Enhanced myocardial contractility but not tachycardia persists in isolated working hyperthyroid rat hearts

Summary It is generally believed that the increased contractility and tachycardia of the hyperthyroid heart are a result of thyroid hormone-induced alterations of the mechanical and electrical properties of the heart, respectively. We compared the contractility (dP/dt_max) and the spontaneous beating rate of hyperthyroid and euthyroid hearts perfused in vitro in either a non-working or a working mode. The dP/dt_max (4196±74 mm Hg s^–1) and beating rate (322±8 beats/min) of the non-working hyperthyroid hearts were significantly higher (p<0.001) than those of the euthyroid hearts (3267±115 mm Hg s^–1 and 260±6 beats/min at an external Ca²⁺ of 2.5 mM). At 2.5 mM Ca²⁺, the working hyperthyroid hearts again displayed enhanced contractility (5636±179 mm Hg s^–1 vs 4508±172 mm Hg s^–1; p<0.001) but the spontaneous beating rate (275±7 beats/min) was not significantly different from euthyroid (261±8 beats/min). When hearts were subjected to periods of alternate non-working and working perfusion, the beating rate of the hyperthyroid hearts was significantly higher than euthyroid during non-working (p<0.02) but not during working perfusion. Increasing the afterload on the non-working preparations in a stepwise fashion from 75 cm H₂O to 120 cm H₂O caused significant changes in left ventricular pressure and dP/dt_max in both heart types but the tachycardia in the hyperthyroid hearts persisted (at 120 cm H₂O; hyperthyroid, 294±9 beats/min; euthyroid, 224±10 beats/min; p<0.001). Alteration of the preload (10 to 25 cm H₂O) and afterload (75 to 105 cm H₂O) on working hyperthyroid and euthyroid hearts caused changes in both left ventricular pressure and dP/dt_max but the beating rates of both heart types were never significantly different. We conclude from our results that (i) the increased contractility of the hyperthyroid rat heart is due to thyroid hormone-induced alteration of the mechanical properties of the heart; (ii) the tachycardia of hyperthyroidism is not due to thyroid hormone-induced changes in the electrical properties of the heart, but probably involves some as yet unidentified chronotropic agent.     

Cardiac and plasma catecholamine response to dynamic exercise in hyperthyroidism]

To investigate cardiac and sympathoadrenal responses to dynamic exercise, heart rate, systolic blood pressure, serial plasma norepinephrine (NE) and epinephrine (E) concentrations during multistage treadmill exercise were measured in 24 hyperthyroid patients (mean age; 42 +/- 16) and 24 age-sex matched control subjects. Eleven patients were re-examined in the euthyroid state after antithyroid therapy. Exercise duration was shorter in patient with hyperthyroidism. Also, the heart rates and systolic blood pressures at rest and in the early stage of exercise were significantly higher in hyperthyroidism. NE at rest (normal vs hyperthyroid: 124 +/- 10 vs 80 +/- 7 pg/ml, p < 0.01) and NE at peak exercise (475 +/- 38 vs 310 +/- 38 pg/ml, p < 0.01) were lower in hyperthyroidism. E at rest (22 +/- 2 vs 29 +/- 4 pg/ml, n.s.) did not differ, however, E during the first stage of exercise (30 +/- 3 vs 69 +/- 12 pg/ml, p < 0.01) was higher in hyperthyroidism. Re-examination for the euthyroid state revealed the decreases in the heart rates and systolic blood pressures at rest and in the early stage of exercise, and the normalization of the NE and E response. Thus, patients with hyperthyroidism was in the hyperdynamic cardiac state at rest and during dynamic exercise, which was accounted for by decreased sympathetic nervous activity and increased adrenomedullary responses. These modifications of sympathoadrenal response seemed reversible when patients were controlled by antithyroid therapy.     

Effect of Corwin (ICI 118587) on resting and exercise heart rate and exercise tolerance in digitalised patients with chronic atrial fibrillation

The effect of Corwin, a new oral beta, partial agonist, on the ventricular response to atrial fibrillation was studied in digitalised patients during 24 hour ambulatory electrocardiography and during exercise on a treadmill in a double blind placebo controlled crossover trial. Corwin reduced the maximum heart rate during exercise from 162(16) beats/min to 120(9) beats/min and reduced the peak heart rate during ambulatory electrocardiography from 113(11) to 90(6) beats/min consistent with a beta adrenoreceptor antagonist action at higher levels of sympathetic nervous system activity. Minimum heart rate during ambulatory electrocardiography was increased from 62(5) to 70(5) beats/min indicating that at lower levels of sympathetic activity the drug acts as a beta agonist. The drug increased exercise tolerance significantly. Serum digoxin concentrations were not affected by the drug. Thus Corwin appears to be effective in stabilising heart rate during atrial fibrillation both at rest and during exercise in digitalised patients.     

Effect of Corwin (ICI 118587) on resting and exercise heart rate and exercise tolerance in digitalised patients with chronic atrial fibrillation.

The effect of Corwin, a new oral beta, partial agonist, on the ventricular response to atrial fibrillation was studied in digitalised patients during 24 hour ambulatory electrocardiography and during exercise on a treadmill in a double blind placebo controlled crossover trial. Corwin reduced the maximum heart rate during exercise from 162(16) beats/min to 120(9) beats/min and reduced the peak heart rate during ambulatory electrocardiography from 113(11) to 90(6) beats/min consistent with a beta adrenoreceptor antagonist action at higher levels of sympathetic nervous system activity. Minimum heart rate during ambulatory electrocardiography was increased from 62(5) to 70(5) beats/min indicating that at lower levels of sympathetic activity the drug acts as a beta agonist. The drug increased exercise tolerance significantly. Serum digoxin concentrations were not affected by the drug. Thus Corwin appears to be effective in stabilising heart rate during atrial fibrillation both at rest and during exercise in digitalised patients.     

Heart rate variability and circulating catecholamine concentrations during steady state exercise in healthy volunteers.

OBJECTIVES--To assess whether exercise induced suppression of heart rate variability in the low frequency domain (0.06-0.15 Hz) is related to the increase in circulating catecholamine concentrations. DESIGN--Randomised crossover trial of three exercise tests characterised by different workloads. Pharmacological simulation of exercise-induced changes in vagal and sympathetic activity. PARTICIPANTS--Six healthy men with a mean age of 31.2 (SD 3.0) years. INTERVENTIONS--Three different workloads of steady state cycling ergometry: control state without cycling, cycling at a target heart rate of 100 beats/min, and cycling at a target heart rate of 150 beats/min. Intravenous infusion of atropine (target heart rate 100 beats/min) followed by the additional infusion of adrenaline and noradrenaline. MAIN OUTCOME MEASURES--Fast Fourier analysis of heart rate variability; blood pressure; and venous plasma concentrations of lactate, adrenaline, and noradrenaline. RESULTS--During the control exercise period there were no changes in the assessed variables compared with the preceding resting period. During exercise at a heart rate of 100 beats/min systolic blood pressure increased and heart rate variability decreased. During exercise at a heart rate of 150 beats/min systolic blood pressure and lactate, adrenaline, and noradrenaline concentrations increased. In addition, low frequency (LF) was lower than during exercise at 100 beats/min, high frequency (HF 0.15-0.80 Hz) resembled that during exercise at 100 beats/min, and diastolic blood pressure was reduced. Infusion of atropine caused no changes in blood pressure or plasma concentrations of lactate, adrenaline, and noradrenaline and decreased heart rate variability. The additional infusion of adrenaline and noradrenaline completely suppressed heart rate variability and increased blood pressure. CONCLUSIONS--The reduction in LF and HF during exercise at a heart rate of 100 beats/min, which is not characterised by increased plasma catecholamine concentrations, and during atropine infusion suggests that heart rate variability in the supine state is largely influenced by vagal activity. The additional reduction in LF during exercise at 150 beats/min and during catecholamine infusion may reflect a negative feedback of circulating catecholamines on the sympathetic control of heart rate.     

Developmental Changes in Modulation of Cardiac Repolarization by Sympathetic Stimulation: The Role of Beta- and Alpha-Adrenergic Receptors

Sympathetic Modulation of Cardiac Repolarization. Introduction : Our goals were to study the role of development in determining the cardiac effects of sympathetic neural activation, and to identify the roles of α- and β-adrenergic receptor-mediated pathways in modulating the effects of sympathetic stimulation.
Methods and Results : We compared responses of young and adult canine hearts in situ to right, left, and bilateral stellate ganglion stimulation. We focused on changes in heart rate, rhythm, QT interval, rate-corrected QT interval (QT), and T wave amplitude. Right stellate stimulation (RSS) induced more pronounced sinus tachycardia in adult than young animals. Left stellate stimulation (LSS) Induced junctional tachycardia in adult more than young animals. In adults, LSS and RSS prolonged QT_c (LSS > RSS). whereas 1-week-olds manifested QT^c shortening with RSS. LSS also increased T wave amplitude, most markedly in adults. In all studies, bilateral stellate stimulation induced responses intermediate between those seen with RSS and LSS. β-Adrenergic blockade (propranolol) aholished all responses to LSS in adult hearts, but α-blockade (prazosin) attenuated only the LSS-induced prolongation in QT_c.
Conclusion : In the postnatal modulation of cardiac rhythm, rate, and repolarization by the sympathetic nervous system, β-adrenergic receptors play a major role at all ages, whereas α-adrenergic receptors play a lesser role, which is manifested only in adults. Moreover, expression of junctional tachycardias, which are β-adrenergically modulated, is seen only in the adults.     

Augmentation index in resistance to thyroid hormone (RTH)

Objective  Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes.
Design  An observational study.
Patients  Twelve RTH patients were recruited from the thyroid clinic (mean value ± SD), age 40·8 ± 18·7 years; BMI 27·2 ± 4·2 kg/m² and compared with 12 healthy, euthyroid, age-matched controls (age 41·4 ± 19·3; BMI 24·8 ± 4·4 kg/m²) with no history of cardiovascular disease. No interventional measures were instituted.
Measurements  Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls.
Results  The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21·0% ± 14·1% vs. 5·4% ± 18·2%, P  < 0·03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3·0 ± 0·6 vs. 2·1 ± 0·5 mmol/l; P  < 0·002).
Conclusion  RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.     

Glycolytic and tricarboxylic acid cycle intermediates during cardiac arrest and recovery in eu-, hyper- and hypothyroid rats

The effects of contractile activity on intermediates of the Embden-Meyerhof and citric acid cycle pathways were studied using perfused hearts from rats in various thyroid states. Hearts were perfused with a normal and 16 mm-potassium Krebs solution containing glucose; most metabolic intermediates were measured by fluorometric, enzymatic assays. Two minutes of cardiac arrest in euthyroid hearts resulted in an increase in the intermediate levels before phosphofructokinase (PFK) step and no change in the intermediate levels below this step, indicating the PFK control of glycolytic flux. Citrate and isocitrate were increased at the same time, whereas there was no change in the adenine nucleotides. The $\text{NAD}\text{NADH}$ ratio was decreased. Upon resumption of heart beats, the raised isocitrate level and PFK control of glycolytic flux remained for at least 2 min. The level of 2-phosphoglycerate was also increased during this period. Most metabolites returned to within normal ranges after 10 min. In hyperthyroid rats, the rate of glycolytic flow during cardiac arrest was again controlled by PFK, but inhibition of this enzyme was not the result of changes in levels of adenine nucleotides or citrate. Metabolic alterations observed in hypothyroid hearts were essentially similar to those in the euthyroid animals. This study demonstrates the major role of PFK in the control of glycolytic flux in various thyroid states. However, the mechanism of inhibition of the enzyme activity in hyperthyroid rats is different from that in euthyroid animals. The turnover of adenine nucleotides and phosphocreatine responds promptly to changing cardiac activity, whereas that of tricarboxylic acid cycle intermediates and pyridine nucleotides does not.     

Cholinergic Stimulation Improves Autonomic and Hemodynamic Profile During Dynamic Exercise in Patients With Heart Failure

BackgroundParasympathetic dysfunction is an independent risk factor for mortality in heart failure for which there is no specific pharmacologic treatment. This article aims to determine the effect of pyridostigmine, an anticholinesterase agent, on the integrated physiologic responses to dynamic exercise in heart failure.Methods and ResultsPatients with chronic heart failure (n = 23; 9 female; age = 48 ± 12 years) were submitted to 3 maximal cardiopulmonary exercise tests on treadmill in different days. The first test was used for adaptation and to determine exercise tolerance. The other tests were performed after oral administration of pyridostigmine (45 mg, 3 times/day, for 24 hours) or placebo, in random order. All patients were taking their usual medication. Pyridostigmine reduced cholinesterase activity by 30%, inhibited the chronotropic response throughout exercise, up to 60% of maximal effort (pyridostigmine = 108 ± 3 beats/min vs. placebo = 113 ± 3 beats/min; P = .040), and improved heart rate reserve (pyridostigmine = 73 ± 5 beats/min vs. placebo = 69 ± 5 beats/min; P = 0.035) and heart rate recovery in the first minute after exercise (pyridostigmine = 25 ± 2 beats/min vs. placebo = 22 ± 2 beats/min; P = .005), whereas peak heart rate was similar to placebo. Oxygen pulse, an indirect indicator of stroke volume, was higher under pyridostigmine during submaximal exercise.ConclusionsPyridostigmine was well tolerated by heart failure patients, leading to improved hemodynamic profile during dynamic exercise.     

T Wave Alternans During Exercise and Atrial Pacing in Humans

T Wave Alternans in Humans. Introduction: Evidence is accumulating that microvolt T wave alternans (TWA) is a marker of increased risk for ventricular tachyarrhythmias. Initially, atrial pacing was used to elevate heart rate and elicit TWA. More recently, a noninvasive approach has been developed that elevates heart rate using exercise.
Methods and Results: In 30 consecutive patients with a history of ventricular tachyarrhythmias, the spectral method was used to detect TWA during both atrial pacing and submaximal exercise testing. The concordance rate for the presence or absence of TWA using the two measurement methods was 84%. There was a patient-specific heart rate threshold for the detection of TWA that averaged 100 ± 14 beats/min during exercise compared with 97 ± 9 beats/min during right atrial pacing (P = NS). Beyond this threshold, there was a significant and comparable increase in level of TWA with decreasing pacing cycle length and increasing exercise heart rates.
Conclusions: The present study is the first to demonstrate that microvolt TWA can be assessed reliably and noninvasively during exercise stress. There is a patient-specific heart rate threshold beyond which TWA continues to increase with increasing heart rates. Heart rate thresbolds for the onset of TWA measured during atrial pacing and exercise stress were comparable, indicating that heart rate alone appears to be the main factor of determining the onset of TWA during submaximal exercise stress.     

Long-Term ECG Recordings in Hyperthyroid Patients before and after Antithyroid Treatment

ABSTRACT Heart rate and heart rhythm were studied in 19 hyperthyroid patients before and after antithyroid treatment inducing a euthyroid state. The mean 24-hour heart rate in patients with sinus rhythm and without drugs influencing heart rate was 100 beats/min before and 80 after antithyroid treatment. The difference was greatest in the sleeping hours. The heart rate, especially in the sleeping hours, correlated significantly with serum triiodothyronine but not with serum thyroxine concentrations.     

Changes in plasma catecholamine concentrations in patients with coronary heart disease during pacing and physical exercise

To study the difference in sympathetic activity during pacing the right atrium or during physical exercise in patients with coronary heart disease, we investigated circulating plasma catecholamine concentrations in the coronary sinus and brachial artery radioenzymatically in 11 male patients with well documented coronary artery disease. Heart rate was increased stepwise 20 beats/min from 90 beats/min up to 150 beats/min by pacing the right atrium and physical exercise was performed by increasing work load stepwise by 25 from 25 up to 100 W on an ergometric bicycle. Plasma noradrenaline and adrenaline concentrations were increased significantly only during physical exercise. In addition, there was an increase in arterial-coronary sinus noradrenaline difference during graded physical exercise, whereas no further release of noradrenaline from the myocardium occurred during pacing. An enhanced cardiac sympathetic tone in patients with coronary heart disease is discussed. It is suggested that atrial pacing is not an adequate stimulus evoking an overall increase of cardiac and peripheral sympathetic tone.     

Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance

Central nervous system dysfunction with myalgic encephalomyelitis (ME) has been suggested as the main cause of chronic fatigue syndrome. Fluctuation of the symptom severity and hierarchy is a characteristic feature in ME patients. The characteristics of the sympathetic activation may differ between the “good days” and “bad days” in them. Twenty-four ME patients with orthostatic intolerance underwent a conventional 10-min active standing test and echocardiography both on a “good day” and a “bad day”, defined according to the severity of their symptoms. The mean heart rate at rest was significantly higher on the “bad days” than on the “good days”. During the standing test on a “bad day”, 5 patients (21 %) failed to maintain an upright posture for 10 min, whereas on a “good day” all the 24 patients maintained it. Postural orthostatic tachycardia (POT) (increase in heart rate ≥30 beats/min) or severe POT (heart rate ≥120 beats/min) was observed on the “bad days” in 10 patients (43 %) who did not suffer from the severe tachycardia on the “good days”, suggesting the exaggerated sympathetic nervous activation. In contrast, POT did not occur or severe POT was attenuated on the “bad days” in 5 patients (21 %) who developed POT or severe POT on the “good days”, suggesting the impaired sympathetic activation. Echocardiography revealed significantly lower mean values of both the left ventricular end-diastolic diameter and stroke volume index on the “bad days” compared with the “good days”. In conclusion, in ME patients with orthostatic intolerance, the exaggerated activation of the sympathetic nervous system while standing appears to switch to the impaired sympathetic activation after the system is loaded with the additional accentuated stimuli associated with the preload reduction.     

Genomic and non-genomic regulation of L-type calcium channels in rat ventricle by thyroid hormone

Hyperthyroidism is associated with low exercise tolerance despite high cardiac output and sometimes with the development of heart failure. L-type calcium channels may play a role in the mechanism, but this has not been fully understood. We examined the effects of thyroid hormone on gene expression and function of L-type calcium channels in rat ventricles by the ribonuclease protection assay and whole-cell patch-clamp technique, respectively. The effects of bisoprolol, beta-blocking agent, on the regulation of calcium channel by thyroid hormone was also studied. In hyperthyroid animals, the mRNA of the calcium channel alpha1c subunit was reduced on day 4, compared with that in euthyroid animals, and remained low on day 8. Bisoprolol did not affect the thyroid hormone mediated decrease in alpha1c subunit mRNA. While L-type calcium current was greater in hyperthyroid than euthyroid myocytes on day 4, it was smaller on day 8. In addition, the isoproterenol-induced increase in calcium current in euthyroid rats was attenuated in hyperthyroid rats. Acetylcholine decreased calcium current in hyperthyroid myocytes, but not in euthyroid myocytes. In conclusion, L-type calcium current was increased by thyroid hormone in rat ventricular myocytes by the activation of the adenylate cyclase cascade, despite a decreased calcium channel gene expression. These genomic and non-genomic modifications may play an important role in the association of high cardiac output with low exercise tolerance, and in the development of heart failure in hyperthyroidism.     

Efficacy of once daily penbutolol in chronic stable angina. An objective comparison with long-acting propranolol

The effects of penbutolol (40 mg daily) and long-acting propranolol (160 mg daily) were assessed in 26 patients with chronic stable angina in a placebo-controlled randomised double-blind crossover study with 2-weekly treatment periods. In addition to conventional subjective assessment, serial multistage treadmill exercise was used to obtain objective data on drug efficacy and 24-hr ambulatory electrocardiography performed for diurnal heart rate analysis. The mean exercise time of 6.3 ± 0.5 (SEM) min on placebo increased to 7.3 ± 0.6 min on penbutolol (P < 0.01) and to 7.9 ± 0.5 min on propranolol (P < 0.001). The pre-exercise resting heart rate was 73 ± 2 beats/min on placebo and decreased to 63 ± 2 beats/min on penbutolol (P < 0.001) and 58 ± 2 beats/min on propranolol (P < 0.001). The maximum exercise heart rate was similarly reduced by both drugs and there was a corresponding reduction in peak exercise double product. The time-corrected maximum ST segment depression was reduced by both drugs and neither produced a delay in ST segment recovery. Both drugs effected significant reductions in ambulatory maximum hourly heart rates throughout 24 hr. The lowest observed heart rate on penbutolol was 40 beats/min and 34 beats/min on propranolol. Penbutolol is an effective antianginal agent with a profile of action similar to that of propranolol.     

Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure

BACKGROUND. Resting sympathetic nervous system activity is increased in heart failure. Whether sympathetic nervous system responses during exercise are increased is controversial. Furthermore, the role of muscle metaboreceptors and central command in regulating sympathetic outflow has been largely unexplored. METHODS AND RESULTS. Muscle sympathetic nerve activity (MSNA, peroneal nerve) was measured in nine heart failure subjects and eight age-matched control subjects during static exercise (30% maximal voluntary contraction) for 2 minutes and during a period of posthandgrip regional circulatory arrest. This maneuver isolates the metaboreceptor contribution to sympathetic nervous system responses. MSNA responses were similar during static exercise in the two groups. During posthandgrip regional circulatory arrest we observed a marked attenuation in MSNA responses in the heart failure subjects (15% increase in heart failure versus 57% increase in control subjects). A cold pressor test demonstrated a normal MSNA response to a potent nonspecific stimulus in the heart failure subjects (heart failure subjects, 141% increase; control subjects, 215% increase; NS). Nuclear magnetic resonance spectroscopy studies in five separate heart failure subjects and five control subjects suggested that the attenuated metaboreceptor response in heart failure was not due to reduced H+ production. CONCLUSIONS. Skeletal muscle metaboreceptor responses are impaired in heart failure. Because MSNA responses during static exercise are similar in the two groups, mechanisms aside from metaboreceptor stimulation must be important in increasing sympathetic nervous system activity.     

Comparison of treadmill exercise testing and psychologic stress testing soon after myocardial infarction.

Are physical or psychologic stressors more useful for evaluating psychologic stress in patients with coronary heart disease? To evaluate this question, patients underwent physical and psychologic testing 7 weeks after myocardial infarction. The psychologic stress test consisted of an open-ended interview, a videotape depicting stressful scenes and a puzzle task. In 20 men whose mean age ± standard deviation was 52 ± 1 years, the interview produced the following peak heart rate and systolic blood pressure responses: 83 ± 18 beats/min and 140 ± 13 mm Hg, which were 8 and 10 percent, respectively, above values at rest (P < 0.05). Symptom-limited treadmill exercise testing in 10 of these patients elicited maximal heart rate and systolic blood pressure values of 152 ± 24 beats/min and 172 ± 32 mm Hg, respectively; ischemic S-T segment depression or angina pectoris occurred in 6 of the 10 patients, whereas none had demonstrated ischemia with psychologic testing. A second consecutive series of 20 patients demonstrated cardiovascular responses to physical and psychologic stress similar to those of the first series. Again, ischemic abnormalities were absent during psychologic stress, whereas exercise-induced ischemic abnormalities were noted in 3 of 20 patients. Ischemic abnormalities are unlikely to appear during psychologic stress testing in patients with a high heart rate and systolic blood pressure threshold for ischemic abnormalities during exercise testing. Standard methods of physical exercise testing are superior to currently available psychologic stress tests for evaluating the cardiovascular response to most commonly encountered psychologic stressors.     

Shortened platelet survival time and enhanced heart rate responses after abrupt withdrawal of propranolol from normal subjects

Although clinical observations suggest that abrupt discontinuation of propranolol therapy may precipitate myocardial ischemia and infarction in patients with coronary occlusive disease, the physiologic consequences of propranolol withdrawal are not fully understood. Platelet survival times and heart rate responses to exercise, upright tilt and isoproterenol were therefore examined in 14 normal subjects before and after abrupt withdrawal of propranolol. Propranolol, 80 to 240 mg/day, was given for 24 to 79 days; its effect was confirmed by a lower heart rate during exercise and during infusion of isoproterenol. In 10 subjects, the mean survival time of chromium-51-tagged blood platelets decreased from 10.0 days before propranolol to 7.8 days after its withdrawal (p <0.05). One day after withdrawal, the rise in heart rate with exercise or tilt was slightly increased from values before propranolol therapy. Two days after withdrawal of propranolol the mean peak heart rate during exercise (165 beats/min) was 12 beats/min higher (p <0.01) than the value before propranolol. On this same day heart rate increased more after tilt without medication (+6 beats/min, p <0.05) and more after tilt following vagal blockade (+8 beats/min, p <0.02) than before treatment with propranolol. Seven days after propranolol withdrawal, heart rate responses to exercise or tilt remained increased. Isoproterenol-induced heart rate responses (5 to 40 ng/kg per min, n = 14), white blood cell beta receptor function (cyclic adenosine monophosphate production after isoproterenol and ³H-I-dihydroalprenolol binding, n = 9) and plasma norepinephrine values at rest and during exercise (n = 7) were each unaltered after propranolol.The results suggest that abrupt withdrawal of propranolol is accompanied by a shortening of platelet survival and enhancement of sympathetically mediated reflex increases in heart rate. These changes may each play a role in the increased incidence of ischemic episodes observed after withdrawal of propranolol from patients with coronary occlusive disease. However, the number of beta receptors and their sensitivity to adrenergic agonists do not seem to be changed uniformly after abrupt withdrawal of propranolol.     

Cardiovascular and sympathetic nervous responses to mental stress in hyperthyroid patients.

We measured the cardiovascular and sympathetic nervous responses to mental stress in subjects with hyperthyroidism. Ten hyperthyroid subjects and 10 age- and sex-matched normal subjects performed mental arithmetic. At rest, the heart rate was higher in hyperthyroid subjects than in normal subjects, but systolic blood pressure, plasma norepinephrine, and epinephrine concentrations did not differ between the two groups. Systolic blood pressure and heart rate during stress, and the changes in blood pressure and in plasma epinephrine concentration from rest to stress, were higher in hyperthyroid subjects than in normal subjects. Therefore, cardiovascular and adrenal responses to mental stress were abnormally high in subjects with hyperthyroidism.     

Sympathetic neural responses to induced ventricular tachycardia

Although sympathetic mechanisms play a major role in buffering abrupt arterial pressure reductions, including those that occur during tachyarrhythmias, human sympathetic nervous system responses to ventricular tachycardia have not been measured. Muscle sympathetic nerve activity was recorded directly from the peroneal nerve in 16 patients during diagnostic induction of 19 episodes of sustained monomorphic ventricular tachycardia (average rate 189 beats/min, range 130 to 250). Average systolic and diastolic pressures decreased from 149/78 to 61/49 mm Hg by 10 s and increased toward baseline levels to 88/64 mm Hg by 1 min of ventricular tachycardia. Average sympathetic nerve activity increased by 92% at 10 s in direct proportion to arterial pressure reductions and in inverse proportion to ventricular rate and remained 83% above baseline levels at 1 min. The late recovery of arterial pressure during ventricular tachycardia was related significantly to the magnitude of early sympathetic responses. Sympathetic activity tended to lose its discrete bursting pattern during ventricular tachycardia, and power spectral analysis showed that the large sympathetic peaks at the heart rate frequency present during sinus rhythm are absent during ventricular tachycardia. This study is the first to delineate human sympathetic nervous system responses to ventricular tachycardia. The results suggest that in the patients studied, large early sympathetic surges differed from those that occur during sinus rhythm and contributed to hemodynamic stability during ventricular tachycardia.