Comparison of Adrenergic Beta-blocking Drugs in Angina Pectoris

The symptomatic, electrocardiographic, and haemodynamic effects of two adrenergic beta-blocking drugs, oxprenolol and propranolol, have been compared in equipotent intravenous doses in six patients with uncomplicated angina pectoris during treadmill exercise. The method of comparison included double-blind assessment and analysis with placebo control and randomized serial comparison in each patient. Both drugs produced an equal amelioration in symptoms in most of the patients. This was closely correlated with improvement in the electrocardiographic changes and a significant reduction in the exercising heart rate and systemic arterial pressure. This method of double-blind combined subjective and objective assessment carries distinct advantages in the comparative assessment of drug treatments in angina pectoris.     

Effects of naloxone on systemic and regional hemodynamic responses to exercise in dogs

To determine whether endogenous opiates have a role in circulatory regulation during mild to moderate exercise, 11 chronically instrumented dogs were exercised on a treadmill up a 6% incline at 2.5 and 5.0 mph, each for 20 min, after treatment with either the opiate receptor antagonist naloxone (1 mg/kg bolus and 20 micrograms.kg-1.min-1 infusion) or normal saline. Naloxone increased plasma beta-endorphin and adrenocorticotropic hormone at rest but had no effect on resting heart rate, aortic pressure, cardiac output, left ventricular time derivative of pressure (dP/dt) and ratio of dP/dt at a developed pressure of 50 mmHg and the developed pressure (dP/dt/P), or plasma catecholamines. Plasma beta-endorphin and adrenocorticotropic hormone increased during exercise. In addition, graded treadmill exercise produced proportional increases in heart rate, cardiac output, aortic pressure, left ventricular dP/dt and dP/dt/P, and blood flow to exercising muscles, right and left ventricular myocardium, and adrenal glands. However, there were no differences in the circulatory responses to exercise between animals receiving naloxone and normal saline. Thus the endogenous opiate system probably does not play an important role in regulating the systemic hemodynamic and blood flow responses to mild and moderate exercise.     

Different Effects of Adrenergic Beta-receptor Blockade on Heart Rate Response to Mental Stress,Catecholamines, and Exercise

The magnitude and duration of effect of a single 40-mg oral tablet of oxprenolol on the tachycardias associated with motor-car driving, isoprenaline infusion, and walking were compared against placebo in six normal people by a double-blind study. The tachycardias due to driving and isoprenaline were both conspicuousy reduced for over eight hours; the magnitude and duration of the reduction in exercise tachycardia was substantially less. Thus relatively small doses of beta-receptor antagonists will suppress the increase in heart rate induced by mental stress or catecholamines with relatively little effect on the response to everyday exercise. Possibly smaller doses of these drugs would relieve emotionally-induced anginal pain and tachycardia.     

Antigenic extracts of Leishmania braziliensis and Leishmania amazonensis associated with saponin partially protects BALB/c mice against Leishmania chagasi infection by suppressing IL-10 and IL-4 production

This study evaluated two vaccine candidates for their effectiveness in protecting BALB/c mice against Leishmania chagasi infection. These immunogenic preparations were composed of Leishmania amazonensis or Leishmania braziliensis antigenic extracts in association with saponin adjuvant. Mice were given three subcutaneous doses of one of these vaccine candidates weekly for three weeks and four weeks later challenged with promastigotes of L. chagasi by intravenous injection. We observed that both vaccine candidates induced a significant reduction in the parasite load of the liver, while the L. amazonensis antigenic extract also stimulated a reduction in spleen parasite load. This protection was associated with a suppression of both interleukin (IL)-10 and IL-4 cytokines by spleen cells in response to L. chagasi antigen. No change was detected in the production of IFN-γ. Our data show that these immunogenic preparations reduce the type 2 immune response leading to the control of parasite replication.     

Effect of Voluntary Ethanol Consumption Combined with Testosterone Treatment on Cardiovascular Function in Rats: Influence of Exercise Training

This study evaluated the effects of voluntary ethanol consumption combined with testosterone treatment on cardiovascular function in rats. Moreover, we investigated the influence of exercise training on these effects. To this end, male rats were submitted to low-intensity training on a treadmill or kept sedentary while concurrently being treated with ethanol for 6 weeks. For voluntary ethanol intake, rats were given access to two bottles, one containing ethanol and other containing water, three 24-hour sessions per week. In the last two weeks (weeks 5 and 6), animals underwent testosterone treatment concurrently with exercise training and exposure to ethanol. Ethanol consumption was not affected by either testosterone treatment or exercise training. Also, drug treatments did not influence the treadmill performance improvement evoked by training. However, testosterone alone, but not in combination with ethanol, reduced resting heart rate. Moreover, combined treatment with testosterone and ethanol reduced the pressor response to the selective α₁-adrenoceptor agonist phenylephrine. Treatment with either testosterone or ethanol alone also affected baroreflex activity and enhanced depressor response to acetylcholine, but these effects were inhibited when drugs were coadministrated. Exercise training restored most cardiovascular effects evoked by drug treatments. Furthermore, both drugs administrated alone increased pressor response to phenylephrine in trained animals. Also, drug treatments inhibited the beneficial effects of training on baroreflex function. In conclusion, the present results suggest a potential interaction between toxic effects of testosterone and ethanol on cardiovascular function. Data also indicate that exercise training is an important factor influencing the effects of these substances.     

Oxygen consumption and distribution of blood flow in rats climbing a laddermill

The purpose of this study was threefold: 1) to determine whether untrained rats that refused to run on treadmill would climb on a laddermill (75 degrees incline); 2) to determine O2 consumption (VO2) in untrained rats as a function of laddermill climbing speed; and 3) to determine whether the circulatory response of untrained rats to laddermill climbing is similar to that previously reported for treadmill running at an equivalent VO2. Eighteen female Sprague-Dawley rats that would not perform on a treadmill as part of another study were used to measure VO2 as a function of laddermill speed (5-17 m/min). Data were obtained from all 18 rats; VO2 increased linearly as a function of laddermill speed (r = 0.83, y = 3.0 x + 63.2). Twenty-four female Sprague-Dawley rats that also refused to run on a treadmill were used to measure mean arterial pressure, heart rate, and blood flow distribution (with microspheres) during climbing at 5 and 10 m/min. These exercise intensities were metabolically equivalent to level treadmill running at 45 and 60 m/min (VO2 approximately 78 and 93 ml.min-1.kg-1, respectively). Of the 24 animals, 23 were willing to climb. Mean arterial pressures were higher (approximately 10%) during laddermill climbing than during equivalent treadmill running, but heart rates were the same. General blood flow distribution among muscles as a function of fiber type (with red muscles receiving higher flows) and between muscles and visceral tissues (muscle blood flow increased as a function of exercise intensity while visceral blood flows decreased) were similar to data for rats running on the level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic effects of glucose, medium chain triglyceride and long chain triglyceride feeding before prolonged exercise in rats

The purpose of this study was to test the hypothesis that oral ingestion of lipids could increase endurance by slowing the rate of glycogen depletion. Trained rats were killed after a 2 h run on a rodent treadmill, following an intragastric infusion of water, glucose, medium chain triglycerides (MCT) or long chain triglycerides (LCT). Glucose and triglycerides were administered in equicaloric concentrations (50 kJ). The results show that oral ingestion of lipids (MCT or LCT) did not reduce glycogen depletion in liver, heart or skeletal muscle after exercise whereas the fat diet increased muscle and heart glycogen stores in resting conditions. In contrast, glucose feeding induced a significant sparing effect on endogenous carbohydrate utilization and reduced physical exercise lipolysis. These data indicated, firstly, that enhanced lipid availability induced by a single lipid meal before exercise was not able to modify the glycogen depletion occurring after exercise and, secondly, that the glucose/fatty acid cycle was not effective in these conditions. The comparison between lipids indicated that the effect on glycogen use of MCT did not differ from that of LCT, and did not seem to be of any particular importance during physical exercise.     

Training-induced bradycardia and intrinsic heart rate in rats

After 10 weeks of treadmill training, female Sprague-Dawley rats had developed a bradycardia at exercise on submaximal work loads. This bradycardia was also present after autonomic denervation and in isolated perfused heart preparations. The heart weight/body weight ratio was increased in these trained animals compared to untrained littermates. Sympathectomized, trained rats developed the same degree of cardiac hypertrophy, but their heart rate after denervation and in the isolated heart was the same as in sympathectomized, untrained rats. It is concluded that the bradycardia of trained and thereafter denervated animals seen in this and a previous investigation represents an adaptation within the heart itself, since it was present in the isolated heart. These results thus provide further evidence for a non-neural component in training-induced bradycardia. Since the trained sympathectomized rats had a cardiac hypertrophy but no reduction of intrinsic heart rate, it seems likely that the myocardial mass is of minor importance for the level of intrinsic heart rate.     

Exercise decreases speedball self-administration

Aims

Epidemiological studies report that individuals who exercise are less likely to abuse drugs. Preclinical studies report that exercise, in the form of treadmill or wheel running, reliably decreases the self-administration of psychomotor stimulants and opioids. To date, preclinical studies have only examined the effects of exercise on responding maintained by individual drugs and not by combinations of multiple drugs. This limits the translational appeal of these studies because polydrug abuse is common among substance abusing populations. The purpose of this study was to examine the effects of exercise on the self-administration of speedball, a combination of cocaine and heroin that is frequently encountered in intravenous drug abusing populations.

Main methods

Female rats were obtained at weaning and assigned to sedentary or exercising conditions. Sedentary rats were housed in standard cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed in similar cages with an activity wheel. After 6 weeks, rats were implanted with intravenous catheters and trained to self-administer cocaine, heroin, and dose combinations of cocaine and heroin (i.e., speedball) on a progressive ratio schedule of reinforcement.

Key findings

Doses of speedball maintained greater levels of responding than corresponding doses of cocaine and heroin alone. Importantly, responding maintained by cocaine, heroin, and speedball was lower in exercising rats than sedentary rats.

Significance

These data indicate that exercise decreases the self-administration of speedball and suggest that exercise may reduce the abuse of drug combinations that have traditionally been resistant to treatment.     

Conservative Treatment of Chronic Heart Block

A study of 203 patients with chronic heart block treated with oral long-acting isoprenaline showed that 85 (42%) were maintained satisfactorily on the drug for a mean period of 18.2 months. The survival rates at one, two, and three years were 76%, 64%, and 57% respectively. In 115 patients treatment by pacing became necessary to control symptoms, and in these patients the survival rates at one, two and three years were 83%, 72%, and 60%.The two most valuable guides to patients'' response to oral isoprenaline are the response to a trial dose of intravenous isoprenaline and the type of dysrhythmia associated with their Adams-Stokes attacks. Patients with heart failure with slow ventricular rates and those with angina of effort do not respond to treatment with sympathomimetic drugs.The majority of patients with chronic heart block are elderly, and in view of the complexity of pacing systems, and the need for skilled supervision of paced patients, oral long-acting isoprenaline remains of value in the longterm management of chronic heart block, provided patients are carefully selected for this form of therapy.     

Fibrinolytic activity is not dependent upon exercise mode in post-myocardial infarction patients

In this study we investigated possible differences in fibrinolytic activity in cardiac patients while they performed treadmill and cycle ergometry. Thirteen post-myocardial infarction patients completed two maximal exercise tests on treadmill and cycle ergometers. Blood was collected before and after each exercise test and was analyzed for the fibrinolytic variables, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activity, and lactate. Maximal oxygen uptake, heart rate, and ventilation were greater (P < 0.05) on the treadmill than during cycle ergometry, however, blood lactate was similar between modes. t-PA activity significantly increased with exercise (P < 0.05) and there was a trend toward a reduction in PAI-1 activity with exercise, but this did not reach statistical significance. The fibrinolytic responses to maximal exercise did not differ between the two modes of exercise studied. Therefore, exercise intensity, but not the mode of exercise, appeared to be the primary determinant of the fibrinolytic response to acute exercise in these patients. Accepted: 29 January 1998     

Effects of dichloroacetate on hemodynamic responses to dynamic exercise in dogs.

To determine whether lactic acid production contributes significantly to the cardiac responses to muscular dynamic exercise, we administered intravenous sodium dichloroacetate (32 mumol.kg-1.min-1), a pyruvate dehydrogenase activator that facilitates lactate metabolism via the tricarboxylic cycle, in 12 dogs during two graded levels of treadmill exercise. Similar exercise was carried out in nine normal dogs receiving equimolar doses of NaCl. In the latter group, arterial lactate increased progressively from 0.80 +/- 0.11 (SE) mmol/l at rest to 2.13 +/- 0.28 mmol/l by the end of exercise. In contrast, arterial lactate did not change significantly (0.98 +/- 0.12 to 0.95 +/- 0.11 mmol/l) during exercise in dogs receiving dichloroacetate infusion. Dichloroacetate infusion also reduced the increases in plasma norepinephrine, heart rate, and left ventricular contractile indexes that occurred during exercise, suggesting that the sympathetic cardiac stimulation occurring during exercise may be related to the production of lactic acid. However, dichloroacetate affected neither the net increase in cardiac output nor the relationship between total body oxygen consumption and cardiac output that occurred during exercise. Thus we conclude that lactic acid production is not essential to the increase in cardiac output that occurs during mild-to-moderate exercise.     

Circulatory effects of prolonged hypoxia before and during antihistamine.

Five chronically instrumented healthy dogs were exposed to a 5-day period of breathing 10% oxygen in a chamber. The response to hypoxia was found to be time dependent. During the first 24 h of hypoxia the circulatory response was characterized by increases in cardiac output, heart rate, pulmonary and systemic arterial blood pressures, and pulmonary vascular resistance. Systemic vascular resistance increased; left atrial pressure decreased. During the early part of hypoxia the animals became hypocapnic; the arterial blood pH rose significantly. During the rest of the hypoxic period cardiac output, heart rate, and arterial blood pH returned to the control values; pulmonary and systemic arterial pressures and pulmonary vascular resistance remained significantly elevated. Systemic vascular resistance rose; left atrial pressure remained below control. This response to hypoxia was not substantially modified when the experiment was repeated during the administration of the antihistamine promethazine, an H1-receptor blocking agent, in a dose which blocked the pulmonary vasoconstrictor response to small doses of exogenous histamine. The circulatory response to acute hypoxia in five anesthetized dogs was not modified by intravenous administration of metiamide, an H2-receptor blocking agent.     

Cardiac responses to exercise in the dog before and after destruction of the sinoatrial node

Chronotropic and dromotropic responses to treadmill exercise were compared in conscious dogs prior to and following excision of the sinoatrial node (SAN). The initial junctional rhythm accompanying removal of the SAN region was replaced within hours to days by subsidiary atrial pacemaker (SAP) foci located in the inferior right atrium along the sulcus terminalis. With SAN intact, cardiac acceleration was immediate at onset of exercise and the tachycardia was directly proportional to work intensity. Atrioventricular (AV) conduction concurrently accelerated during exercise as manifest by shortening in P-R and atrioventricular (A-V) intervals. Following SAN excision, subsidiary atrial pacemaker foci likewise demonstrated prompt tachycardias during exercise, although heart rate was significantly reduced at rest and during steady state exercise. In the SAP state, tachycardia during exercise was related to work intensity and was mediated by changes in cardiac autonomic nerve activity. Combined propranolol-atropine blockade increased heart rate at rest in the SAP state, and significantly attenuated the tachycardia accompanying treadmill exercise. Following SAN excision the P-R (A-V) interval was significantly reduced in the resting animal. In response to exercise, AV conduction time decreased in the SAP state, though the absolute levels during steady state exercise were not significantly different from prior control runs with SAN intact. Blood pressure response to exercise was similar during both SAN and SAP states. We conclude that following an initial unstable period, SAP foci maintain adequate heart rate increases in response to dynamic exercise, primarily mediated via autonomic nerve regulation.     

Initial ventilatory and circulatory responses to dynamic exercise are slowed in the elderly.

To elucidate the characteristics of ventilatory and circulatory responses at the onset of brief and light exercise in the elderly, 13 healthy, elderly men, aged 66.8 yr (mean), exerted bilateral leg extension-flexion movements for only 20 s with a weight around each ankle, with each weight being approximately 2.5% of their body mass. Similar movements were passively performed on the subjects by the experimenters. These results were compared with those of 13 healthy, young men (22.9 yr). Minute ventilation increased at the onset of voluntary exercise and passive movements in both groups but showed a slower increase in the elderly. Heart rate also increased in both groups but showed less change in the elderly. Mean blood pressure temporarily decreased in both groups but less in the elderly. The magnitude of relative change (gain) of heart rate in the elderly was significantly smaller than that in the young, whereas the increasing rate to reach one-half of the gain (response time) of ventilation in the elderly was significantly slower than that in the young. Similar tendencies were observed in the passive movements. It is concluded that the elderly show slower ventilatory response and attenuated circulatory response at the onset of dynamic voluntary exercise and passive movements.     

Release of beta endorphin and met-enkephalin during exercise in normal women: response to training.

Plasma beta endorphin and met-enkephalin concentrations were measured in response to treadmill exercises in 15 normal women before, during, and after an intensive programme of exercise training. Significant release of beta endorphin occurred in all three test runs, and the pattern and amount of release were not altered by training. Before training dramatic release of met-enkephalin was observed in seven subjects and smaller rises observed in a further four, and this response was almost abolished by training. This represents the first observed "physiological" stimulus to met-enkephalin release. Endogenous opioid peptides play a part in adaptive changes to exercise training and probably contribute to the menstrual disturbances of women athletes.     

Cardiorespiratory response to low-intensity walking in water and on land in elderly women.

The purpose of the present study was to determine whether or not the exercise intensity of water-walking for elderly women could be accurately prescribed by heart rate data obtained during treadmill exercise on land. Six healthy female volunteers, with a mean age of 62.2 +/- 4.2 years, took part in this study. Walking on land was performed on a treadmill. Each subject completed three consecutive 4-minute walks at a progressively increasing velocity (40, 60 and 80 m.min-1), with a 1-minute rest after both the first and second walks. The room temperature and relative humidity were 24.5 +/- 0.2 degrees C and 54.8 +/- 4.0%, respectively. Walking in water was performed in a Flowmill, which is a treadmill positioned at the base of a water flume. Each subject completed three consecutive 4-minute walks at a progressively increasing belt and water-flow velocity (20, 30 and 40 m.min-1), with a 1-minute rest after both the first and second walks. The water depth was at the level of the xiphoid process of each subject. The water temperature was 30.7 +/- 0.1 degrees C. The exercise intensity at the highest workrate was equivalent to 44.2 +/- 10.3% of the heart rate reserve (HRR) during water-walking and 38.4 +/- 4.7% of the HRR during land-walking. There was a highly significant linear relationship between heart rate (HR) and oxygen uptake (VO2) during both water-walking and land-walking. The relationship between HR and VO2 in both exercise modes was similar. Thus, the relationship of HR to VO2 derived from a treadmill-graded walking test on land may be used to prescribe exercise intensity for water-walking in thermoneutral water.     

Ethnographic study of incidence and severity of intravenous drug errors

ObjectivesTo determine the incidence and clinical importance of errors in the preparation and administration of intravenous drugs and the stages of the process in which errors occur.DesignProspective ethnographic study using disguised observation.ParticipantsNurses who prepared and administered intravenous drugs.Setting10 wards in a teaching and non-teaching hospital in the United Kingdom.Results249 errors were identified. At least one error occurred in 212 out of 430 intravenous drug doses (49%, 95% confidence interval 45% to 54%). Three doses (1%) had potentially severe errors, 126 (29%) potentially moderate errors, and 83 (19%) potentially minor errors. Most errors occurred when giving bolus doses or making up drugs that required multiple step preparation.ConclusionsThe rate of intravenous drug errors was high. Although most errors would cause only short term adverse effects, a few could have been serious. A combination of reducing the amount of preparation on the ward, training, and technology to administer slow bolus doses would probably have the greatest effect on error rates.

What is already known on this topic

Errors in preparing and administering intravenous drugs can cause considerable harm to patientsReduction of drug errors is a government health target in the United Kingdom and the United States

What this study adds

Errors occurred in about half of the intravenous drug doses observedErrors were potentially harmful in about a third of casesThe most common errors were giving bolus doses too quickly and mistakes in preparing drugs that required multiple steps     

Activation of JNK in rat heart by exercise: effect of training

The purpose of the study was to determine whether exercise would activate JNK in the heart and whether chronic exercise training would alter the response. Untrained rats were familiarized with the treadmill and assigned to one of four groups: low intensity (LI), 10 min, 0%, 15 m/min; medium intensity (MI), 10 min, 0%, 33 m/min; high intensity (HI), 10 min, 25%, 33 m/min; long duration (LD), 30 min, 0%, 15 m/min. Another cohort of rats was subjected to a progressive 6 wk high-intensity training protocol that produced a 12% increase in heart mass. In untrained rats, JNK activity was LI: 1.5 (fold nonrun control), MI: 2.0, HI: 2.5, LD: 1.25 immediately after a single bout of exercise. In trained rats, no activation of JNK above baseline was detected after either a 10-min or 1-h bout of exercise. We concluded that treadmill exercise activates JNK in the rat heart in an intensity-dependent manner and that chronic training abrogates the myocardial JNK response to a bout of exercise.     

Assessment of dermal glyceryl trinitrate and isosorbide dinitrate for patients with angina pectoris.

Dermal nitrate preparations are claimed to be useful in the treatment of angina, as their slow absorption by-passing the liver leads to a sustained action. Ten patients with angina were exercised on a treadmill after dermal application of 16.64 mg glyceryl trinitrate or 100 mg isosorbide dinitrate or placebo. Exercise duration was significantly increased at one and three hours for both nitrate preparations but not at six hours after application. The calculated workload achieved was significantly increased (p less than 0.01) at one and three hours for both preparations and at six hours (p less than 0.05) for isosorbide dinitrate. Headaches were common with glyceryl trinitrate cream. The dermal nitrate preparations studied had a duration of antianginal action similar to that of oral nitrate tablets. Aside from their value when the oral route cannot be used or absorption may be delayed, dermal nitrate preparations have no advantage over oral preparations for angina pectoris.