Acute effects of β-endorphin on cardiovascular function in patients with mild to moderate chronic heart failure

Article Outline

• Abstract
• Methods
  • Subjects
  • Study protocols
  • Echocardiography
  • Hemodynamics
  • Exercise testing
  • Laboratory
    • BE assay
  • Endothelin assay
  • Catecholamine assay
  • Glucagon assay
  • BNP assay
  • PRA assay
  • GH assay
  • IGF-1 assay
  • Statistics
• Results
  • Echocardiography
  • Hemodynamics
  • Exercise testing
  • Laboratory
• Discussion
• References
• Copyright

Abstract 

Background

Cardiomyocytes produce opioid peptides and receptors. β-Endorphin is increased in the plasma of patients with congestive heart failure (CHF). We evaluated whether an intravenous infusion of β-endorphin exerted any effect on cardiovascular function and on the neurohormonal milieu in patients with mild to moderate CHF.

Methods

According to a double-blind, placebo-controlled design, 10 patients (5 men, age 46.9 ± 8.2 years [mean ± SD]) with CHF and New York Heart Association functional class II to III received, in random order, 1-hour intravenous infusion of β-endorphin (500 μg/h) and, on a separate occasion, received placebo and underwent echocardiographic and laboratory measurements at baseline and during infusions.

Results

β-Endorphin significantly increased left ventricular ejection fraction (LVEF) (P = .0001) and stroke volume (P = .0001), and reduced systemic vascular resistance (P = .031) in patients with CHF. These changes were paralleled by a significant increase in plasma levels of glucagon (P = .0001), GH (P = .0001), and IGF-1 (P = .0001), and a significant decrease in plasma levels of endothelin (P = .0001) and catecholamines (P = .01). No hemodynamic and neurohormonal changes were observed during the placebo study in any patient.

Conclusions

We conclude that a short-term, high dose infusion of β-endorphin improves LVEF, reduces systemic vascular resistance, blunts the neurohormonal activation, and stimulates the GH/IGF-1 axis in patients with mild to moderate CHF.

Mounting evidence suggests that the endogenous opioid system is involved in the regulation of a number of cardiovascular functions.¹, ² The endogenous opioid system is activated by various stimuli including hypoglycemia, intensive exercise, severe hypotension, acute myocardial ischemia, and congestive heart failure (CHF). In fact, these conditions are associated with increased plasma levels of β-endorphin (BE), one of the major endogenous peptides. Naloxone, a nonspecific opiate receptor-blocking agent, has been demonstrated to reverse both endotoxic and hemorrhagic shock and to affect left ventricular (LV) function when given acutely or continuously to conscious dogs with right-sided CHF.³, ⁴ After sympathetic stimulation, opioid peptides and catecholamines are coreleased from neuronal endings in the myocardium of different animal species.⁵ Recent studies have shown that cultured cardiomyocytes from rats produce opioid peptides.⁶, ⁷ Increased levels of various circulating neurohormones have been found in patients with CHF.⁸ The neurohormonal activation in CHF (ie, augmented plasma levels of catecholamines, endothelin, and natriuretic peptides) has been reported to play a role in the pathogenesis of CHF and to be a negative prognostic predictor in this disease.⁹ In a previous report, circulating BE was significantly increased in patients with CHF and was closely correlated with New York Heart Association (NYHA) functional class.¹⁰ These observations suggest a relation between BE and ventricular mechanical function in patients with CHF. It is still unclear whether the activation of the opioid system plays any role in cardiovascular function in patients with CHF or whether high plasma levels of BE simply represent a biochemical prognostic marker in these patients. This study was designed to evaluate whether BE infused at high doses and for a short period in patients with mild to moderate CHF was able to (a) improve cardiovascular function and (b) affect the neurohormonal milieu.

Back to Article Outline

Methods 

Subjects 

Ten patients with idiopathic dilated cardiomyopathy and CHF (5 men; age, 46.9 ± 8.2 years, mean ± SD; body mass index, 25.9 ± 0.4 kg/m²; heart rate, 84 ± 8 beats/min; systolic blood pressure, 111 ± 9 mm Hg; diastolic blood pressure, 79 ± 6 mm Hg) who were admitted to our department were enrolled in the study (Table I). All patients were symptomatic for LV dysfunction for at least 3 months, and all were treated with different combinations of digitalis (n = 9), diuretics (n = 10), and ACE inhibitors (n = 10). Exclusion criteria included coronary artery disease, LV ejection fraction (LVEF) ≥40% (assessed by radionuclide angiography or echocardiography), NYHA class IV, aortic or important mitral valve disease, supraventricular or ventricular arrhythmias, and history of hypertension, hyperthyroidism, pheochromocytoma, diabetes mellitus, or other major diseases. All patients were on an isocaloric (2200 to 2400 Cal) and sodium-restricted (1500 to 2000 mg) diet. Fully informed written consent to participate in the study was obtained from all patients after a clear explanation of its nature. The study protocol was approved by the Ethics Committee of our University.

Table I. Clinical characteristics of the patients investigated

IDC, Idiopathic dilated cardiomyopathy; dig, digitalis; diu, diuretic; ACEi, angiotensin-converting enzyme inhibitor; NYHA, New York Heart Association; LVDd, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction.

Study protocols 

All patients were studied after an overnight fast at 8 am in a quiet room. All subjects were initially equilibrated for 45 minutes at a constant temperature of 24° to 26°C room temperature. During this time, an intravenous cannula was immediately introduced into one antecubital vein and kept patent by a slow infusion of 150 mmol/L NaCl solution. Venous blood samples for laboratory analyses were obtained from this cannula. Two basal samples were obtained a few minutes after this venous insertion, and the mean of the two served as baseline values for statistical comparisons. Another intravenous cannula was introduced into the other antecubital vein just before the start of infusions and served for both BE and placebo administrations. On two separate occasions, 1 week apart, all patients received an infusion of human synthetic BE (Biogenesis, Poole, England) or placebo in random order. BE was dissolved in 150 mmol/L NaCl solution containing 3 g/L human albumin in the morning of the study and administered at a constant rate of 500 μg/h for 60 minutes. A 150-mmol/L NaCl solution plus human albumin (3 g/L) served as the placebo. The volume of liquids (1 mL/min) infused in each patient was similar during the two studies. Blood samples were taken every 30 minutes during infusions of BE or placebo.

Echocardiography 

Complete 1-dimensional, 2-dimensional, and pulsed Doppler echocardiography was performed by an ultrasound mechanical system equipped with 2.5- to 3.5-MHz transducer (Apogee CX; Interspec, Inc, Ambler, Pa) in all patients. One- and two-dimensional recordings were made with the subject in the lateral recumbent position, according to the standardization of the American Society of Echocardiography.¹¹ An electrocardiogram tracing was displayed simultaneously on the echo-tracings. The scans were performed at baseline and 30 and 60 minutes after the start of BE infusion or placebo and stored on videotape for later analysis. The examinations were carried out and analyzed by one experienced physician who was blinded as to whether the recordings he was interpreting were made during infusion of BE or placebo. LV end-diastolic (LVDd) (normal range, 33 to 56 mm) and end-systolic (LVSd) dimensions were determined below the tips of the mitral leaflets. LV fractional shortening (LVFS) was measured as (LVDd − LVSd)/LVDd × 100. LV end-diastolic (LVDv) and end-systolic (LVSv) volumes were obtained by 2-dimensional echocardiography with the single-plane area-length method.¹² Stroke volume was determined as LVDv − LVSv. LVEF was calculated as (LVDv − LVSv)/LVDv × 100 (normal value, >55%). Cardiac output was calculated by multiplying stroke volume by heart rate. All measurements were calculated from an average of 3 consecutive cardiac cycles. In our laboratory, the intraobserver mean coefficients of variation of the main variables considered, as assessed in 7 healthy subjects by repeating the measurements 14 days apart, were as follows: 6% ± 6% for LVFS, 4.8% ± 3.2% for LVEF, 3.7 ± 3.7 mL for stroke volume, and 3.7 ± 3.7 L/min for cardiac output.

Hemodynamics 

In each patient, heart rate and finger arterial pressure were noninvasively and continuously determined by a plethysmographic technique (Finapres; Ohmeda, Englewood, Calif) that has been shown to be as accurate as intra-arterial blood pressure measurements.¹³ Data were elaborated by a software that allowed systolic, diastolic, mean arterial pressure, and heart rate to be expressed in graphs. Systemic vascular resistance was determined at baseline and 30 and 60 minutes after the start of BE infusion or placebo in each patient. Systemic vascular resistance was calculated as (mPA − mPRA)/cardiac output × 80, where mPA is the mean aortic pressure derived by plethysmographic method as diastolic blood pressure + 1/3 (systolic − diastolic blood pressure), mPRA (0 mm Hg) is the mean right atrial pressure.

Exercise testing 

Maximal exercise capacity was assessed before and immediately after the end of BE infusion or placebo in 8 patients with CHF. They underwent graded exercise testing on a treadmill, having been familiarized with the exercise program before the study, and were encouraged to exercise to a symptom-limited maximum of dyspnea or fatigue (peak). The incremental (2-minute stages) Weber treadmill exercise protocol was used in the study.¹⁴ Expired gas was collected and continuously analyzed with on-line breath-by-breath computer data acquisition (Oxycon Gamma Mijnhardt). Oxygen consumption at peak, rate-pressure product at peak, and exercise duration were calculated.

Laboratory 

Samples for BE, endothelin, glucagon, brain natriuretic peptide (BNP), plasma renin activity (PRA), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) were collected in tubes containing a mixture (0.1 mL per mL of blood) of EDTA-aprotinin solution (5000 U/mL, Trasylol; Bayer, Leverkusen, Germany; 1.2 g/L di-sodium EDTA) and immediately centrifuged for 15 minutes at 4°C at 2000g. All plasma samples were stored at −20°C until assayed.

Plasma BE was determined by the radioimmunoassay (RIA) method. The assay had an intra-assay variability of 4.5% and an interassay variability of 6.8%; the sensitivity limit was 0.2 pmol/L. Mean normal values in our laboratory were 2.9 ± 1.0 pmol/L.

Endothelin assay 

The resulting plasma was separated on c-18 columns. The eluate was evaporated in a speed vacuum concentrator and stored at −20°C until assayed by the RIA method. For endothelin values approaching 13 pg/mL, the assay had an intra-assay variability of 4.5% and an interassay variability of 6.8%; the sensitivity limit was 0.1 pg/mL. Mean normal values in our laboratory were 2.1 ± 0.4 pg/mL.

Catecholamine assay 

Plasma catecholamines were partially purified by batch alumina extraction, separated through the use of ion-pairing reverse-phase HPLC (μBondapak C18-column, Powerline 600A chromatography system, and WISP 700 as autoinjector; Waters, Milford, Mass), and quantified by means of a current produced on exposure of the column effluent to oxidizing and then reducing potentials connected in series (Coulochem 5100A; ESA, Bedford, Mass). Recovery through the alumina extraction step, calculated with dihydroxybenzylamine used as an internal standard, ranged from 60% to 70%, and each sample was corrected for its recovery. Intra-assay and interassay variability coefficients were 4.1% and 9.8% for norepinephrine, and 6.2% and 12% for epinephrine, respectively; the sensitivity limits for norepinephrine and epinephrine were 3 and 5 pg/mL, respectively. Mean normal values of epinephrine and norepinephrine in our laboratory were 55 ± 9 and 181 ± 47 pg/mL, respectively.

Glucagon assay 

Plasma glucagon was determined by the RIA method. This assay had an intra-assay variability of 11%, and an interassay variability of 20%; the sensitivity limit was 15 ng/L. Mean normal values in our laboratory were 81 ± 21 ng/L.

BNP assay 

Plasma BNP was determined by the RIA method. This assay had an intra-assay variability of 9% and an interassay variability of 14%; the sensitivity limit was 3 pg/mL. Mean normal values in our laboratory were 14 ± 2 pg/mL.

PRA assay 

Plasma PRA was determined by the RIA method. This assay had an intra-assay variability of 3.4% to 5.1% and an interassay variability of 3.8% to 5.2%; the detection limit was 0.03 μg/L per hour. Mean normal values in our laboratory were 0.8 ± 0.2 μg/L per hour.

GH assay 

Plasma GH was determined by the immunoradiometric method. This assay had an intra-assay variability of 2.4% to 4.0% and an interassay variability of 2.9% to 4.5%; the sensitivity limit was 0.15 μg/L. Mean normal values in our laboratory were 0.8 ± 0.3 μg/L.

IGF-1 assay 

Plasma IGF-1 was determined by the immunoradiometric method. This assay had an intra-assay variability of 1.5% to 3.4% and an interassay variability of 3.7% to 8.2%; the sensitivity limit was 0.3 ng/mL. Mean normal values in our laboratory were 204 ± 53 ng/mL.

Samples from each individual were analyzed in duplicate. Laboratory staff were blinded to the infusion code.

Statistics 

Data were analyzed statistically with the use of a software package (version 11.0, SPSS, Inc, Chicago, Ill). Baseline was defined as the mean of two measurements taken at time zero. The change from baseline in each parameter was calculated as the measurement at peak minus baseline during infusions of BE and placebo and was indicated as Δ value. A 2-way analysis of variance for repeated measures was used to test for within-treatment changes and between-treatment differences. Comparisons between baseline values and responses to BE and placebo infusions at 30 and 60 minutes within the same treatment were analyzed by the Student t test for paired data. A value of P < .05 was considered statistically significant. All data were presented as mean values ± SD.

Back to Article Outline

Results 

Echocardiography 

In patients with CHF, basal LVDd was significantly higher and LVEF lower than normal (Table I).

In patients with CHF, BE infusion caused a progressive increase in LVEF, with a peak at 60 minutes, an increase that was significant versus baseline (Δ value, 4.9% ± 3.1%, P = .0001) and versus placebo (Δ value, 0.2% ± 2.2%, P = .005) (Table II). A similar pattern of response to BE infusion was observed in stroke volume and cardiac output that significantly increased compared with baseline (Δ value, 10.2 ± 11.7 mL, P = .0001; 0.64 ± 0.95 L/min, P = .008, respectively) and with placebo (Δ value, −0.3 ± 11.5 mL, P = .0001; −0.1 ± 1.0 L/min, P = .005, respectively) (Table II). Both BE infusion and placebo did not significantly change LVDd and LVFS in patients with CHF (Table II).

Table II. Effects of β-endorphin (BE) and placebo (P) infusions on echocardiographic, hemodynamic, and cardiopulmonary parameters in the patients investigated

Data (mean ± SD) are given as absolute values. LVDd, Left ventricular end-diastolic dimension; LVFS, left ventricular fractional shortening; LVEF, left ventricular ejection fraction; SVR, systemic vascular resistance; HR, heart rate; MBP, mean blood pressure; SBP, systolic blood pressure.

Hemodynamics 

In patients with CHF, intravenous infusion of BE induced a progressive reduction of systemic vascular resistance with a nadir at the end of the study protocol, a reduction that was significant versus baseline (Δ value, −140 ± 330 dyne/s per centimeter⁻⁵, P = .031) and versus placebo (Δ value, 26 ± 247 dyne/s per centimeter⁻⁵, P = .01) (Table II). No changes in heart rate and mean blood pressure were observed in patients with CHF when they received BE infusion or placebo (Table II).

Exercise testing 

Two patients with CHF were not able to do exercise tests. In the remaining 8 patients with CHF, BE infusion provoked a rise in oxygen consumption at peak, a rise that was significant versus baseline (Δ value, 1.6 ± 0.7 mL/min per kilogram, P = .0001) and versus placebo (Δ value, −0.1 ± 0.8 mL/min per kilogram, P = .0001) (Table II). Similarly, rate-pressure product at peak and exercise duration increased at the end of BE infusion and were higher than baseline (Δ value, 1397 ± 1439 mm Hg/s per 10³, P = .007; 179 ± 99 seconds, P = .002, respectively) and than those in the placebo study (Δ value, −131 ± 1643 mm Hg/s per 10³, P = .005; 5 ± 60 seconds, P = .002, respectively) (Table II). None of the graded exercise tests caused any complications in the patients investigated.

Laboratory 

In patients with CHF, basal plasma levels of BE, endothelin, catecholamines, BNP, and PRA were higher than normal, whereas plasma IGF-1 levels were lower (Table III).

Table III. Effects of β-endorphin (BE) and placebo (P) infusions on plasma levels of neurohormones in the patients investigated

Data (mean ± SD) are given as absolute values. BNP, Brain natriuretic peptide; IGF-1, insulin-like growth factor-1.

Intravenous BE infusion caused a marked and sustained increase in plasma BE levels that reached concentrations approaching 400 to 500 pmol/L (Table III). In patients with CHF, BE infusion caused an increase in plasma levels of glucagon, with a peak at 30 minutes, an increment that was significant versus baseline (Δ value, 73 ± 19 pg/mL, P = .0001) and versus placebo (Δ value, 5 ± 18 pg/mL, P = .0001) (Table III). In patients with CHF, BE infusion produced a rise in plasma levels of both GH and IGF-1, with a peak at 60 minutes, a rise that was significant when compared with baseline (Δ value, 6.0 ± 0.9 μg/L, P = .0001; 128 ± 61 ng/mL, P = .0001, respectively) and with placebo (Δ value, −0.2 ± 0.2 μg/L, P = .0001; −9 ± 35 ng/mL, P = .0001, respectively) (Table III). On the contrary, BE infusion provoked a decrease in plasma levels of endothelin with a nadir at 60 minutes, a decrease that was statistically significant versus baseline (Δ value, −1.7 ± 0.9 pg/mL, P = .0001) and versus placebo (Δ value, −0.3 ± 0.8 pg/mL, P = .006) (Table III). Circulating catecholamines showed a similar pattern of response to BE infusion. In fact, BE infusion caused a reduction of plasma epinephrine and norepinephrine, a reduction that was significant versus baseline (Δ value, −23 ± 18 pg/mL, P = .01; −102 ± 79 pg/mL, P = .015, respectively) but not versus placebo (Δ value, −3 ± 20 pg/mL, P = not significant; −12 ± 99 pg/mL, P = not significant, respectively) (Table III). No significant changes in plasma levels of BNP and PRA were found in patients with CHF when they received BE infusion and placebo (Table III). The study protocols were well tolerated by all subjects investigated. There were no systemic reactions.

Back to Article Outline

Discussion 

The findings of this study can be summarized as follows: (1) acute increases in BE plasma concentrations to levels commonly observed during acute stress improve cardiovascular function and exercise capacity in patients with idiopathic dilated cardiomyopathy and CHF II-III NYHA functional class; and (2) BE blunts neurohormonal activation and stimulates the GH/IGF-1 axis in this type of patient. BE is known to play a potent agonistic action on μ- and δ-opioid receptors.¹⁵ During exogenous BE infusion, plasma BE concentrations were in the pharmacologic range (∼400 pmol/L) in our patients and very similar to those observed during acute stress.¹⁶ These findings are in agreement with those from Kawashima et al,¹⁰ who described in patients with CHF an increase in BE plasma levels that closely related to NYHA functional class. Whether the beneficial effects on cardiovascular function observed in patients with CHF during BE infusion depend on an improvement in LV inotropic function, a reduction of systemic vascular resistance, or both is difficult to establish.

In the current study, BE induced a significant decrease in circulating catecholamines in patients with CHF. Accordingly, much evidence suggests that μ-opioid receptor stimulation decreases muscle sympathetic nervous system and is responsible for presynaptic inhibition of norepinephrine release from neuronal endings.¹⁷, ¹⁸ In addition, there is evidence that a β-blockade–mediated reduction in sympathetic drive leads to a better outcome in patients with CHF.¹⁹ It is pertinent, moreover, to recall that opioid peptides exert inhibitory effects on the sarcolemmal ouabain-sensitive Na⁺-K⁺–dependent ATPase activity in bovine cardiomyocytes.²⁰ Thus, a glycoside-like cardiac action of BE could contribute to improved inotropic function observed in our patients on BE infusion. Our patients had a significant increase in BE-mediated glucagon production. These data are in line with those from a previous study in human beings that showed a marked increase in plasma glucagon on BE infusion.²¹ Given that glucagon positively affects heart mechanical function by stimulating cardiomyocyte Ca²⁺ transient via activation of adenylyl cyclase and inhibition of phosphodiesterase,²² one can speculate that this pancreatic hormone beneficially affected LV inotropic function found during BE infusion in our patients. Interestingly, a marked activation of the GH/IGF-1 axis was found on BE infusion in all patients investigated in the current study. These data are in agreement with others from De Marinis et al,²³ who reported the ability of opioid peptides to stimulate GH production in human beings. These findings support the hypothesis that the activation of the GH/IGF-1 axis is one of the many factors involved in BE-mediated improvement in LV systolic function in patients with CHF. The beneficial cardiovascular effects observed in our patients during BE infusion, moreover, are comparable to those found after GH administration in patients with dilated cardiomyopathy.²⁴ All these considerations strongly support the hypothesis that BE infusion plays a direct and/or an indirect positive role in LV inotropic function in patients with CHF.

In addition, because BE infusion caused a significant decrease in systemic vascular resistance in our patients with CHF, it cannot be excluded that reduced afterload indirectly improved LV performance. Our findings are in agreement with other reports indicating a vasorelaxing action of opioids in animals and human beings.² These effects could be secondary to both an opioid-mediated decrease in circulating endogenous substances with vasoconstrictive properties and a contemporary increase in vasodilating mediators. In fact, BE infusion reduced plasma levels of endothelin and catecholamines in our patients with CHF. Accordingly, an inhibitory opioid-mediated effect on endothelin release was reported in porcine aortic endothelial cells.²⁵ Moreover, there is evidence that opioid receptor stimulation is able to inhibit adrenergic drive in human beings.¹⁷ On the other hand, a BE-mediated increase in circulating GH and IGF-1 could contribute to reduced vascular resistance in patients with CHF during BE administration. In fact, it has recently been demonstrated that both acute and chronic activation of the GH/IGF-1 axis lowers peripheral vascular resistance by activating the endothelial nitric oxide pathway both in patients with CHF and in healthy subjects.²⁶, ²⁷

BE infusion induced an improvement in exercise capacity in patients with CHF, as indicated by increase in oxygen consumption at peak and by improvement in exercise duration soon after opioid administration. These data are consistent with those from a recent study that reported beneficial effects on exercise tolerance in patients with CHF when they received dihydrocodeine, an opiate drug.²⁸

The small sample size in this study hampers definite conclusions related to BE efficacy in CHF. However, although further studies are needed to confirm such findings, the changes in LV function and hemodynamics that occurred during BE infusion and placebo were consistent in both magnitude and direction with plasma levels of hormones.

In conclusion, the endogenous opioid system is activated in patients with CHF. High doses of BE given for a short period could preserve cardiovascular function in patients with mild to moderate heart failure.

Back to Article Outline

References 

1. Atweh SF, Kuhar MJ. Distribution and physiological significance of opioid receptors in the brain. Br Med Bull. 1983;39:47–52
   • View In Article
   • MEDLINE
2. Holaday JW. Cardiovascular effects of the endogenous opiate system. Annu Rev Pharmacol Toxicol. 1983;23:541–594
   • View In Article
   • MEDLINE
   • CrossRef
3. Holaday JW, Faden AI. Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock. Nature. 1978;275:450–451
   • View In Article
   • MEDLINE
   • CrossRef
4. Imai N, Kashiki M, Woolf PD, et al.  Comparison of cardiovascular effects of μ- and δ-opioid receptor antagonists in dogs with congestive heart failure. Am J Physiol. 1994;267(Heart Circ Physiol 36):H912–H917
   • View In Article
   • MEDLINE
5. Springhorn JP, Claycomb WC. Translation of heart preproenkephalin mRNA and secretion of enkephalin peptides from cultured cardiac myocytes. Am J Physiol. 1992;263(Heart Circ Physiol 32):H1560–H1566
   • View In Article
   • MEDLINE
6. Caffrey JL, Boluyt MO, Younes A, et al.  Aging, cardiac proenkephalin mRNA and enkephalin peptides in the F344 rat. J Mol Cell Cardiol. 1994;26:701–711
   • View In Article
   • Abstract
   • Full-Text PDF (575 KB)
   • CrossRef
7. Ventura C, Spurgeon H, Lakatta EG, et al.  κ and δ opioid receptor stimulation affects cardiac myocyte function and Ca²⁺ release from an intracellular pool in myocytes and neurons. Circ Res. 1992;70:66–81
   • View In Article
   • MEDLINE
8. Francis GS, Goldsmith SR, Levine TB, et al.  The neurohormonal axis in congestive heart failure. Ann Intern Med. 1984;101:370–377
   • View In Article
   • MEDLINE
9. Swedberg K, Eneroth P, Kjekshus J, et al.  for the CONSENSUS Trial Study Group   Hormones regulating cardiovascular function in patients with severe congestive heart failure and relation to mortality. Circulation. 1990;82:1730–1736
   • View In Article
   • MEDLINE
   • CrossRef
10. Kawashima S, Fukutake N, Nishian K, et al.  Elevated plasma beta-endorphin levels in patients with congestive heart failure. J Am Coll Cardiol. 1991;17:53–58
    • View In Article
    • Abstract
    • Full-Text PDF (301 KB)
    • CrossRef
11. Sahn DJ, De Maria A, Kissio J, et al.  The committee on M-mode standardization of the American Society of Echocardiography: recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiography measurements. Circulation. 1978;58:1072–1083
    • View In Article
    • MEDLINE
12. Folland ED, Parisi AF, Moynihan PF, et al.  Assessment of left ventricular ejection fraction and volumes by real-time, two-dimensional echocardiography (a comparison of cineangiographic and radionuclide techniques). Circulation. 1979;60:760–766
    • View In Article
    • MEDLINE
13. Coppola L, Cozzolino D, Giugliano D, et al.  Hemorheological and cardiovascular responses to beta-endorphin and naloxone in healthy subjects and patients with essential hypertension. J Clin Endocrinol Metab. 1994;79:1510–1514
    • View In Article
14. McElroy PA, Janicki JS, Weber KT. Cardiopulmonary exercise testing in congestive heart failure. Am J Cardiol. 1988;62:35A–40A
    • View In Article
    • MEDLINE
    • CrossRef
15. Lord JAH, Waterfield AA, Hughes J, et al.  Endogenous opioid peptides (multiple agonists and receptors). Nature. 1977;267:495–499
    • View In Article
    • MEDLINE
    • CrossRef
16. Cozzolino D, Sessa G, Salvatore T, et al.  The involvement of the opioid system in human obesity (a study in normal-weight relatives of obese people). J Clin Endocrinol Metab. 1996;81:713–718
    • View In Article
    • MEDLINE
    • CrossRef
17. Kienbaum P, Heuter T, Michel MC, et al.  Chronic μ-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity. Circulation. 2001;103:850–855
    • View In Article
18. Gaddis RR, Dixon WR. Modulation of peripheral adrenergic neurotransmission by methionine-enkephalin. J Pharmacol Exp Ther. 1982;221:282–287
    • View In Article
    • MEDLINE
19. Bristow MR. β-Adrenergic receptor blockade in chronic heart failure. Circulation. 2000;101:558–569
    • View In Article
20. Ventura C, Muscari C, Spampinato S, et al.  Inhibitory action of opioid peptides on ouabain-sensitive Na⁺-K⁺ and Ca²⁺ dependent ATPase activities in bovine cardiac sarcolemma. Peptides. 1987;8:709–713
    • View In Article
    • MEDLINE
    • CrossRef
21. Giugliano D, Salvatore T, Cozzolino D, et al.  Hyperglycaemia and obesity as determinants of glucose, insulin, and glucagon responses to β-endorphin in human diabetes mellitus. J Clin Endocrinol Metab. 1987;64:1122–1128
    • View In Article
    • MEDLINE
    • CrossRef
22. Sauvadet A, Rohn T, Pecker F, et al.  Synergistic actions of glucagon and miniglucagon on Ca²⁺ mobilization in cardiac cells. Circ Res. 1996;78:102–109
    • View In Article
    • MEDLINE
23. De Marinis L, Mancini A, Valle D, et al.  Physiological role of the opioid-cholinergic interaction in growth hormone neuroregulation: effect of sex and food intake. Metabolism. 1997;46:740–744
    • View In Article
    • Abstract
    • Full-Text PDF (449 KB)
    • CrossRef
24. Fazio S, Sabatini D, Capaldo B, et al.  A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;334:809–814
    • View In Article
    • MEDLINE
    • CrossRef
25. Arendt RM, Schmoeckel M, Wilbert-Lampen U, et al.  Bidirectional effects of endogenous opioid peptides on endothelin release in porcine aortic endothelial cell culture (mediation by delta opioid receptor and opioid receptor antagonist-insensitive mechanisms). J Pharmacol Exp Ther. 1995;272:1–7
    • View In Article
    • MEDLINE
26. Napoli R, Guardasole V, Matarazzo M, et al.  Growth hormone corrects vascular dysfunction in patients with chronic heart failure. J Am Coll Cardiol. 2002;39:90–95
    • View In Article
    • Full-Text PDF (142 KB)
    • CrossRef
27. Napoli R, Guardasole V, Angelini V, et al.  Acute effects of growth hormone on vascular function in human subjects. J Clin Endocrinol Metab. 2003;88:2817–2820
    • View In Article
    • MEDLINE
    • CrossRef
28. Chua TP, Harrington D, Ponikowski P, et al.  Effects of dihydrocodeine on chemosensitivity and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol. 1997;29:147–152
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (182 KB)
    • CrossRef