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Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible ...

Clinical Science (2000) 98, 65–70 (Printed in Great Britain)

Venous endothelin receptor function in patients with chronic heart failure Michael P. LOVE*, William G. HAYNES†, David J. WEBB† and John J. V. MCMURRAY* *Department of Cardiology, Western General Hospital, Edinburgh EH4 2XU, Scotland, U.K., and †Department of Medicine, Western General Hospital, Edinburgh EH4 2XU, Scotland, U.K.

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Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-1 in this disease. Two main subtypes of endothelin receptor, ETA and ETB, exist in human blood vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective ETA and ETB agonist) and sarafotoxin S6c (a selective ETB agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least 1 week apart, locally active doses of endothelin-1 or sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-1 was significantly blunted in heart failure patients compared with controls (26p7 % and 51p6 % peak reduction in vein calibre respectively ; P l 0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17p5 % and 17p4 % peak reduction in vein calibre respectively). Both ETA and ETB receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic heart failure may therefore require administration of an antagonist with ETA- and ETB-receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ETA receptor sensitivity, but further studies are required to clarify the functional significance of this observation.

INTRODUCTION Drugs that block the synthesis or receptor binding of endothelin-1 (ET-1) might be of therapeutic benefit in chronic heart failure (CHF) [1–3]. To date, focus has been placed upon the role of ET-1 in regulating arterial resistance in CHF, with little attention being paid to the actions of the peptide in the venous circulation [2–4]. A thorough understanding of the actions of ET-1 through-

out the circulatory system is essential, given that the preferred haemodynamic profile of a drug for CHF is balanced preload and afterload reduction [5–7]. Two subtypes of endothelin receptor, designated ETA and ETB, mediate the vascular effects of ET-1 in human blood vessels [8–11]. ETA receptors are widely expressed on arterial and venous smooth muscle cells, where their stimulation results in slow-onset and sustained vasoconstriction. ETB receptors are present on vascular

Key words : chronic heart failure, endothelin-1, endothelin receptors, veins. Abbreviations : ANOVA, analysis of variance ; CHF, chronic heart failure ; CI, confidence intervals ; ET-1, endothelin-1. Correspondence : Dr M. P. Love, Department of Medical Cardiology, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER, Scotland, U.K. (e-mail MLove39495!aol.com).

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endothelial as well as smooth muscle cells. Stimulation of endothelial ETB receptors results in vasodilatation through nitric oxide and\or dilator prostanoid release, while stimulation of smooth muscle ETB receptors results in vasoconstriction [11–13]. Preliminary clinical data suggest that ET-1 might contribute to the regulation of venous tone in CHF [2]. Functional studies have consistently demonstrated ETAreceptor-mediated venoconstriction in isolated human veins, with a rather more variable contribution to the constrictor response being made by ETB receptors [10,14–16]. ETB receptors may be present in relatively greater numbers in venous than in arterial smooth muscle [17]. ETB-mediated venoconstriction has been demonstrated in healthy subjects in vivo, but there are currently no in vivo data available with respect to venous endothelin receptor function in patients with CHF [11]. This is obviously important in terms of predicting whether an ETA-selective or non-selective receptor antagonist would more effectively antagonize the venoconstrictor actions of endogenous ET-1 in CHF. We studied the venoconstrictor effects of ET-1 itself (a non-selective ETA and ETB receptor agonist) and the highly selective ETB receptor agonist sarafotoxin S6c in dorsal hand veins of patients with CHF, and compared the responses with those in age-matched healthy control subjects [18]. Responses in these vessels, which are known to participate in venomotor reflexes, have previously been predictive of responses in the largercapacitance vessels that regulate venous tone and play a key role in determining cardiac preload [19].

Table 1

METHODS Subjects Studies were conducted with the approval of the local ethics committee and conformed with the principles outlined in the Declaration of Helsinki. We recruited eight men with established CHF, stable for at least 3 months, together with eight healthy male control subjects. Written informed consent was obtained from all study participants. Each subject attended on two occasions at least 1 week apart for separate, single-blind dorsal hand vein infusions of ET-1 and sarafotoxin S6c. Ischaemic heart disease was the underlying cause of CHF in six cases, while one patient had alcoholic cardiomyopathy and another had idiopathic dilated cardiomyopathy. No patients had concomitant hypertension, diabetes mellitus or chronic renal failure. All healthy volunteers were asymptomatic at the time of studies ; none were hypertensive or had overt clinical, electrocardiographic or echocardiographic evidence of significant cardiac disease. Medication was withheld from CHF patients for 24 h prior to studies, while no control subject was taking any regular medication. All CHF # 2000 Biochemical Society and the Medical Research Society

Patient and control subject characteristics

Abbreviations : NYHA, New York Heart Association ; ACE, angiotensin-converting enzyme. Patients with ischaemic heart disease were identified by definite prior myocardial infarction or confirmed by coronary angiography. There were no statistically significant differences in plasma cholesterol, vein diameter, mean arterial pressure or heart rate between groups or protocols. No CHF patient was receiving treatment with a calcium channel blocker, beta blocker or 3-hydroxy-3methylglutaryl-CoA reductase inhibitor CHF patients (n l 8) Mean age (years)

66p4

Primary diagnosis Ischaemic heart disease Dilated cardiomyopathy Alcoholic cardiomyopathy Ejection fraction (%)

6 1 1 25p4

NYHA clinical class II III

3 5

Control subjects (n l 8) 68p3 – – – 60p4 – –

Plasma cholesterol (mmol/l)

5.2p0.2

5.0p0.2

Basal vein diameter (units) ET-1 protocol S6c protocol

3.7p0.7 4.0p0.9

3.1p1.1 3.4p0.8

Mean arterial pressure (mmHg) ET-1 protocol S6c protocol

103p5 101p6

95p7 99p6

Heart rate (beats/min) ET-1 protocol S6c protocol

75p3 78p5

73p5 77p4

Drug therapy ACE inhibitor Diuretic Digoxin Aspirin Oral nitrate

8 8 6 3 3

0 0 0 0 0

patients and control subjects were non-smokers. Table 1 summarizes patient and control subject characteristics.

Measurement of vein diameter Subjects were asked to fast for a minimum of 2 h prior to studies and to avoid caffeine-containing drinks and alcohol on study days. Studies were performed with subjects resting semi-recumbent in a quiet clinical laboratory maintained at a constant temperature between 25 mC and 27 mC, with one hand supported above atrial level by an angled arm rest. A 23 G butterfly needle was inserted in a suitable dorsal hand vein in the direction of blood flow without the use of local anaesthesia. Physiological saline (0.9 % NaCl) was infused at 0.25 ml\min for at least 30 min until a stable baseline vein diameter

Endothelin receptors in chronic heart failure

(p10 %) was recorded. Locally active doses of ET-1 and sarafotoxin S6c (5 pmol\min) were dissolved in physiological saline and subsequently administered at 0.25 ml\ min for 60 min [3,11]. Vein diameter was measured using the Aellig technique [20]. Briefly, this involves centring a small tripod supporting a linear variable differential transformer over the infused vein. A lightweight magnetized rod resting on the vein summit approx. 10 mm downstream from the tip of the infusion needle is positioned to pass vertically through the transformer core. Care is taken to ensure that the feet of the tripod are clear of other superficial veins. Since dorsal hand veins have no intrinsic tone in warm and relaxed subjects, an upper-arm sphygmomanometer cuff is inflated to 40 mmHg to maintain distension of the infused vein. Deflation of this cuff results in collapse of the infused vein and downward displacement of the magnetized rod by a distance equivalent to the internal diameter of the vein under study. Rod displacement creates a linear change in the voltage generated by the transformer, which is transferred to an Apple Macintosh computer using a MacLab analogue–digital converter and Chart software (v3.2.8). Calibration against standard displacements allows precise determination of internal vein diameter. Vein diameter was measured every 10 min during saline equilibration and every 5 min during ET-1 or sarafotoxin S6c infusion. The percentage change from baseline in vein diameter was calculated at each time point. Blood pressure and heart rate were measured in the non-infused arm at 10 min intervals throughout all studies using a well validated semi-automated technique (UA-751 sphygmomanometer ; Takeda Medical Inc.).

in human resistance and capacitance vessels [3,11]. Infusion of these doses would be expected to achieve a local concentration of each agonist in the infused vein of approx. 5 nM, assuming dorsal hand vein flow of approx. 1 ml\min [21]. ET-1 at this local concentration would be predicted to act as a non-selective agonist at ETA and ETB receptors, given that its Ki values at ETA and ETB receptors are 0.6 nM and 0.12 nM respectively [18]. Sarafotoxin S6c would be predicted to be highly selective for ETB receptors at such a local concentration, given that its Ki values at ETA and ETB receptors are 0.25 nM and  7300 nM respectively [18].

Data interpretation and statistical analyses All results are expressed as mean values with 95 % confidence intervals (CI) in the text, and with S.E.M. in Figures. The significance of the effects of ET-1 and sarafotoxin S6c on vein diameter 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-tests were employed to test the significance of the difference in peak agonist effects between healthy control subjects and patients with CHF. Differences were considered statistically significant at a P value of 0.05.

RESULTS Dorsal hand vein infusion of ET-1 caused slow-onset, progressive venoconstriction in both control subjects and patients with CHF (Figure 1). The peak reduction in vein

Plasma ET-1 determination Plasma ET-1 was measured in each CHF patient and healthy control subject on the day of dorsal hand vein infusion of ET-1. A 23 G antecubital venous cannula was sited in the non-infused arm at the beginning of each study. A 10 ml venous blood sample was withdrawn into a chilled plastic tube containing EDTA at the end of the period of saline equilibration, i.e. after the subject had been resting semi-recumbent for at least 30 min and immediately before commencing dorsal hand vein infusion of ET-1. Plasma immunoreactive ET-1 was measured by RIA (ITS Production BV) as previously described [21]. Assay sensitivity was 2 pg\ml, and the crossreactivities of the assay with ET-1, ET-2, ET-3 and big ET-1 were 100 %, 52 %, 96 % and 7 % respectively.

Infusion of ET-1 and sarafotoxin S6c Pharmaceutical-grade ET-1 (Clinalfa AG) and sarafotoxin S6c (Sigma Chemical Co.) were infused into the same dorsal hand vein on separate days at least 1 week apart. Each was infused at 5 pmol\min for 60 min, a dose shown previously to cause slow-onset vasoconstriction

Figure 1 Effects of dorsal hand vein infusion of ET-1 (5 pmol/min) for 60 min in eight patients with CHF ($) and eight age-matched healthy controls ( )

The hatched area represents the period of ET-1 infusion. ET-1 caused a peak reduction in vein calibre of 26p7 % in CHF patients and 51p6 % in control subjects (CHF compared with controls : P l 0.013). # 2000 Biochemical Society and the Medical Research Society

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Figure 2 Effects of dorsal hand vein infusion of sarafotoxin S6c (5 pmol/min) for 60 min in eight patients with CHF ($) and eight age-matched healthy controls ( )

The hatched area represents the period of sarafotoxin S6c infusion. Sarafotoxin S6c caused a peak reduction in vein calibre of 17p5 % in CHF patients and 17p4 % in control subjects (no significant difference). calibre was 51p6 % in control subjects (CI k63 to k39 % ; ANOVA compared with baseline, P 0.0001) and 26p7 % in CHF patients (CI k39 to k13 % ; ANOVA compared with baseline, P 0.0001 ; CHF patients compared with controls, P l 0.013). Infusion of sarafotoxin S6c also caused slow-onset, progressive venoconstriction, with a peak reduction in vein calibre of 17p4 % in control subjects (CI k25 to k10 % ; ANOVA compared with baseline, P l 0.0003) and 17p5 % in CHF patients (CI k24 to k10 % ; ANOVA compared with baseline, P l 0.0009 ; CHF patients compared with controls, not significant ; Figure 2). The mean endogenous plasma ET-1 concentration measured immediately prior to dorsal hand vein infusion of ET-1 was significantly higher in CHF patients (12.4p2.2 pg\ml) than in control subjects (6.2p1.0 pg\ml ; CHF patients compared with controls, P l 0.022). No significant correlation was observed between plasma ET-1 concentration and the percentage venoconstriction in response to infused ET-1.

DISCUSSION Patient studies with antagonists of either the synthesis or the receptor binding of ET-1 have indicated that activation of the endothelin system contributes importantly to resistance and capacitance vessel vasoconstriction in CHF [2,3]. Potent, orally active endothelin receptor antagonists have been developed for possible therapeutic use, and this has hastened the need for a fuller under# 2000 Biochemical Society and the Medical Research Society

standing of the role of the endothelin system in cardiovascular disease [22]. In CHF, an important priority is further clarification of the relative roles of the two principal endothelin receptor subtypes, ETA and ETB, in mediating vasoconstriction [2,3]. We studied the venoconstrictor role of ETA and ETB receptors in healthy control subjects and in patients with CHF. ET-1, a non-selective agonist at ETA and ETB receptors, and sarafotoxin S6c, a highly selective ETB receptor agonist, each caused local venoconstriction when infused into superficial dorsal hand veins in both control subjects and CHF patients. ET-1 caused greater venoconstriction than sarafotoxin S6c in both groups, suggesting that both ETA and ETB subtypes contribute to the vasoconstrictor response. Venoconstriction to ET-1 was significantly blunted in CHF patients compared with controls, while the venoconstrictor effect of sarafotoxin S6c was very similar in the two groups. Although it is important to acknowledge that such responses to exogenous agonists do not necessarily reflect the role of endothelin receptors in mediating the venoconstrictor activity of endogenous ET-1, these data suggest that there might be a selective decrease in venous ETA receptor sensitivity in CHF. A blunted arterial vasoconstrictor response to exogenously administered ET-1 has been observed previously in the coronary and renal vasculatures of dogs with experimental heart failure, as well as in the forearm vasculature of patients with CHF [3,23,24]. In contrast with our studies in veins, however, an enhanced arterial constrictor response to sarafotoxin S6c was seen in CHF [3,23]. It was postulated that endothelial dysfunction in CHF might have contributed to the enhanced arteriolar constriction to sarafotoxin S6c, given its agonist activity at both dilator endothelial and constrictor smooth muscle ETB receptors. Nitric oxide, however, appears to be a less important modulator of the constrictor response to ET1 in human veins than in arteries [25]. Consequently any alteration in basal or stimulated nitric oxide production in CHF would be less likely to result in significant modulation of the overall venoconstrictor response to sarafotoxin S6c. This may explain why we found no difference in venous responses to sarafotoxin S6c between CHF patients and controls. Another possible explanation for the similar effects of sarafotoxin S6c in CHF patients and controls is that a decrease in endothelial ETBreceptor-mediated dilatation consequent upon endothelial dysfunction may be equally offset by a reduction in vascular smooth muscle ETB-receptor-mediated constriction. Further studies in conjunction with inhibitors of nitric oxide and prostacyclin generation are needed to clarify these issues. Agonist-induced receptor down-regulation is an established concept in human cardiovascular pathophysiology, and has been demonstrated for other important neuroendocrine systems that are activated in

Endothelin receptors in chronic heart failure

CHF [26,27]. Although ET-1 probably acts mainly in a paracrine fashion to alter vascular tone, circulating ET-1 may also have important biological activity [28,29]. Plasma ET-1 levels are consistently raised in patients with CHF, and are correlated with the severity of haemodynamic disturbance [30–32]. Consequently, one might expect this to result in endothelin receptor desensitization and possibly down-regulation. As discussed, the blunted effect of ET-1, but not sarafotoxin S6c, in our CHF patients raises the possibility of selective downregulation of venous ETA receptors in CHF. At present there is only indirect evidence of possible differential regulation of vascular ETA and ETB receptors in CHF [3,23]. Other groups have reported variable alterations in ETA and ETB receptor expression in the lung [33] and myocardium [34–36] in human and experimental CHF, but a consistent pattern has yet to emerge. Further studies are needed in order to delineate the effects of CHF on endothelin receptors throughout the cardiovascular system and to correlate these changes with the functional effects of endothelin receptor agonists and antagonists. Three of our CHF patients were taking regular doses of aspirin until 24 h before the studies, but this would not explain their blunted response to ET-1, given that aspirin has been shown previously to potentiate venoconstriction to ET-1 in vivo [25]. We must also consider the possibility that the effects of other drugs, in particular inhibitors of angiotensin-converting enzyme, may not have worn off completely within 24 h of stopping therapy and might have modulated venous responses. It is difficult, however, to postulate a mechanism whereby this would selectively blunt venoconstriction to ET-1 but not sarafotoxin S6c. It is also important to acknowledge that there were small baseline differences in basal vein diameter, mean arterial pressure and heart rate between and within groups, although none of these differences reached the level of statistical significance. These factors may also have influenced venous responsiveness but, on their own, would not explain the different responses observed in patients and controls. An important limitation of our study is that we have studied the venoconstrictor effects of only single agonist doses. It is not feasible to construct dose–response curves for ET-1 and sarafotoxin S6c in vivo, because their uniquely slow onset of effect means that only single doses can be studied on any one occasion. Furthermore, it is important to point out that our results reflect the role of ETA and ETB receptors in mediating the effects of exogenous rather than endogenous ET-1. Assessment of venous function and responsivness in vivo using the Aellig technique is limited by the fact that superficial hand veins have no intrinsic tone in warm and relaxed subjects [37]. Consequently, preconstriction with exogenously administered ET-1 would have been required to enable us to study the effects of endothelin antagonists.

Such studies would, however, still reflect the role of ETA and ETB receptors in mediating the effects of exogenous rather than endogenous ET-1. Our demonstration that both ETA and ETB receptors play a role in mediating venoconstriction in dorsal hand veins suggests that administration of a non-selective receptor antagonist may be necessary in order to achieve optimal inhibition of the venoconstrictor effects of endogenous ET-1. Further studies are obviously needed to determine the functional, and perhaps therapeutic, significance of our observation that venous ETA receptor sensitivity may be selectively reduced in CHF. Systemic studies comparing the regional haemodynamic effects of selective and non-selective endothelin receptor antagonists in patients with CHF are awaited with interest.

ACKNOWLEDGMENTS M. P. L. was supported by a Bristol-Myers Squibb Cardiovascular Fellowship, and W. G. H. by a Wellcome Trust Advanced Training Fellowship (042145\114). We thank E. Stanley and Dr. N. Lannigan (Pharmacy Department, Western General Hospital) for assistance with peptide preparation.

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Received 14 May 1999/23 July 1999; accepted 8 September 1999

# 2000 Biochemical Society and the Medical Research Society

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