naloxone and Coronary-Disease

To evaluate whether endogenous opioids (EO) play a role in the perception of anginal pain, a randomized double blind clinical trial, using naloxone (N) and placebo (P) and measuring beta-endorphin (beta-ep) plasma levels, was performed. We studied 10 patients with angiographically assessed coronary artery disease (CAD) and stable exercise-induced myocardial ischemia (established by 2 preliminary bicycle ergometric tests) of whom 5 symptomatic (SYM) and 5 asymptomatic (ASYM) and 5 subjects without CAD as a control group (CON). On a third exercise test the beta-ep plasma level (fmol/ml) was measured at rest (SYM 5.4 +/- 2.3 vs ASYM 7.2 +/- 2.3 vs CON 6.8 +/- 2.6, NS), at peak exercise (SYM 4.4 +/- 1.8 vs ASYM 8.0 +/- 4.2 and vs CON 6.2 +/- 2.7, NS) and during recovery (SYM 7.5 +/- 4.2 vs ASYM 7.2 +/- 3.0 vs CON 6.7 +/- 2.5, NS). On 2 subsequent tests patients received N (0.2 mg/kg) or P intravenously and chest pain was evaluated on an analogue scale (score from 1 to 10). After N compared to P we observed: an increased perception of chest pain in SYM (6.8 +/- 1.5 vs 4.2 +/- 1.0; p less than 0.01) without significant changes of the ischemic threshold (total work, heart rate-blood pressure product, ST segment changes, 2D-echocardiographic wall motion abnormalities); no modifications in ASYM and CON.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; beta-Endorphin; Coronary Disease; Double-Blind Method; Exercise Test; Female; Humans; Male; Middle Aged; Naloxone; Pain Measurement

The hypothesis that endogenous opioids may be involved in reduced exercise-induced ischemic pain or in silent ischemia was tested. Fifteen male patients with coronary artery disease were tested in a randomized, double-blind crossover study. After a preliminary screening effort test they were divided into two groups: the first group of nine patients received an i.m. injection of naloxone 0.4 mg, or saline as placebo, and the second group, comprising six patients, received 4 mg naloxone or saline i.v. Effort testing was performed at weekly intervals on an ergometric bicycle, following the Bruce protocol. ECG, heart rate, blood pressure and pain perception were monitored continually. Blood was sampled through an indwelling venous catheter for beta-endorphin determination before, at the peak of, and 10-20 min following exercise. ST depression, heart rate, blood pressure and the double product were similar after naloxone and following saline administration. Beta-endorphin concentrations in plasma were significantly increased following exercise in the second group of patients. The increase in beta-endorphin concentration was larger when the patients were pretreated with naloxone (4 mg) than with placebo. However, chest pain was not significantly altered by either dose of naloxone.

Topics: Angina Pectoris; beta-Endorphin; Coronary Disease; Double-Blind Method; Exercise Test; Humans; Male; Middle Aged; Naloxone; Randomized Controlled Trials as Topic

In a double-blind study, eight patients with symptomatic myocardial ischaemia and nine with asymptomatic myocardial ischaemia were compared during physical exercise under naloxone (6 mg i.v.) or placebo. Plasma beta-endorphin, cortisol and catecholamines were measured before exercise, during maximal exercise, and 10, 20 and 60 min after exercise. A tourniquet pain test (on the forearm, under control of transcutaneous PO2), and an electrical pain test (intracutaneous electrode placed in the finger with the electrical stimulus under computer control and two-interval forced-choice psychophysical technique) were performed before exercise as well as immediately after, and 60 min after exercise. Plasma beta-endorphin levels increased significantly (P less than 0.01) during exercise in symptomatic and asymptomatic patient groups; every patient showed an increase on beta-endorphins during and after exercise. However, the increase found in beta-endorphins during and after exercise was significantly larger (P less than 0.01) in asymptomatic than in symptomatic patients. After naloxone, this difference was no longer evident. Angina pectoris during exercise was reported with less latency in symptomatic patients (P less than 0.05) and occurred in two of nine asymptomatic patients following naloxone. The time course of plasma cortisol levels exhibited the same pattern as beta-endorphins with the same significant differences between symptomatic and asymptomatic groups. Electrical pain thresholds, though on average higher in asymptomatic patients (2.21 mA vs. 0.79 mA), were not affected by exercise or naloxone. Asymptomatic patients required more time to reach pain thresholds in the tourniquet pain test (P less than 0.02). After exercise, tourniquet pain thresholds were significantly lower (P less than 0.01) under naloxone compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angina Pectoris; Catecholamines; Coronary Disease; Endorphins; Exercise; Humans; Hydrocortisone; Injections, Intravenous; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Time Factors

Naloxone has been advanced as a potential neuroprotectant against ischemic injury. This study examined the involvement of classical opioid receptors in the reduction of middle cerebral arterial ligation-induced cortical infarction in rats. The infarct volume was significantly reduced after infusion of (-)-naloxone, but not its inert stereoisomer (+)-naloxone. Beta-funaltrexamine (beta-FNA), a mu opioid antagonist, also reduced ischemic infarct volume. Both (-)-naloxone and beta-FNA attenuated cerebral ischemia/reperfusion (I/R)-induced increases in neutrophil-associated myeloperoxidase activity and chemokine mRNA expression, including macrophage inflammatory protein-1 alpha and -2. However, (-)-naloxone and beta-FNA failed to decrease cerebral I/R-induced brain edema. The findings suggest that naloxone, acting through a blockade of mu opioid receptor activation, is beneficial to cerebral I/R insult in terms of reducing brain infarction, neutrophil accumulation, and chemokine expression.

Topics: Animals; Carotid Artery, Common; Cerebral Infarction; Coronary Disease; Functional Laterality; Hypoxia-Ischemia, Brain; Infarction, Middle Cerebral Artery; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Time Factors

1. Opioid receptor antagonists such as naloxone have shown antiarrhythmic activity in animal models of coronary artery occlusion. Studies have indicated that these effects are stereospecific but both isomers of naloxone prolong action potential duration and refractoriness in guinea-pig and rabbit isolated ventricular myocardium (Class III effect). 2. This study was performed to identify whether this Class III effect of naloxone could be reproduced in human myocardium in vivo. Twenty patients with coronary artery disease received intravenous racemic naloxone (1-40 micrograms kg-1 min-1). Surface electrocardiographic parameters were measured and refractory periods were determined during fixed rate pacing by programmed stimulation. 3. The corrected QT interval during sinus rhythm (SR-QTc) was prolonged by 5(3)% (P = 0.06) at a dose of 20 micrograms kg-1 min-1 and by 9(10)% at 40 micrograms kg-1 min-1 (P = 0.03). These small changes were lost at higher paced heart rates. No significant effects on atrial, atrioventricular nodal or ventricular refractoriness were seen. 4. Plasma naloxone concentrations well into the micromolar range were achieved with both of the higher doses of naloxone administered. Plasma beta-endorphin concentrations invariably increased following naloxone infusion. There was no statistical relationship between peak plasma naloxone concentrations and the absolute or percent prolongation of SR-QTc. 5. It seems unlikely that racemic naloxone would have any clinical utility as an antiarrhythmic agent. Racemic naloxone may enhance cardiac adrenergic nerve activity and this receptor mediated effect may have prevented the demonstration of any nonreceptor mediated prolongation of cardiac refractoriness. Studies with the individual stereoisomers of naloxone would be of interest.

Topics: Action Potentials; beta-Endorphin; Coronary Disease; Electrocardiography; Electrophysiology; Female; Heart Rate; Humans; Injections, Intravenous; Male; Naloxone; Radioimmunoassay; Stereoisomerism

The effects of the stereoisomers of naloxone during myocardial ischemia were studied. (-)-Naloxone (but not the (+)-isomer naloxone) attenuated the ischemia-induced cardiac arrhythmias, hypotension, and bradycardia that result from coronary artery occlusion in anesthetized rats. From these findings, it may be inferred that endogenous opioid peptides may play a role in the pathophysiology of myocardial ischemia. It is also suggested that naloxone may have therapeutic value in the prevention and treatment of ischemic heart disease.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Coronary Vessels; Endorphins; Female; Heart Rate; Male; Naloxone; Rats; Rats, Inbred Strains; Stereoisomerism; Time Factors

The antiarrhythmic actions of low and high doses of U-50,488H, a selective kappa-receptor agonist, were examined in pentobarbitone-anaesthetized rats subjected to occlusion of the left anterior descending coronary artery. At a high dose (16 mumol/kg) U-50,488H reduced blood pressure, heart rate and prolonged the P-R and QRS intervals of the electrocardiogram. This dose reduced the incidence of ventricular arrhythmias produced by occlusion. The blood pressure, heart rate, ECG and antiarrhythmic actions of a high dose of U-50,488H were not antagonized by 8 mumol/kg naloxone, a dose which had no cardiovascular or ECG actions. Naloxone alone reduced arrhythmia incidence but to a lesser extent than U-50,488H. A low dose (0.2 mumol/kg) of U50,488H in the absence or presence of naloxone had no effect on arrhythmias. Thus, U-50,488H had antiarrhythmic actions at a high dose which were independent of opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atenolol; Blood Pressure; Coronary Disease; Dose-Response Relationship, Drug; Drug Interactions; Electrocardiography; Heart Rate; Male; Naloxone; Potassium; Pyrrolidines; Rats; Rats, Inbred Strains

A series of studies with humans as well as experiments carried out on animals could show that physical exercise leads to temporary hypoalgesia. Reduced sensitivity to pain is not only demonstrable after long-distance exercise (such as marathon run) but also after intensive physical exercise on a laboratory ergometer. Pain threshold elevation is most pronounced during maximal exertion, but hypoalgesia remains present also after exercise is stopped demonstrating that a systemic analgetic effect is induced by the exercise process. Pre-exercise pain threshold level is returned to approximately 60 minutes after the exercise. The cause of the exercise-induced hypoalgesia is probably an activation of central pain inhibitory mechanisms by the "stimulus" of physical exercise (stimulation- or stress-induced analgesia). Central pain inhibitory systems are thereby triggered by the stimulation of afferent nerve endings (group III and IV) in the skeletal muscle. The same trigger mechanism also plays a role as a release stimulus for hormones such for beta-endorphin which is increased under physical exercise. Plasma-beta-endorphin is probably not directly involved in the exercise-induced hypoalgesia but is rather a "marker" for the activating of central analgesia mechanisms. Stress-induced hypoalgesia plays also a role in the coronary heart disease. The activation of endogenous analgetic mechanisms leads to a part of the myocardial ischaemia provoked by exercise being silent under exercise. Completely asymptomatic myocardial ischaemia patients display a generalized hypoalgesia which is demonstrable independent of an exertion stimulus and which indicates a central set-point change in the antinociceptive system.

Topics: Adult; Analysis of Variance; beta-Endorphin; Coronary Disease; Double-Blind Method; Epinephrine; Exercise; Exercise Test; Humans; Hydrocortisone; Male; Naloxone; Norepinephrine; Pain; Pain Measurement; Sensory Thresholds

The aim was to evaluate the effects of an opiate agonist (U50,488H) and an opiate antagonist (naloxone) in myocardial ischaemia.. A left thoracotomy was performed and the left coronary artery was ligated in adult Sprague-Dawley rats of either sex (350-400 g). Blood pressure, heart rate and electrocardiogram were measured before and after injections of U50,488H or naloxone and throughout the 30 min postligation period.. Following coronary artery occlusion, all rats in the control group developed arrhythmias, bradycardia, and hypotension. U50,488H potentiated and naloxone attenuated the ischaemia induced arrhythmias, bradycardia, and hypotension.. The potentiating and blocking effects of U50,488H and naloxone, respectively, suggest that endogenous opioid peptides are involved in the pathophysiology of myocardial ischaemia and play an important role in ischaemic heart disease.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Disease Models, Animal; Female; Heart Rate; Male; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains

Silent--asymptomatic--ischaemia is one of the forms of ischaemic heart disease. Present possibilities of non-invasive diagnostics are based primarily on long-term ECG monitoring. With regards to the hypothesis that the raised algesic threshold at high level of analgetically reacting beta endorphins seems to be the pathophysiologic basis of this particular syndrome, we tried to verify the presumption by administering a beta-endorphin antagonist-naloxon. In 13 patients with a silent form of ischaemic heart disease (absence of stenocardia in objectively proved ischaemia in loading test) we made the loading test in a standard form and after administering of 2 mgs of naloxan intravenously. Owing to the fact that stenocardia developed only in one patient after endogenous opiate effect blockage we presume that pathophysiologic basis of this syndrome must be discovered elsewhere.

Topics: beta-Endorphin; Coronary Disease; Electrocardiography; Exercise Test; Female; Humans; Male; Middle Aged; Naloxone

Acute experiments on cats have shown that the naloxone blocks of opiate receptors increased essentially the incidence of idioventricular arrhythmias in myocardial ischemia. These results may evidence of the endogenous opioid peptides involvement in the body response on the acute myocardial ischemia.

Topics: Acute Disease; Animals; Arrhythmias, Cardiac; Cats; Coronary Disease; Electrocardiography; Female; Heart Rate; Male; Naloxone; Receptors, Opioid

1. The effects of a range of opioid receptor agonists and antagonists with differing opioid receptor selectivities on ischaemia-induced arrhythmias in anaesthetised rats was investigated. 2. Naloxone was antiarrhythmic only at doses expected to antagonise kappa- and delta-receptors in addition to mu-receptors. 3. The opioid receptor antagonist Mr 2266, which is twice as potent at kappa-receptors as at mu-receptors dose-dependently reduced the incidence and severity of the arrhythmias resulting from coronary artery occlusion. 4. The opioid receptor antagonist M 8008 (1 mg kg-1), which is twice as potent at delta-receptors as at mu-receptors but has very little affinity for the kappa-receptor, did not exhibit any beneficial antiarrhythmic properties. 5. MrZ 2593, a quarternary complex of naloxone which does not readily cross the blood brain barrier, was antiarrhythmic which implies that the antiarrhythmic actions of opioid receptor antagonists may be mediated via peripheral opioid receptors. 6. The agonists, diamorphine, [Leu] enkephalin and U-50,488H exhibited no significant arrhythmogenic effects under the present experimental conditions. 7. It is tentatively suggested that blockade of peripheral kappa-receptors during acute myocardial ischaemia may result in an antiarrhythmic effect.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Coronary Vessels; Enkephalin, Leucine; Heart Rate; Heroin; Male; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Time Factors

Topics: Animals; Anti-Arrhythmia Agents; Coronary Disease; Female; In Vitro Techniques; Naloxone; Naltrexone; Rats; Rats, Inbred Strains

1. The cardiovascular responses to acute myocardial ischaemia were studied in opiate-dependent animals before and after 2 weeks morphine withdrawal. 2. Rats were treated with morphine sulphate in drinking water for 2, 3 or 5 weeks. The development of morphine tolerance and dependence was verified by the tail-immersion test for analgesia and the naloxone-precipitated withdrawal syndrome, respectively. 3. Acute left coronary artery ligation induced a decrease in blood pressure, a slight increase in heart rate and ventricular tachycardia or fibrillation in anaesthetized naive rats. 4. Chronic morphine treatment did not alter the haemodynamic responses to coronary artery ligation. However, a significantly lowered incidence, and prolonged time of onset, of ventricular arrhythmias was found in 3 and 5 week morphine-treated rats. This phenomenon did not occur in animals receiving morphine for 2 weeks and in a 3 week morphine-treated group which was subsequently withdrawn for 2 weeks. 5. It is suggested that the decreased occurrence of early ventricular arrhythmias resulting from acute myocardial ischaemia in chronic morphine-treated rats may be related to the degree of opiate tolerance and dependence.

Topics: Animals; Blood Pressure; Body Weight; Coronary Disease; Coronary Vessels; Drug Tolerance; Heart Rate; Hemodynamics; Male; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Tachycardia; Ventricular Fibrillation

The contribution of stress-induced and opioid-dependent mechanisms to the modulation of experimental pain was studied in man under different conditions. The contribution of these mechanisms to the possible attenuation of acute cardiac pain in human patients was also studied. According to the present series of investigations, stress-induced mechanisms might be involved in the modulation of pain caused by physical exercise but not by concurrent subacute pain or transcutaneous nerve stimulation. The lack of any negative correlation between the pain intensity and the release of stress hormones indicates that stress mechanisms do not attenuate acute ischaemic pain of the cardiac origin. The use of an opioid-antagonist, naloxone, and the measurement of plasma levels of beta-endorphin did not reveal any contribution of endogenous opinoids to pain modulation in the current study.

Topics: beta-Endorphin; Coronary Disease; Endorphins; Humans; Naloxone; Neurosecretory Systems; Pain; Physical Exertion; Stress, Physiological; Stress, Psychological; Transcutaneous Electric Nerve Stimulation

The effects of acute coronary artery ligation on cardiac rhythm and haemodynamics were studied in rats receiving either acute or chronic morphine-treatment. In chronic opiate-treated animals, increasing concentrations of morphine sulphate were administered in drinking water over a 3 week period, and the development of morphine tolerance and dependence was verified by decreased analgesic responses to morphine in the tail-immersion test and the occurrence of naloxone-precipitated withdrawal syndromes, respectively. Acute coronary artery ligation induced a decrease in blood pressure, a slight increase in heart rate, and ventricular tachycardia or fibrillation in anaesthetized rats. The changes in blood pressure and heart rate following acute coronary artery ligation were not significantly altered by acute or chronic morphine administration. The incidence and the time of onset of ventricular tachycardia or fibrillation were found to be significantly reduced and prolonged, respectively, in chronically morphine-treated rats, but were not significantly affected by acute morphine administration in naïve animals. These findings suggest that chronic morphine treatment lessens the occurrence of early ventricular arrhythmias caused by acute myocardial ischaemia in rats. The mechanism of this effect is unclear.

Topics: Animals; Blood Pressure; Coronary Disease; Coronary Vessels; Electrocardiography; Hemodynamics; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Tachycardia; Ventricular Fibrillation

The effects of myocardial ischaemia and reperfusion on arrhythmias and cAMP levels were studied using the Langendoff isolated perfused rat heart preparation. Myocardial ischaemia and reperfusion caused arrhythmias and augmentation of cAMP levels concurrently, supporting the suggestion that myocardial cAMP is related to arrhythmias. Pretreatment with naloxone attenuated both arrhythmias and augmentation of cAMP levels to a similar extent. The results suggest that the anti-arrhythmic effect of naloxone may involve myocardial cAMP.

Topics: Animals; Anti-Arrhythmia Agents; Coronary Disease; Cyclic AMP; Female; Myocardium; Naloxone; Perfusion; Rats; Rats, Inbred Strains

Ischemic pain threshold and tolerance levels using the tourniquet pain technique and electrical cutaneous pain thresholds were measured in patients with asymptomatic ischemic heart disease. Thirty asymptomatic patients, who repeatedly exhibited no angina pectoris pain during the occurrence of exercise-induced coronary ischemia (greater than or equal to 0.1 mV ST segment depression in exercise ECG) were compared to 30 randomly selected symptomatic control patients. In a smaller patient group (6 symptomatic, 6 asymptomatic) the degree of forearm ischemia during the tourniquet test was determined non-invasively by monitoring transcutaneous pO2. Results indicated that asymptomatic patients needed significantly more time to reach pain threshold following occlusion of forearm blood flow and exhibited significantly lower tcpO2 values at threshold than symptomatic patients. Electrical pain thresholds were also elevated in the asymptomatic group. These findings indicate that the phenomenon of asymptomatic myocardial ischemia can be explained by an extracardiac pain modifying mechanism.

Topics: Angina Pectoris; Blood Pressure; Coronary Disease; Electrocardiography; Heart Rate; Humans; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Physical Exertion; Sensory Thresholds

The intravenous administration of naloxone 2 min before coronary artery occlusion in anaesthetized dogs reduced the incidence and severity of cardiac arrhythmias during coronary occlusion (20 min) and reperfusion (120 min) in a dose-related manner. It also reduced the mortality. At a dose of 1 mg kg-1 (the maximum dose used in this study) naloxone abolished the appearance of the life threatening ventricular fibrillation (VF) and ventricular tachycardia (VT) and as a consequence all dogs in this group survived. The results suggest a possible involvement of endogenous opioid peptides in arrhythmogenesis during coronary occlusion and reperfusion in the dog.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Coronary Disease; Dogs; Female; Heart Rate; Male; Naloxone

The effects of naloxone, propranolol, or both on the release of creatine kinase (CK) from the isolated ischemic rat heart were studied. Naloxone at concentrations of 1.1 and 3.6 mmole liter-1 in the perfusate at a rate of 1-2 ml min-1 reduced the release of CK from the isolated ischemic rat heart during myocardial ischemia in a dose-dependent manner. Propranolol at a concentration of 7 mumole liter-1 in the perfusate also reduced the release of CK. Addition of naloxone (1.1 mmole liter-1) to propranolol further reduced the release of CK. The effect of the joint administration of the two drugs seemed to be additive.

Topics: Animals; Coronary Disease; Creatine Kinase; Female; In Vitro Techniques; Myocardium; Naloxone; Propranolol; Rats; Rats, Inbred Strains

It has been demonstrated in experiments on rats that acute myocardial ischemia gives rise to a decrease in diuresis, elevation of antidiuretic activity of blood plasma and the blood concentration of immunoreactive aldosterone. Intraperitoneal injection of a synthetic enkephalin analog D-ala2-leu5-arg6-enkephalin in a dose of 1.25 nmol/kg bw resulted in partial normalization of diuresis, reduction in antidiuretic activity of blood plasma and blood aldosterone level to the control values. Naloxone eliminated the effects described. It is concluded that enkephalins have an inhibitory action on aldosterone and vasopressin secretion, with this action being mediated via opiate receptors.

Topics: Aldosterone; Animals; Coronary Disease; Diuresis; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Male; Naloxone; Rats; Vasopressins

Topics: Adult; Anesthesia; Coronary Disease; Humans; Male; Naloxone; Pulmonary Edema

Naloxone pretreatment (1.0, 3.0 and 10.0 mg/kg i.v.) failed to protect anesthetized pigs from cardiac arrhythmias including ventricular fibrillation (VF) and death following acute occlusion (20 min) or reperfusion of the left anterior descending coronary artery. These findings suggest that opiate-like substances possibly released by the ischemic myocardium do not contribute significantly to the etiology of cardiac arrhythmias, or sudden death associated with the early stages of myocardial infarction in pigs. The effectiveness of naloxone in preventing acute ischemia-induced arrhythmias in rats may be due to mechanisms other than opiate-receptor blockade.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Female; Heart Rate; Hemodynamics; Male; Morphine; Naloxone; Swine; Ventricular Fibrillation