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Effect of passive smoking on angina pectoris.

The effect of passive smoking on exercis-induced angina in a well ventilated and in an unventilated room was evaluated in 10 patients with angina. Patients exposed to 15 cigarettes smoked within two hours in a well ventilated room or an unventilated room increased their resting heart rate, systolic and diastolic blood pressure, and venous carboxyhemoglobin and decreased their heart rate and systolic blood pressure at angina. Patients exposed to passive smoking in an unventilated room had a larger increase in resting heart rate, systolic and diastolic blood pressure, and venous carboxyhemoglobin and a greater reduction in heart rate and systolic blood pressure at angina. The duration of exercise until angina was decreased 22 per cent after passive smoking in a well ventilated room (P less than 0.001), and decreased 38 per cent after passive smoking in an unventilated room (P less than 0.001). Passive smoking aggravates angina pectoris.

Aged

Selectivity of beta adrenoreceptor antagonist drugs assessed by histamine bronchial provocation.

In a double-blind, within-patient, randomized study, 12 mild asthmatics were given single oral doses of propranolol (80 mg), metoprolol (100 mg), timolol (10 mg), or placebo. Resting heart rate and forced expiratory volume in one sec (FEV1) were measured before and 90 min after treatment. Nonspecific bronchial reactivity was measured by inhaled histamine at 90 min. Following each active drug, resting heart rate changed to a similar extent and to a greater degree than after placebo (p less than 0.01). Changes in FEV1 were small and not different from those after placebo. In contrast, after each active drug, bronchial reactivity increased more than after placebo. The degree of reactivity with each active drug was similar but the differences from corresponding placebo values were significant (p less than 0.05). We conclude that, in mild asthmatics, nonspecific bronchial reactivity is a more sensitive index of airway effects than resting FEV1. Moreover, in the context of this study, since the beta-blockers were given in doses likely to induce equivalent cardiac beta-blockade, there is no evidence to suggest that any one of them is more "cardioselective" than the others.

Adolescent

Development of autonomic control of fetal circulation.

Development of parasympathetic and sympathetic reflexes controlling heart rate, vascular pressures, and blood flows was investigated in fetal lambs weighing 300-5,800 g (65-165 days' gestation). Cardiovascular responses to veratridine injections, atrial stretching, bilateral cervical vagotomy, and cholinergic blockade with atropine were used to test parasympathetic activities. Responses to propranolol and phenoxybenzamine were used to test beta- and alpha-adrenergic activities. Autonomic ganglionic blockade and stimulation provided additional information on both cholinergic and adrenergic systems. Fetal responses to various tests were compared to those of the mother. Results show: a) little parasympathetic tone on resting heart rate and other circulatory functions exists prior to fetal maturity; b) despite the feeble resting tone, the parasympathetic system is capable of exerting significant control when stimulated in both premature and mature fetuses, the capability increases as fetus approaches term; c) alpha- and beta-adrenergic tone in control of resting heart rate and peripheral circulation exists in early fetal life and increases as the fetus reaches maturity, and both adrenergic receptors respond strongly to stimuli in immature, premature, and mature fetuses; d) in immature fetuses, veratridine does not elicit a vagally mediated reflex; instead, it produces a centrally mediated alpha- and beta-adrenergic stimulation; e) the fetal cardiovascular response to any given test is dampened by the existence of the various vascular shunts, the umbilicoplacental circulation and, possibly, by incomplete maturation of vasomotor tone.

Anesthetics

Carbon monoxide, nicotine and the 'safer' cigarette.

15 healthy adults (5 women, 10 men) have been exposed to each of four experimental conditions: rebreathing of air or carbon monoxide, and the smoking of two low-nicotine (0.3 mg) or medium-nicotine (1.2 mg) cigarettes. The dose of carbon monoxide selected (80 ml) had no effect on resting heart rate or electrocardiogram, nor did it modify the exercise heart rate, ventilation, oxygen consumption or electrocardiogram. Both types of cigarette produced variable changes in the blood carboxyhaemoglobin level, increments being greatest in heavy smokers, and least in former smokers, pipe and cigar smokers, Gains of carboxyhaemoglobin were less with low-nicotine than with medium-nicotine cigarettes. Both types of cigarette produced some increase of resting heart rate, but the smoking of two cigarettes was insufficient to modify the exercise heart rate, ventilation, or oxygen consumption. The electrocardiogram also showed no signs of ischaemia during either rest or effort. It is suggested that, for the light and moderate smoke, the 'safest' cigarette may be one with a low tar and a very low nicotine yield. On the present data, this would also induce only small increments of blood carboxyhaemoglobin levels.

Adult

Autonomic control of cardiovascular functions during neonatal development and in adult sheep.

We studied the autonomic control of resting heart rate of systemic and pulmonary vascular blood pressures (BP) in chronically instrumented neonatal lambs 1-8 weeks of age. The maximum response to ganglionic blockade and sympathetic and parasympathetic antagonists was taken as an index of the magnitude of the total neural, adrenergic, and cholinergic tones. The reactivity of the circulatory parameters to adrenergic and cholinergic agonists also was investigated. All findings were compared with those in adult nonpregnant sheep studied concomitantly and with data previously obtained from term fetal lambs. The results of our studies show: (1) resting heart rate declines spontaneously throughout the 8 weeks of neonatal life approaching that of adult sheep; (2) the progressive bradycardia is not related to changes in the parasympathetic or sympathetic tone; (3) resting systemic BP is under strong neurohumoral control during the first two to three weeks of neonatal life; the control decreases progressively, becoming similar to that of adult sheep; (4) resting pulmonary artery pressure of neonatal and adult sheep has no neurohumoral control; (5) the systemic BP response of the neonate to autonomic agonists is greater than that of the term fetus and is similar to that of the adult; (6) in neonatal and adult sheep, compared to the term fetus, the pressor response to norepinephrine is accompanied by a baroreceptor-mediated bradycardia, and acetylcholine-induced systemci hypotension is accompanied by a "paradoxical" tachycardia mediated through beta-adrenergic stimulation; (7) in contrast to our finding for the fetus, the pulmonary vascular pressure of neonatal and adult sheep is unresponsive to autonomic agonists.

Acetylcholine

Effects of a physical activity program on middle-aged, sedentary corporation executives.

This study determined the effects of controlled physical training program on resting heart rate, blood pressure, serum cholesterol and body weight in middle-aged, sedentary, corporation executives. Two groups were established: an active group consisting of invited subjects hat exercised on a regular basis, and a comparison group consisting of subjects that were invited to use the facility but did not. Both groups were classified by the Medical Deartment as being "clinically normal." The training intensity of the active group was at 65% to 85% of age predicted maximum heart rates as established by the Tennessee Heart Association. Each exercise session was closely monitored by the subjects and by the instructors. Training continued for 24 months. Statistical analysis indicated that resting heart rate, systolic blood pressure, and serum cholesterol were significantly reduced after the training as compared to the comparison group. However, there were no significant changes in diastolic blood pressure or body weight.

Administrative Personnel

Comparative beta-adrenoreceptor-blocking effects and pharmacokinetics or propranolol and pindolol in hypertensive Africans.

1. The beta-adrenoreceptor-blocking effects of pindolol were compared with those of propranolol and a placebo in a double-blind cross-over trial involving nine hypertensive African patients. 2. Heart rate, systolic blood pressure and diastolic blood pressure were measured at rest and immediately after exercise before and at intervals up to 6 h after oral administration of the drugs. In addition, plasma pindolol and propranolol concentrations were determined at the same intervals. 3. Pindolol diminished systolic blood pressure at rest and after exercise and antagonized exercise-induced tachycardia, but had no effect on resting heart rate. Propranolol diminished systolic blood pressure predominantly after exercise and reduced both resting and exercise heart rate. Both drugs had no effect on diastolic pressure. 4. The mean plasma concentration reached a peak at 2 h for each drug and this coincide with the interval at which maximal beta-adrenoreceptor-blocking effect was observed.

Adult

Haemodynamic observations with KO. 1366 (bunitrolol), a new beta-adrenergic blocking agent.

The haemodynamic effects of a new beta-adrenergic blocking agent KO.1366 (bunitrolol) were assessed in 10 males admitted to hospital for investigation of chest pain. Measurements were made at rest, during atrial pacing at 100 beats/min, and during hand grip exercise, before and afterintravenous administration of KO.1366 at a dosage of 0.05 mg/kg body weight. There was a 12% (p less than 0.01) slowing in resting heart rate and alpha 4% (p less than 0.05) slowing in exercise heart rate after drug administration. Resting left ventricular end diastolic pressure rose by 2.2 mm Hg (p less than 0.01) following the drug, but there was no significant change during pacing or exercise. Left ventricular systolic pressure and its first derivative did not change significantly. Cardiac output rose slightly, and stroke volume at rest and during exercise showed a considerable increase. In the dosage used, KO.1366 has an important chronotropic effect on the heart without causing significant myocardial depression.

Adrenergic beta-Antagonists

Pharmacokinetics of oxprenolol in normal subjects.

The effect of oxprenolol administered intravenously (10 and 20 mg) and orally (20, 40, 80, and 160 mg) on plasma concentrations of the drug, resting heart rate, exercise-induced tachycardia, and arterial blood pressure was assessed as a function of time in 6 healthy subjects. The pharmacokinetics of oxprenolol following intravenous administration are best described as 2-compartnent open model with dose-dependent parameters. The mean (+/-SD) plasma half-life for oral doses is 1.94 +/- 0.37 and for intravenous doses is 2.31 +/- 0.64 hr. After oral administration, peak plasma concentrations are reached within 30 to 90 min, and the area under the plasma concentration-time curve varies linearly with the dose. Comparison of oral and intravenous data reveals the variation in bioavailabilty of orally administered oxprenolol to range from 19% to 74%. Unlike propranolol, oxprenolol does not show a saturable "first-pass" elimination effect. Blockade of beta-receptors occurs at plasma levels in excess of 60 ng/ml as evidenced by significant reductions in resting heart rate and exercise-induced tachycardia. Higher plasma concentrations of oxprenolol are required to lower blood pressure compared to those necessary to slow heart rate. These data suggest significant pharmacokinetic differences between oxprenolol and other beta-adrenergic receptor antagonists.

Administration, Oral

Alteration in heart rate response to hemorrhage in conscious dogs with volume overload.

The heart rate response to hemorrhage was studied in conscious dogs before and up to 2 mo after the establishment of volume overload due to systemic arteriovenous (a-v) fistulas. Before a-v fistula, heart rate increased markedly during hemorrhage. When hemorrhage was preceded by dextran infusion, bleeding resulted in a gradual reduction in heart rate. The a-v fistula caused marked increases in resting heart rate, central venous pressure, pulse pressure, and blood volume. During hemorrhage, heart rate initially remained constant, but then declined abruptly from the resting value of 121 +/- 3.7 beats/min to a nadir of 89 +/- 6.5 beats/min (P less than 0.01). Although mean arterial pressure decreased markedly, there was no significant change in pulse pressure, and central venous pressure tended to stabilize with the heart rate decline. The abrupt heart rate decline was prevented by atropine but unaltered by propranolol. The response was observed as early as 5 days after a-v fistula. We conclude that an alteration in the heart rate response to hemorrhage appears early during volume overload. This alteration appears to be reflex in nature and to be mediated by the parasympathetic nervous system.

Animals

Racial differences of parameters associated with blood pressure levels in children--the Bogalusa heart study.

Racial differences in prevalence of essential hypertension are well known. In order to explore these differences at an early age in terms of etiology, we investigated schoolchildren in an entire, biracial community. A sample of 278 children, stratified by diastolic (fourth-phase) blood pressure and specific for age, race, and sex, was reexamined 1--2 yr after initial observation for the following: (1) a physical examination and urinalysis to exclude secondary hypertension; (2) 24-hr urine sodium, potassium, plasma renin activity, and serum dopamine beta-hydroxylase; (3) 1-hr oral glucose tolerance test; and (4) heart rate and blood pressure at rest and under standarized physical stress. We found that 24-hr urine sodium was positively associated with blood pressure level as measured on the same day for the high blood pressure strata of black children. Urine potassium excretion was lower in blacks than in whites, although their intakes seemed equal. In the high blood pressure strata especially, black boys had lower renin activity than whites, and the resting-supine and stressed systolic blood pressures were higher in black boys than in any other group. In these black boys, resting and stressed systolic pressures were negatively related to plasma renin activity. On the other hand, dopamine beta-hydroxylase levels in white children were higher than in blacks for all blood pressure strata, and in the high blood pressure strata white children had higher 1-hr glucose levels and faster resting heart rates than black children. Different mechanisms may play a role in and contribute to the early stage of essential hypertension.

Adolescent

Antihypertensive effects of clonidine in tetraplegic subjects devoid of central sympathetic control.

1. The effects of 300 microgram of oral clonidine on blood pressure, heart rate, plasma noradrenaline and adrenaline concentrations were studied in seven tetraplegic subjects with physiologically complete cervical spinal cord transections. 2. Clonidine did not significantly change resting blood pressure during the 8 h of the study. Resting heart rate fell. Resting plasma noradrenaline and adrenaline concentrations, when measured 2 h after clonidine, were not significantly lower. 3. Urinary bladder stimulation resulted in a marked rise in blood pressure accompanied by an elevation in plasma noradrenaline but not adrenaline. The hypertensive response to bladder stimulation was substantially reduced by clonidine, the maximum suppression occurring 2-4 h after administration of the drug. The plasma noradrenaline response to bladder stimulation, when measured 2 h after clonidine, was significantly lower than the response before clonidine. In two tetraplegic subjects with indwelling catheters the rise in intravesical pressure caused by bladder stimulation was unchanged by clonidine. 4. The pressor response to intravenous noradrenaline in two tetraplegic subjects and to intravenous phenylephrine in a further two tetraplegic subjects was unchanged by clonidine. 5. Clonidine may have additional antihypertensive effects which occur independently of actions in the brain. These effects may be exerted by an action either on sympathetic neurones in the spinal cord or on presynaptic alpha-adrenoreceptors in the periphery.

Adult

Maximum exercise heart rate reduction with maturation in the rat.

Maximum exercise heart rate decreases with maturation in the rat as well as in man. The present study was undertaken to investigate the mechanism(s) which might be responsible for this reduction in max exercise heart rate in the rat. Maximum exercise heart rates were 618 +/- 7 vs. 580 +/- 9 beats/min for the young (5 wk) and mature (19 wk) rats, respectively. Atropine had no effect on max exercise heart rate. Propranolol reduced max heart rate in both groups with the older rats having the lowest value. Resting heart rates were recorded following injections of atropine propranolol, and propranolol plus atropine. Under all conditions, including control, heart rates were lower in the mature rats. Electrical stimulation in situ showed a significant difference in the threshold voltage for stimulation at 600 beats/min: 1.1 +/- 0.2 vs. 1.6 +/- 0.1 V for the young and mature rats, respectively. These data suggest that intrinsic changes occur in the myocardium with maturation and the reduction in max exercise heart rate is due to these intrinsic changes as opposed to changes in neural influences.

Aging

Indirect blood pressure and heart rate measured quickly without observer bias using a semi-automatic machine (auto-manometer)--response to isometric exercise in normal healthy males and its modification by beta-adrenoceptor blockade.

1 In a double-blind crossover study, six volunteers performed sustained handgrip at 50% of maximal voluntary contraction before and 90 min following oral administration of 0.25 and 100 mg metoprolol tartrate, a beta1 selective adrenoceptor blocking agent. Blood pressure and heart rate were measured with the Auto-Manometer, an electronic semi-automatic device based on the principles of the London School of Hygiene and Tropical Medicine sphygmomanometer. It eliminates observer and digital bias completely, and also records heart rate at the same time as blood pressure is recorded. 2 Resting heart rate fell 15% after 25 mg, 21% after 100 mg and was unchanged after placebo. Systolic blood pressure fell 6% on both doses and was unchanged on placebo. Diastolic pressure did not change with any of the doses. 3 At 1 min of handgrip, heart rate was significantly lower after 25 and 100 mg than before drug or after placebo. There was no difference between the blood pressure levels attained before or after any of the dose levels. The rise of heart rate tended to be somewhat dampened after 100 mg only. The rise in blood pressure was unchanged after any dose compared with before.

Adult

Cardiovascular control in recently injured tetraplegics in spinal shock.

Cardiovascular control was studied in five tetraplegic patients with physiologically complete cervical spinal cord transections. All had been injured less than two weeks previously and were in spinal shock. Blood pressure, heart rate, and plasma noradrenaline and adrenaline were measured at rest and during and after bladder stimulation and application of cold stimuli to skin below the level of the lesion. In three patients the cardiovascular responses to intravenously infused 1-noradrenaline and to the Valsalva manoeuvre were recorded. Measurements were also made in six chronic tetraplegic patients (in whom reflex spinal cord activity had returned) at rest, and during and after bladder stimulation, and in six normal subjects at rest. Average resting blood pressure in the recently injured tetraplegics was 130/57 (mean 81) mmHg, in the chronic tetraplegics 107/55 (mean 73) mmHg and in normal subjects 122/82 (mean 95) mmHg. Average resting heart rate was 64, 73 and 77 beats/min in the three groups respectively. Resting plasma noradrenaline and adrenaline levels in both the recently injured and chronic tetraplegics were lower than than in normal subjects. In the recently injured tetraplegics bladder stimulation caused minimal changes in blood pressure, heart rate and plasma noradrenaline and adrenaline levels. In the chronic tetraplegics similar stimulation caused marked hypertension, bradycardia and elevation in plasma noradrenaline but not adrenaline levels. Cold stimuli in the recently injured tetraplegics did not change blood pressure or heart rate. In the recently injured tetraplegics intravenous infusion of 1-noradrenaline resulted in greater elevation in blood pressure than normal. There was a decrease in heart rate. One patient was able to perform the Valsalva manoeuvre. His blood pressure responses were consistenly abnormal ('blocked' Valsalva).

Adolescent

Exercise performance and hemodynamics during dietary potassium depletion in dogs.

Dietary potassium depletion plus high sodium intake has been reported to elevate resting heart rate and cardiac output and to cause heart failure during exercise. We implanted aortic root electromagnetic flowmeters and aortic and pulmonary artery catheters in five splenectomized dogs condition-trained to run at 9 km/h on an 11% grade for 20 min. Postoperatively, the dogs ate a potassium-enriched diet until completion of control studies; then potassium was withdrawn. During 4 wk of depletion, skeletal muscle potassium fell from 380 +/- 22 to 311 +/- 8 meq/kg, and muscle sodium rose from 142 +/- 14 to 207 +/- 27 meq/kg (mean +/- SE). Cardiac output, aortic blood pressure, heart rate, acceleration of aortic blood flow at rest or during exercise, and the oxygen cost of exercise remained at control levels. Serum creatine phosphokinase at rest, an indicator of rhabdomyolysis, was never elevated. A 24% dietary depletion of muscle potassium in the dog did not change resting and exercise hemodynamics and exercise performance from control.

Animals

Cardiorespiratory variables in middle-aged men.

The purpose of this investigation was to assess the relationship among selected physican and cardiorespiratory variables in active men, aged 40-59 years. Thirty-one subjects who had been running for only an average of five years volunteered for treadmill testing, running to volitional exhaustion. For the total group (40-59 yrs), significant negative correlations were found between age and maximal heart rate (HR max) and age and maximal oxygen uptake (VO2 max), suggesting an inverse relationship between these variables. In both the 40-49 and the 50-59 yr groups, significant positive correlation coefficients were obtained between VO2 max (liters/min) and VO2 max (ml/kg/min), between VO2 max (ml/kg/min) and O2 pulse (ml/kg/min), and between VO2 max (liters/min) and V E max (maximal pulmonary ventilation) liters/min), In both these groups, resting heart rate (HR rest) was significantly positively related to HR max and also to HR 1 min after recovery (1 min rec). Overall, however, the correlation coefficients between selected variables were low, implying that the evaluation of cardiorespiratory variables in these age groups should be based upon several variables.

Adult

Cardiac autonomic blockade in exercising dogs.

Pharmacological blockade of autonomic control of the heart was studied in dogs performing mild, moderate, and severe running exercise on a level treadmill. The dogs were studied without drugs, after atropine, after propranolol, and after both atropine and propranolol. As compared with results without drugs, cardiac denervation resulted in elevated resting heart rate (+45 beats/min) but reduced heart rate during moderate (-17 beats/min) and severe exercise (-47 beats/min); no change in cardiac output at rest or during mild exercise but decreases (-23% and -25%) during moderate and severe exercise; and reduced first derivatives of left ventricular pressure at rest (-24%) and during exercise (-35, -41, and -52% for mild, moderate, and severe loads, respectively). Cardiac denervation did not alter end-diastolic left ventricular diameter but significantly increased end-systolic diameter during exercise. It is concluded that blockade of autonomic control of the heart diminishes cardiac output during exercise by reducing heart rate and myocardial contractile force but does not alter cardiac output at rest.

Animals