Small Increase In Heart Rate Research Articles

Sympathetic nerve activity after acupuncture in humans

The aim of the present study was to determine if acupuncture stimulation inhibits sympathetic nerve activity in humans. Multiunit efferent postganglionic sympathetic activity was recorded with a tungsten microelectrode inserted in a muscle fascicle of the peroneal nerve. Mean arterial pressure, heart rate and skin blood flow were also monitored. Pain thresholds were measured by electrical tooth pain stimulation. After a 30 min rest, acupuncture needles were inserted bilaterally into the Li 11 and the Li 4 acupuncture points, and manipulated until `chi' cramp-like sensation was reported. Electrical stimulation (2 Hz, 0.6–0.8 ms duration, maximal tolerated stimulation without discomfort) was delivered for 30 min and the physiological recordings were continued for 90 min after the end of acupuncture. In a placebo control experiment, the same procedure was followed, except that acupuncture needles were inserted subcutaneously and no manipulation or stimulation was given. The stimulator delivered pulses to an unconnected channel, hence, the same audiovisual stimuli were experienced as with acupuncture, and care was taken to ask the same questions about sensations in the placebo and the acupuncture groups. Electroacupuncture produced an increase in pain threshold which was paralleled by a transient increase in muscle sympathetic nerve activity. During acupuncture, there was a small increase in heart rate and mean arterial pressure, but there was no post-acupuncture hypotension. The placebo control procedure did not change pain threshold or sympathetic nerve traffic. The findings suggest that electroacupuncture produces moderate hypoalgesia in humans paralleled by a significant increase in muscle sympathetic nerve activity.

The lateral parabrachial nucleus is involved in mediation of rostral ventrolateral medulla cholinergic inputs in rats

These studies examined the role of spinal N-methyl-D-aspartic acid (NMDA) receptors in mediating Sympathoexcitation evoked by stimulation of neurons in the rostral ventrolateral medulla (RVLM). In urethane-anesthetized rats, blood pressure, heart rate, and splanchnic sympathetic nerve activity (SNA) were recorded. The NMDA receptor antagonist D-2-amino-7-phosphonoheptanoic acid (D-AP7) was administered to the spinal cord via intrathecal (IT) catheter. Blockade of spinal NMDA receptors reduced arterial blood pressure, heart rate, and SNA. Spinal administration of D-AP7 markedly attenuated the pressor and sympathoexcitatory responses evoked by L-glutamate stimulation of the RVLM. The small increases in heart rate evoked by stimulation of the RVLM were not affected by IT administration of D-AP7. These results indicate that NMDA receptors in the spinal cord mediate the pressor and sympathoexcitatory responses evoked by activation of a bulbospinal pathway originating from the RVLM. Moreover, these data suggest that excitatory amino acid neurotransmitters and NMDA receptors in the spinal cord play an important role in the maintenance and regulation of SNA and cardiovascular function.

Ascending noradrenergic pathways from the nucleus of the solitary tract to the subfornical organ in rats

These studies examined the role of spinal N-methyl-D-aspartic acid (NMDA) receptors in mediating Sympathoexcitation evoked by stimulation of neurons in the rostral ventrolateral medulla (RVLM). In urethane-anesthetized rats, blood pressure, heart rate, and splanchnic sympathetic nerve activity (SNA) were recorded. The NMDA receptor antagonist D-2-amino-7-phosphonoheptanoic acid (D-AP7) was administered to the spinal cord via intrathecal (IT) catheter. Blockade of spinal NMDA receptors reduced arterial blood pressure, heart rate, and SNA. Spinal administration of D-AP7 markedly attenuated the pressor and sympathoexcitatory responses evoked by L-glutamate stimulation of the RVLM. The small increases in heart rate evoked by stimulation of the RVLM were not affected by IT administration of D-AP7. These results indicate that NMDA receptors in the spinal cord mediate the pressor and sympathoexcitatory responses evoked by activation of a bulbospinal pathway originating from the RVLM. Moreover, these data suggest that excitatory amino acid neurotransmitters and NMDA receptors in the spinal cord play an important role in the maintenance and regulation of SNA and cardiovascular function.

Influence of age on the sympathetic neural adjustments to alterations in systemic oxygen levels in humans.

We tested the hypothesis that aging influences the regulation of sympathetic nervous system activity (SNA) and arterial blood pressure during alterations in systemic O2 levels in humans. To accomplish this, we performed direct (intraneural) measurements of SNA to skeletal muscle (MSNA) in 10 young and 7 older healthy normotensive men during room air breathing (normoxic-control), moderate isocapnic hypoxemia [15 min of 10% fractional inspired O2 (FIO2)], and hyperoxemia (10 min of 50% FIO2). After hypoxemia, arterial O2 saturation (SaO2) declined similarly in the young and older men. MSNA (burst frequency and total minute activity) increased significantly (P < 0.05) in both groups. The magnitudes of the absolute increases in MSNA and the delta MSNA/delta SaO2 were not significantly different in the young and older men; however, because of higher normoxic baseline levels, the percentage increases in burst frequency were smaller (P = 0.02) and those for total minute activity tended to be smaller (P = 0.11) in the older men. Arterial blood pressure increased modestly (P < 0.05) and similarly in both groups, although the older men demonstrated a smaller increase in heart rate. After hyperoxemia [corrected], SaO2 increased and MSNA decreased (both P < 0.05) similarly in the young and older men. Arterial blood pressure did not change significantly from normoxic control levels in either group; however, a small (P < 0.05) reduction in heart rate was observed in both groups. In conclusion, aging does not obviously influence the regulation of absolute levels of MSNA or arterial blood pressure during alterations in systemic O2 levels in healthy men, although older men demonstrate a smaller percentage increase in MSNA from their elevated baseline levels, as well as an attenuated tachycardia in response to acute hypoxemia. As such, the present results are consistent with our previous findings on aging and sympathocirculatory control during other types of acute stress in humans.

Pressor effect mediated by bradykinin in the paratrigeminal nucleus of the rat.

1. The participation of the paratrigeminal nucleus (Pa5) in the pressor response produced by bradykinin in the dorsolateral medulla of rats was investigated. The microinjection of 6 pmol of bradykinin directly over the paratrigeminal nucleus of unanaesthetized rats produced a significant increase in arterial pressure and a moderate increase in heart rate. 2. Bradykinin microinjections in different sites surrounding the Pa5 compromising the external cuneate nucleus, the trigeminal nucleus, the lateral and ventral spinal trigeminal tract and the dorsal trigeminal tract rostral and caudal to the Pa5 did not elicit significant pressor responses. In contrast, microinjections in the paratrigeminal nucleus produced pressor effects. Injections in the dorsolateral medulla directly over the paratrigeminal nucleus produced larger responses than when injections were made in the nucleus. Saline injections in the different nuclei did not produce pressor effects. 3. Neurochemical lesioning of the Pa5, with microinjections of ibotenic acid in the Pa5, abolished the pressor response to bradykinin injected over the lesioned nucleus. The effect was present, however, when bradykinin was injected on the contralateral side to the lesion, over the intact nucleus of the same animal. Pretreatment with capsaicin (injected in the lateral cerebral ventricle), which causes selective degeneration of afferent sensory fibres, did not alter the pressor effect of bradykinin injected over the paratrigeminal nucleus. 4. Dose-related responses were produced by different concentrations of bradykinin (0.6-1.8 pmol) microinjected over the nucleus. The bradykinin receptor antagonist HOE 140, injected over the paratrigeminal nucleus 30 min earlier, abolished the pressor response caused by bradykinin. 5. Low doses of bradykinin injected in or directly over the paratrigeminal nucleus increased arterial pressure and caused a small increase in heart rate by stimulating kinin receptors of the paratrigeminal nucleus in the dorsolateral medulla of awake and unrestrained rats. The pattern of the response was consistent with that of sympathetic stimulation. The paratrigeminal nucleus, which receives primary afferents and projects to the nucleus tractus solitarii and the rostral ventral lateral medulla, may be positioned as relay nucleus possibly connecting sensory input to structures that regulate blood pressure.

Modifications of Oxygen Saturation During Transesophageal Echocardiography.

The present study was designed: (1) to establish the effects of transesophageal echocardiography (TEE) on arterial oxygen saturation (SAO(2)%); (2) to verify the possible clinical consequences of this phenomenon; and (3) to study the possibility of predicting modifications of SAO(2)% by clinical or hemodynamic variables or by specific factors related to the TEE procedure. We prospectively studied 116 unselected patients, aged 61 +/- 12 years, who underwent diagnostic TEE for various clinical indications. Thirty-seven patients had mitral valve disease, 19 aortic valve disease, 14 combined mitroaortic disease, 8 congenital heart disease, and 38 other cardiovascular diseases. Eight patients were affected by chronic obstructive pulmonary disease. Ninety-seven patients were sedated by 4 +/- 2 mg of diazepam IV SAO(2)% (5-min average) (Ohmeda Biox 3700 pulse oxymeter finger probe), heart rate (HR), and blood pressure (BP) were considered during baseline transthoracic examination, after pharmacological sedation but before the introduction of the probe, and finally during TEE. Neither clinical complications nor major arrhythmias were observed. Baseline SAO(2)%, HR and BP were, respectively, 93.6 +/- 3.3%, 76 +/- 14 beats/min, and 129 +/- 20/75 +/- 10 mmHg. Pharmacological sedation did not modify SAO(2)%, HR, and BP (P > 0.1). During TEE a small but significant reduction in SAO(2)% by an average of 1.2 +/- 3.2% was observed (P < 0.005), as well as a small and significant increase in HR by an average of 3 +/- 10 beats/min (P < 0.01). BP did not change significantly (P > 0.1 for both systolic and diastolic). The changes of SAO(2)% and HR were not interrelated and were not related to the duration of the procedure and to any of the clinical and hemodynamic variables taken into consideration. TEE can induce a small but significant drop in SAO(2)% and a small increase in HR even without any clinical relevance. No clinical or hemodynamic variable or specific factors related to the TEE procedure were related to these changes.

Post-exercise cutaneous hyperaemia resulting from local exercise of an extremity.

Large changes in skin blood flow occur after exercise. Most studies have concentrated on the systemic effects of vigorous exercise on skin blood flow. We were interested in the post-exercise response in the neighbourhood of focal exercise. We used a painless neuromuscular electronic stimulator to exercise the muscles of the forearm, producing flexion of the fingers. There was no change in blood pressure and only a small increase in heart rate during this exercise. We measured blood flow during a 5-min pre-exercise period and a 5-min post-exercise period at the forearm, at the dorsum of the index finger and on the pad of the index finger. We also measured values on the contralateral non-exercised extremity during exercise as well as during matched time periods in control experiments with no exercise. Exercise did elicit an increased blood flow in the post-exercise period at all three sites compared with the control experiments with no exercise and on the contralateral extremity. For example, the increase in blood flow at the finger dorsum was 2.1 +/- 0.1 ml (min 100 g)-1 after exercise compared with -0.08 +/- 0.09 ml min-1 100 g-1 during the control experiment and 0.1 +/- 0.1 ml (min 100 g)-1 on the contralateral arm (all P < 0.01). The local application of heat at the site of blood flow monitoring produced a substantial increase in the post-exercise response at the two finger locations [27.4 +/- 0.4 ml (min 100 g)-1 at the finger dorsum], but not at the arm. This is the first demonstration that highly focal exercise, unaccompanied by a systemic haemodynamic response, can elicit a post-exercise cutaneous hyperaemia. Local heating produced a large synergistic increase in the post-exercise hyperaemia at sites with arteriovenous microvascular perfusion but not at sites with primarily nutritive perfusion. These findings show that local vasoregulatory changes occur in response to exercise, even in the absence of whole-body haemodynamic and thermal change.

REFLEX CONTROL OF ARTERIAL BLOOD PRESSURE WITH STANDING IN ENDURANCE TRAINED AND SEDENTARY POSTMENOPAUSAL WOMEN 513

The prevalence of orthostatic hypotension increases with age in both men and women. It has been reported that highly trained older male endurance athletes demonstrate better maintenance of arterial blood pressure (BP) and smaller increases in heart rate during an orthostatic challenge vs age-matched untrained men. To determine if these findings can be generalized to middle-aged and older females, 9 endurance trained postmenopausal women (ET, 55±2 yr, mean±SE) and 11 healthy sedentary controls (C, 56±2) were studied during supine rest (SUP), the transition to standing(TRANS), and early (2 min) steady-state standing (ESS). ET had lower body mass and% fat (both p<0.01), and a higher maximal oxygen uptake (45.6±3.4 vs 26.5±1.1, p<0.001) vs C; casual resting supine BP was similar in the two groups (113±3/72±2 vs 117±5/74±3 mmHg). SUP mean R-R interval was greater (1061±40 vs 866±30 ms, p<0.001) in ET vs C. The peak reduction in BP during TRANS (Finapres monitor) was almost identical in ET vs C (-30±5/-17±3 vs-29±3/-17±2 mmHg). However, ET demonstrated a 120% greater peak reflex reduction in R-R interval during this period vs C (-450±82 vs-205±27 MS, p<0.01); the decrease in R-R interval per mmHg reduction in mean BP (Δ R-R/Δ BP) was ≈ 115% higher in ET vs C(25±5 vs 12±2 ms, p<0.05). Similarly, the SUP to ESS increases in BP did not differ in the two groups (7±4/12±3 vs 6±3/10±2 mmHg), although the corresponding decreases in R-R interval again were greater in ET vs C (-175±45 vs -76±25 ms, p=0.05). The baseline R-R interval was positively related to both the reflex reduction in R-R interval during TRANS (r=0.80, p<0.001) and Δ R-R/Δ BP (r=0.48, p<0.05). We conclude that in response to a real-life orthostatic challenge (standing), BP is similarly well-defended in ET vs C. Moreover, the reflex tachycardia in response to standing is markedly greater in ET, and is related to their resting training bradycardia. These results do not support recent findings in older men.

Tilt test results in young and elderly patients with syncope of unknown origin.

The effects of aging on the results of prolonged drug-free tilt testing were studied in 175 consecutive patients with unexplained syncope divided into 3 groups: 59 patients < 40 years old; 57 patients between 40 and 60 years; and 59 patients > 60 years old. Tilt-induced vaso-vagal syncope occurred respectively in 17 (29%), 20 (35%), and 18 patients (31%) in the 3 age groups. Vasodepressor, mixed, and cardioinhibitory vaso-vagal syncope occurred similarly in the 3 groups; organic heart disease and systemic hypertension were more frequent in elderly patients without affecting the incidence of tilt-induced syncope. Blood pressure and heart rate variations during syncope were similar in the 3 age groups; in the first 20 minutes of tilt testing, before the appearance of the vaso-vagal reflex, elderly patients showed greater reduction in blood pressure and smaller increase in heart rate than younger patients. Our data indicate that increasing age determines a different blood pressure and heart rate behavior during tilt testing, but apparently does not influence the incidence of vaso-vagal syncope in patients with syncope of undetermined etiology. As the proportion of patients with a positive isoproterenol tilt test was reported to decline with age, our results suggest that the reduced incidence of syncope during isoproterenol tilt testing could be the expression of impaired autonomic response among elderly syncope patients.

Smoking produces a smaller increase in heart rate in the natural smoking environment than in the laboratory

We tested whether the physiological effects of smoking a cigarette under standard conditions in a laboratory are similar to those seen in a room at home. On two separate test days ten healthy smokers were prepared with a small physiological recorder and were then requested to carry out a protocol requiring them to smoke one of their cigarettes in their usual way either (1) in the laboratory where they had never smoked previously, or (2) at home, alone in a quiet room where they regularly smoke. The experiment which counterbalanced the order of testing showed that in both test situations smoking produced a clear increase in heart rate (HR) and in skin conductance (SC); however, when testing was carried out in the home environment the increase in the HR was significantly less than in the laboratory. No significant differences were found for the baseline HR values in the two environments and there were no significant situational effects in the SC data. It was concluded that under conditions of normal smoking, data on the physiological effects of a cigarette in the laboratory may not be fully generalizable to those seen in the natural smoking situation. Several possible mechanisms of this situationally-specific effect of smoking were discussed.

Impaired heart rate response to graded exercise. Prognostic implications of chronotropic incompetence in the Framingham Heart Study.

Previous reports have suggested that an attenuated exercise heart rate response may be associated with coronary heart disease risk and with mortality. These observations may parallel the association between reduced heart rate variability during normal activities and adverse outcome. This investigation was designed to look at the prognostic implications of exercise heart rate response in a population-based sample. In this prospective cohort investigation, 1575 male participants (mean age, 43 years) in the Framingham Offspring Study who were free of coronary heart disease, who were not taking beta-blockers, and who underwent submaximal treadmill exercise testing (Bruce protocol) were studied. Heart rate response was assessed in three ways: (1) failure to achieve 85% of the age-predicted maximum heart rate, which has been the traditional definition of chronotropic incompetence; (2) the actual increase in heart rate from rest to peak exercise; and (3) the ratio of heart rate to metabolic reserve used by stage 2 of exercise ("chronotropic response index"). Proportional hazards analyses were used to evaluate the associations of heart rate responses with all-cause mortality and with coronary heart disease incidence during 7.7 years of follow-up. Failure to achieve target heart rate occurred in 327 (21%) subjects. During follow-up there were 55 deaths (14 caused by coronary heart disease) and 95 cases of incident coronary heart disease. Failure to achieve target heart rate, a smaller increase in heart rate with exercise, and the chronotropic response index were predictive of total mortality and incident coronary heart disease (P <.01). Failure to achieve target heart rate remained predictive of incident coronary heart disease even after adjusting for age, ST-segment response, physical activity, and traditional coronary disease risk factors (adjusted hazard ratio, 1.75; 95% confidence interval, 1.11 to 2.74; P=.02). After adjusting for the same factors, the increase in exercise heart rate remained inversely predictive of total mortality (P=.04) and coronary heart disease incidence (P=.0003). The chronotropic response index also was predictive of total mortality (P=.05) and incident coronary heart disease (P=.001) after adjusting for age and other risk factors. An attenuated heart rate response to exercise, a manifestation of chronotropic incompetence, is predictive of increased mortality and coronary heart disease incidence.

Haemolymph flow distribution, cardiac performance and ventilation during moderate walking activity in Cancer magister (Dana) (Decapoda, Crustacea)

Adult male Cancer magister (Dana) were equipped with pulsed-Doppler flowmeters and pressure transducers for simultaneous measurement of heart and ventilation frequencies, haemolymph flow through each of the major arterial systems and cardiac output and for calculation of stroke volume. Each variable was measured at rest and during two consecutive periods of moderate treadmill walking activity and recovery. During activity, haemolymph flow through the sternal and anterolateral arteries increased, while flow through the hepatic arterial system decreased. This resulted in a redistribution of haemolymph flow in which a proportion of cardiac output was shifted from the anterior, posterior and hepatic arterial systems to the sternal arterial system. The relative proportion of the cardiac output flowing through the anterolateral artery remained constant. This indicated that oxygen supply was shifted away from the digestive system to the muscles of the walking legs and the respiratory system. Cardiac output, heart rate and stroke volume all increased in response to activity. The increase in cardiac output is the result of a large increase in stroke volume and a small increase in heart rate. A doubling of ventilation rate also occurred during activity. Both the circulatory and ventilatory systems were restored to pre-activity values by 60 min of recovery.

The preclinical development of bicalutamide: pharmacodynamics and mechanism of action

Objectives. To describe the preclinical development of bicalutamide and clarify its pharmacodynamics and mechanism of action. Bicalutamide was developed from a series of nonsteroidal compounds related to flutamide that showed a range of pharmacologic activity from full androgen agonist to pure antiandrogen, including progestational and antiprogestational properties. Methods and Results. Bicalutamide is a pure antiandrogen that binds to rat, dog, and human prostate; the affinity compared with the natural ligand 5α-dihydrotestosterone is low, but bicalutamide has an affinity for the rat androgen receptor approximately four times higher than hydroxyflutamide, the active metabolite of flutamide. Bicalutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, bicalutamide behaves as a pure antiandrogen and inhibits gene expression and cell growth stimulated by androgen. Studies with the LNCaP cell line are particularly interesting, as these cells contain a mutated androgen receptor (codon 868, Thr → Ala), which behaves idiosyncratically with other antiandrogens (cyproterone acetate and flutamide): both these antiandrogens act as agonists in this cell line and stimulate proliferation. Studies in vivo show that bicalutamide is a potent antiandrogen in the rat. In immature, castrated male rats treated daily with testosterone propionate, bicalutamide produces a profound inhibition of accessory sex organ (ventral prostate and seminal vesicles) growth at oral doses as low as 0.25 mg/kg; it is more active in this test than flutamide or cyproterone acetate. In mature male rats, daily oral doses of bicalutamide produce a dose-related reduction in weights of the ventral prostate glands and seminal vesicles: in this test, bicalutamide is around five times as potent as flutamide. In contrast to flutamide, which produces dose-related, marked increases in serum luteinizing hormone (LH) and testosterone as a consequence of the central inhibition of the negative feedback effects of androgens on the hypothalamic—pituitary—testes axis, bicalutamide has little effect on serum LH and testosterone; i.e., it is peripherally selective. The peripheral selectivity of bicalutamide in the rat is not due to differences between the prostate versus hypothalamic or pituitary receptors, as bicalutamide reverses the suppressive effect of testosterone on luteinizing hormone-releasing hormone (LHRH) secretion from hypothalamic slices in vitro and is as effective as flutamide at sensitizing the pituitary gland to secrete LH in response to administered LHRH. The peripheral selectivity of bicalutamide has now been shown to be due to poor penetration across the blood—brain barrier: tissue distribution studies with [ 3H]bicalutamide show that although it is concentrated in the organs of metabolism and secretion as well as in the prostate, the pituitary glands, and the seminal vesicles, levels in the hypothalamus and the central nervous system (CNS) are much lower than in blood. Indeed, it is probable that levels found in the CNS reflect levels of blood contamination. In dogs, bicalutamide has exquisite potency and causes dose-related atrophy of the prostate gland and epididymides; with an oral ED 50 of 0.1 mg/kg, it is around 50 times as potent as flutamide in this species and also more potent than the steroidal antiandrogen WIN49596 and the 5α-reductase inhibitor MK-906. Even at substantial multiples of the active dose (up to 100 mg/kg orally), bicalutamide failed to increase serum testosterone, so it is also peripherally selective in the dog. Magnetic resonance imaging studies have shown that bicalutamide is also a potent antiandrogen in the monkey; oral doses of 1 and 5 mg/kg produced significant reductions in seminal vesicle and ventral prostate size. At a daily oral dose of 25 mg/kg, bicalutamide effected a highly significant reduction in growth of Dunning R3227H transplantable rat prostate tumors that was equivalent to that achieved by either surgical castration or medical castration with the LHRH agonist goserelin acetate. In a comparative study, flutamide was shown to be both less potent and less active than bicalutamide. In all these preclinical studies, bicalutamide was well tolerated. It had no significant effects in any general pharmacology tests except in the dog, in which, on chronic administration, it caused a small increase in heart rate and a reduction in PR interval at doses of >25 times the ED 50 value for prostate atrophy. Because there was neither impairment of cardiac function nor pathologic observations when cardiac histology was examined in chronic toxicity studies, it is concluded that this idiosyncratic finding is of no toxicologic consequence. Conclusions. Bicalutamide was shown to be a pure antiandrogen and specifically did not possess estrogenic or anestrogenic, progestational or antiprogestational, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid activity in classic endocrine tests. Bicalutamide also showed no androgenic activity and did not inhibit steroid 5α-reductase.

Lesser vagal withdrawal during isometric exercise with age

The tachycardia that accompanies isometric exercise decreases with age in humans; however, the mechanism of this decline is unknown. To determine whether less cardiac vagal withdrawal is associated with the age-related decrease in this response, we assessed high-frequency R-R interval variability (0.15-0.40 Hz), an index of cardiac vagal tone, before (control) and during isometric exercise to exhaustion in healthy young (21-29 yr; n = 12) and older (61-72 yr; n = 11) men. During control, the two groups did not differ in respiratory rate, mean arterial pressure, or heart rate, although the older subjects had a lower high-frequency amplitude (12.2 +/- 1.1 vs. 29.4 +/- 4.6 ms/Hz; P < 0.05). During isometric exercise, the respiratory rate and arterial pressure responses did not differ; however, the older men had a lower absolute heart rate and a smaller increase in heart rate, and only the young men demonstrated a significant decline in high-frequency amplitude. The heart rate responses to exercise were correlated with the declines in high-frequency amplitude (initial, r = -0.808; midpoint, r = -0.714; peak, r = -0.632; all P < 0.005), which were, in turn, correlated with the control high-frequency amplitude (initial, r = -0.727; midpoint, r = -0.643; peak, r = -0.610; all P < 0.01). Thus smaller declines in high-frequency amplitude, related to lower baseline amplitude, corresponded to smaller increases in heart rate throughout isometric exercise. Therefore, we conclude that the smaller tachycardiac response to isometric exercise in older humans is associated with an inability to decrease cardiac vagal tone below an already reduced baseline level.

Cardiac chronotropic responsiveness to beta-adrenoceptor stimulation is not reduced in the elderly

This study evaluated cardiac beta-adrenoceptor responsiveness in the elderly. The hypothesis of reduced cardiac beta-adrenoceptor responsiveness in the elderly is based on a smaller increase in heart rate after administration of isoproterenol, a nonselective beta 1- and beta 2-adrenoceptor agonist. By means of dobutamine-stress-echocardiography we were able to retest the hypothesis more accurately because dobutamine is a relatively selective beta 1-adrenoceptor agonist with weak beta 2- and alpha-adrenoceptor stimulant activity that prevents baroreflex-mediated changes in heart rate. After administration of stepwise incremental infusions of dobutamine, we measured heart rate and blood pressure responses in 360 patients who had no beta-adrenergic blocking agent therapy and no side effects during the stress test. For each patient we calculated the dose of dobutamine required to increase heart rate by 50% of the maximal heart rate during the highest dose of dobutamine. No relation was found between age and sensitivity to dobutamine (n = 293). Power analysis revealed that this negative finding was not the result of inadequate sample size. In contrast to the prevailing hypothesis, an increased heart rate response to dobutamine was found even in a subgroup of "healthy" elderly subjects (i.e., those without concomitant disease or acute myocardial ischemia, n = 67) that was not related to changes in blood pressure during stress. However, in subjects with acute ischemia (n = 109), smokers (n = 151) or patients with a history of a previous myocardial infarction (n = 148), dobutamine sensitivity was reduced in the elderly despite a diminished change in systolic blood pressure with advanced age during dobutamine infusion. This phenomenon could be explained by a decrease in efferent cardiac baroreflex sensitivity, as has been observed during acute myocardial ischemia. There were no age-related differences in plasma concentrations of dobutamine. No evidence for reduced beta-adrenoceptor responsiveness to dobutamine was found in "healthy" elderly subjects.

Changes in ganglion nodosum neurons associated with stress-related cardiac deficiency

Cell bodies of cardio-vascular receptors localized in the ganglion nodosum of rabbits exposed to experimental emotional stress were studied with the light and electron microscope and histochemically. Under emotional stress some rabbits demonstrated almost unchanged arterial pressure and only a small increase in heart rate, while other animals displayed strongly marked disturbances of their blood circulation leading to the acute heart deficiency at the end of the experiment. In the stress-resistant rabbits, microscopic anatomy and ultrastructure of neurons indicated their increased activity. Activities of lysosomal enzymes--acid phosphatase and aminopeptidase--were found to be at the control level, while the activity of mitochondrial enzyme--glutamate dehydrogenase--was slightly increased. On the other hand morphological evidence of severe hyperactivity and exhaustion was revealed in neurons of the stress-predisposed rabbits. Moreover the activities of all three enzymes studied were significantly increased. These results indicate correlation between the structural and metabolic changes occurring under experimental emotional stress in nodosal neurons and the extent of hemodynamic changes.

Oral Dexmedetomidine Preserves Baroreceptor Function and Decreases Anesthetic Requirements of Halothane-anesthetized Dogs

The alpha 2-adrenergic agonist, dexmedetomidine, alters hemodynamics by diminishing sympathetic and/or augmenting parasympathetic neurogenic tone to the heart and peripheral vasculature. However, the specific actions of dexmedetomidine on baroreceptor function are unknown. The purpose of the current investigation was to determine baroreceptor function during an anesthetic state produced by halothane and a similar anesthetic state produced by halothane after dexmedetomidine pretreatment. Dogs were instrumented for measurement of arterial and left ventricular pressures, coronary blood flow velocity, segment shortening and cardiac output. Five experimental conditions were studied in the same dogs (n = 8). Measurements of baroreceptor sensitivity (via abrupt decreases and increases in arterial pressure resulting in changes in the cardiac cycle) and hemodynamics were made in the conscious state in dogs in conditions 1 and 2 before and after 25 and 50 micrograms.kg-1 of oral dexmedetomidine, respectively. Dogs in conditions 3 and 4 received the same doses of dexmedetomidine and were then anesthetized with halothane. Baroreceptor sensitivity was determined after 60 min of halothane anesthesia. For comparison, dogs in condition 5 had baroreceptor sensitivity measured after 60 min of halothane anesthesia in the absence of dexmedetomidine. Dexmedetomidine decreased heart rate, rate-pressure product, rate of increase of left ventricular pressure at 50 mmHg, cardiac output and percent segment shortening. Diastolic coronary vascular resistance and systemic vascular resistance were increased with both oral doses. In addition, diastolic coronary blood flow velocity and stroke volume were significantly reduced by the high dose of dexmedetomidine. Anesthesia with halothane increased heart rate and decreased mean arterial pressure, left ventricular systolic pressure, rate of increase of left ventricular pressure at 50 mmHg, stroke volume and segment shortening. Administration of dexmedetomidine before halothane anesthesia in dogs pretreated with dexmedetomidine resulted in small increases in heart rate and decreases mean arterial pressure and left ventricular systolic pressure. Both doses of dexmedetomidine demonstrated anesthetic-sparing effects. The end-tidal concentration of halothane to maintain dogs unconscious and unresponsive was reduced by 30% and 40% (1.03 +/- 0.08% to 0.67 +/- 0.09% and to 0.58 +/- 0.06% end-tidal, respectively) at 25 and 50 micrograms.kg-1, respectively. Baroreceptor sensitivity was profoundly depressed by halothane alone. Dexmedetomidine did not significantly change the slope of the baroreflex response when compared with conscious control measurements. After pretreatment with dexmedetomidine, the reduction in halothane concentration required for a comparable level of anesthesia resulted in significant preservation of baroreceptor sensitivity. The results indicate that dexmedetomidine alone does not alter baroreflex sensitivity. In addition, possibly through an anesthetic-sparing action, dexmedetomidine preserves baroreflex responses during halothane anesthesia. Such a preservation of the baroreceptor reflex by dexmedetomidine might provide an important mechanism for maintenance of cardiovascular stability by retaining buffer reflexes during general anesthesia.

Renal Effects of Local Infusion of Adenosine in Man

1. The effects of local intra-arterial infusion of adenosine on renal blood flow, glomerular filtration and renin release in eight healthy awake subjects have been examined. 2. Renal blood flow and glomerular filtration rate were measured as the clearances of p-aminohippurate and inulin, respectively. After basal samplings, adenosine was infused intra-arterially at successive rates of 2 and 10 micrograms min-1 kg-1 for 40 min at each rate. 3. Apart from a small increase in heart rate (65 +/- 4 to 71 +/- 4 beats/min), there were no signs of sympathetic activation (unchanged blood pressure and catecholamine levels) during the infusion. Clearance of p-aminohippurate tended to increase, but not significantly, during adenosine infusion (518 +/- 48 ml/min basal, 563 +/- 52 ml/min during the highest dose of adenosine). The arterial plasma concentration of p-aminohippurate decreased by 9 +/- 3% (P < 0.05), consistent with a small increase in renal blood flow in the infused kidney. Inulin clearance was reduced from 115 +/- 3 to 97 +/- 2 ml/min (P < 0.001). The extraction of inulin, reflecting the filtration fraction, was 18% in both kidneys in the basal state. During infusion of adenosine the extraction in the infused kidney decreased to 12 +/- 3% (P < 0.01 compared with the control kidney, 23 +/- 3%). 4. The total excretion of Na+ was unchanged, but there was a minor decrease in K+ clearance. Thus, the K+/Na+ excretion ratio decreased from a basal value of 13 +/- 2 to 10 +/- 2 (P < 0.01) at the highest dose of adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of body fat on exercise hemodynamics in sedentary older men

Morbid obesity is often associated with cardiac dilatation and left ventricular dysfunction. The present study investigated whether a similar relationship exists between mild and moderate obesity and left ventricular reserve function in 28 middle aged and older men (58.6 +/- 6.1 years, mean +/- SD). Subjects had a body mass index of 26.4 +/- 2.9 kg/m2, a percent body fat determined by hydrodensitometry ranging from 9.5% to 33.8%, and were carefully screened to exclude cardiovascular disease. Left ventricular function was assessed by gated blood pool scans at rest and during exhaustive upright cycle exercise. There were no significant relationships between resting or exercise cardiac volumes or ejection fraction with percent body fat; however, peak work rate/kg correlated inversely with percent body fat (r = -0.68, p < 0.0001). Heart rate reserve, defined as heart rate at peak work rate minus resting heart rate, declined significantly with increasing percent body fat (r = -0.47, p = 0.01). End diastolic volume index reserve also tended to decline with increasing percent body fat, but stroke volume index and cardiac index reserve were maintained because the decrease in end systolic volume index from rest to maximal exercise was greatest in those subjects with highest percent body fat (r = -0.41, p = 0.03). Therefore, rest and exercise left ventricular function are not related to percent body fat in healthy older men. However, older more obese men have a smaller increase in heart rate and end diastolic volume and a greater decrease in end systolic volume from rest to peak effort as a mechanism to augment exercise cardiac output.

Sympathetic neural reactivity to stress does not increase with age in healthy humans

Sympathetic nervous system reactivity to stress is though to increase with age in humans. We tested this hypothesis by recording postganglionic sympathetic nerve activity to skeletal muscle (MSNA) (peroneal microneurography) and by measuring plasma norepinephrine concentrations (PNE), heart rate, and arterial pressure before (prestress control) and during cognitive challenge (mental arithmetic and colored word test), thermal stress (i.e., the cold pressor test), and exhaustive isometric handgrip exercise (40% of maximum voluntary force)/postexercise ischemia in 15 older (60-74 yr, mean +/- SE = 64 +/- 1) and 15 young (19-30 yr, mean +/- SE = 25 +/- 1) healthy men and women (8 males, 7 females each). The initial prestress control level of MSNA was higher in the older subjects (P < 0.01 vs. young), but there were no significant differences for PNE, heart rate, or arterial pressure. The MSNA and PNE responses to mental stress were small and not different in the two groups. MSNA and PNE increased markedly in response to the cold pressor test and isometric handgrip exercise/post exercise ischemia in both groups. The absolute unit increases in MSNA were similar in the two groups, but the relative (percentage) increases were actually smaller in the older subjects (P < 0.05 vs. young) due to their elevated baseline levels. The stress-evoked increases in arterial pressure were similar in the groups, but the older subjects tended to demonstrate smaller increases in heart rate. In general, no gender differences were noted in either age group. These findings fail to support the long-held concept that stress-induced sympathetic nervous system stimulation becomes exaggerated with age. Thus, sympathetic neural hyperreactivity does not appear to be a fundamental property of the aging process in humans.