. However, more prolonged infusion of the same dose of BQ-788 causes similar vasoconstriction in healthy subjects [15] and it appears that BQ-123 gains ready access to smooth muscle when administered intra-luminally. Further work is needed to help clarify whether the effect of BQ-788 is due to displacement of bound ET-1 from ETB receptors, to failure of ET-1 clearance by endothelial ETB receptors or to some other mechanism. Consistent with previous observations, we found that acute administration of a selective ETA receptor antagonist caused substantial vasodilatation in healthy subjects and patients with CHF [5,14,15]. ETA receptors therefore play an important role in regulating basal vascular tone and possibly the increased peripheral arteriolar resistance characteristic of CHF. Given that responses in the forearm vasculature are generally representative of responses in other resistance beds [24,29], these data suggest that ETA receptor antagonists may be useful as vasodilator agents in the treatment of CHF, even in patients already receiving treatment with an ACE inhibitor. Further comparative studies are needed to clarify whether there is any significant difference in the systemic haemodynamic effects of ETA selective and mixed ETA/ETB receptor antagonists in patients with CHF. It has been demonstrated that acute co-infusion of selective ETA and ETB receptor antagonists in healthy subjects causes less vasodilatation than an ETA antagonist alone [15]. In conjunction with our current data, this suggests that mixed ETA/ETB receptor antagonists may be less effective vasodilator agents than ETA selective antagonists. It would have been of obvious interest for us to have compared the effects of BQ-123 and BQ-788 with a mixed ETA/ETB antagonist, but these agents are not currently available for clinical studies of this type. We found that the peak vasodilator effect of BQ-123 was significantly blunted in CHF patients compared to controls. Although a steady state had not clearly been achieved in control subjects receiving BQ-123, other similar studies with BQ-123 have shown no significant incremental vasodilatation to the antagonist beyond 60 min of infusion [15]. Whether the blunted effect of BQ-123 in CHF patients reflects the modulating effects of concurrent drug therapy or possibly altered ETA receptor function cannot be established from a single dose comparison of this type. It is likely, however, that the dose of BQ-123 we employed achieved fairly maximal inhibition of ETA receptors given that infusion of nine-fold lower [15] and 36-fold lower [30] doses of BQ-123 have been reported to cause a similar degree of forearm vasodilatation in healthy subjects. It has been suggested previously that ETA and ETB receptor sensitivity may be altered in CHF [5,13,16]. Further work is needed to clarify whether there are functionally significant changes in ETA and ETB receptor function in CHF which might influence the haemodynamic actions or clinical efficacy of endothelin receptor antagonists. Our other novel observation was that plasma CTF immunoreactivity was significantly higher in CHF patients than controls, the presence of CTF in plasma confirming that ECE mediated conversion of big ET-1 to ET-1 has taken place [26]. This is further evidence that the ET system is activated in CHF, though it is possible that reduced plasma clearance might have contributed to the elevated levels of CTF. Despite the relatively short plasma half life of CTF [31], we propose that the ratio of CTF to big ET-1 might be a more useful index of ECE activity than plasma ET-1 given that newly synthesized ET-1 binds rapidly to ET receptors [32]. We noted that the ratio of CTF to big ET-1 was significantly greater in CHF patients than controls. The effect of CHF on the plasma half life of CTF is not known but it is improbable that CTF would accumulate more than its larger precursor big ET-1. Although myocardial ECE activity is not altered in human CHF [33], our current data suggest that CHF may be associated with increased vascular ECE activity as may be the case in atherosclerotic human blood vessels [34]. In agreement with previous work, we observed a predominant increase in plasma big ET-1 rather than mature ET in CHF patients compared to controls [20,21]. The most likely explanation for this is that endothelial synthesis of big ET-1 is enhanced in CHF, though again it is possible that reduced plasma clearance of big ET-1 may have been a contributory factor. Treatment with an ACE inhibitor can decrease plasma ET-1 in CHF [35] and our results may have been influenced accordingly. However, ACE inhibitors do not affect ECE activity [22] and consequently would not be expected to suppress only plasma ET-1. Anti-ET drugs will only secure a place in the treatment of CHF if they can be shown to be of value in patients already receiving conventional medical therapy. Our findings and other recent observations suggest that both ETA selective and non-selective receptor antagonists may offer haemodynamic benefits over and above the effects of an ACE inhibitor [5,7]. 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TI - Endothelin receptor antagonism in patients with chronic heart failure
JF - Cardiovascular Research
DO - 10.1016/S0008-6363(00)00081-X
DA - 2000-07-01
UR - https://www.deepdyve.com/lp/oxford-university-press/endothelin-receptor-antagonism-in-patients-with-chronic-heart-failure-p9FYsXAxFg
SP - 166
EP - 172
VL - 47
IS - 1
DP - DeepDyve
ER -