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Influence of digitalis on cardiac function before and after autonomic blockade.

The influence of Deslanoside C (D), 1.2 mg intravenously on the systolic time intervals (STI) was assessed in 15 individuals with right ventricular pacemakers, who were studied on two occasions, ten days apart. In the first case D was given under basal conditions, and in the second after autonomic blockade (with practolol 20 mg intravenously and atropine 1.5 and 1.0 mg intravenously) at 1 hour's interval. There were similar changes of the STI with digitalis administration both before and after automic blockade. Autonomic blockade is not necessary for full expression of digitalis action on the human heart, as advocated by some authors to be the case in experimental animals.

Adult

Moderate alcohol intake and heart rate variability adaptations to high-intensity interval training in healthy young adults: the BEER-HIIT study.

BACKGROUND: It is unknown whether daily alcohol consumption influences training effects on heart rate variability (HRV). This study investigated: (i) the effects of a 10-week high-intensity interval training (HIIT) on HRV in healthy young adults; and (ii) the effects of daily alcohol consumption on HRV responses to exercise. METHODS: 71 healthy young adults (18-40 years old; 52.1% women) participated in the BEER-HIIT study. We conducted a 10-week (2 days/week) controlled trial (ClinicalTrials.gov ID: NCT03660579). Participants were allocated to 5 groups: a non-training group (N-T) and four HIIT groups. Participants in the training groups chose whether to consume alcohol. Those choosing alcohol were randomly allocated to receive beer (5.4%; T-Beer) or an equivalent amount of alcohol (vodka; T-Ethanol) in sparkling water. Those choosing no alcohol were randomly allocated to receive alcohol-free beer (0.0%; T-Zero) or sparkling water (T-Water). Training comprised eight weight-bearing exercises performed in circuit form. HRV was measured before and after the intervention. RESULTS: No statistically significant between-group differences in HRV outcomes were detected after the intervention (all p > 0.05). CONCLUSIONS: Our findings indicate that: (i) no statistically significant differences in HRV responses were detected following a 10-week HIIT program using weight-bearing exercises performed twice per week; and (ii) no statistically significant differences in HRV responses were observed among the assigned beverage intervention groups. These findings should be interpreted cautiously because HRV was a secondary outcome and the study was not specifically powered to detect differences in these parameters.

alcohol

Cardiac effects of acute ethanol ingestion unmasked by autonomic blockade.

We assessed the effects of ethanol and autonomic blockade on left ventricular function in nine normal subjects, age 20--35 years, using M-mode echocardiography and systolic time intervals. On day 1, measurements were made of heart rate, mean velocity of circumferential fiber shortening, and left ventricular pre-ejection period and left ventricular ejection time ratio (PEP/LVET), during a control period and after autonomic blockade. Autonomic blockade was produced with intravenous propranolol (0.2 mg/kg body weight) and atropine (0.04 mg/kg body weight). On day two, measurements were again made during a control period, then with ethanol alone, followed by addition of autonomic blockade to ethanol. One hundred eighty milliliters of ethanol were ingested over 60 minutes, resulting in a mean blood ethanol level of 110 mg/dl (range 77--135 mg/dl) at 60 minutes post-ingestion. There were no significant differences between the control data on days 1 and 2. Blood pressure was unchanged throughout the study. study. On day 1, autonomic blockade alone resulted in the expected increase in heart rate (p less than 0.001), with a proportional increase in mean velocity of circumferential fibr shortening (p less than 0.01), and an increase in PEP/LVET (p less than 0.01). On day 2, ethanol alone resulted in no significant changes except for a slight increase in PEP/LVET (p less than 0.02). Ethanol plus autonomic blockade, (day 2), compared with autonomic blockade alone (day 1), revealed a decrease in mean velocity of circumferential fiber shortening (p less than 0.05), and an increase in PEP/LVET (p less than 0.01), with a decrease in intrinsic heart rate (p less than 0.001). We conclude that in normal subjects: 1) autonomic blockade does not directly affect contractility; 2) acute ethanol ingestion alone does not produce important changes in cardiac function; and, 3) ethanol in the autonomic blockaded heart causes a significant decrease in contractility. Thus, we infer that ethanol has a negative inotropic effect which is masked by catecholamines and/or autonomic nervous system discharge.

Adult

Cardiovascular responses to changes in carotid sinus transmural pressure in man.

To study the relative importance of cardiac and peripheral effector mechanisms in the carotid sinus baro-reflex in man cardiovascular responses to equal changes of the carotid sinus transmural pressure (Ptm) in either direction of the normal were recorded and compared in eight physically well-trained young male volunteers. In both the supine and the 70 degrees head-up position, a decrease in Ptm produced a more potent reflex response of the systemic arterial pressure than did a similar increase in Ptm. Whereas the arterial pressure response to increased Ptm was due solely to a reduction in vascular resistance, a significant increase in cardiac output contributed to the more potent pressor response to a decrease in Ptm and thus to the predominantly antihypotensive properties that characterize the carotid sinus baroreceptor control system in man. However, since combined beta-adrenergic and parasympathetic blockade abolished the effect of reduced Ptm on cardiac output without greatly impairing the blood pressure response, it is concluded that adjustments in cardiac output are not of critical importance in the buffering function of the carotid sinus baroreceptors. Autonomic cardiac blockade exaggerated the fall in cardiac output on head-up tilt, the arterial pressure remaining unaffected due to a compensatory increase in systemic vascular resistance.

Adrenergic beta-Antagonists

Sympathectomy revisited: Dodo or phoenix?

Personal experience with temporary or permanent interruption of adrenergic impulses to brain, heart, kidney, pancreas, and the extemities is reviewed and certain concepts which were formulated long ago are re-emphasized. First, adrenergic blockade unmasks the cholinergic activity of the autonomic nervous system. This is apparent particularly when cardiac, renal, or pancreatic functions are studied under stress. Second, in the immediate treatment of cerebral, cardiac, or digital ischemia, the potentially reversible halo of edema around the irreversible necrosis is rapidly influenced by ganglionic blockade. And third, attention is called to the effect of adrenergic stimulation on sensory nerve endings which develop a higher threshold for pain when sympathetic fibers are interrupted. Although potent drugs inhibiting alpha and beta receptors or the release of catecholamines are widely in use, the obvious advantages of regional vs. systemic interruption of adrenergic impulses is pointed out. When the latter approach is pursued aggressively, the side effects are those of a total sympathectomy.

Adrenal Glands

The beta-adrenergic blocking agents and the treatment of glaucoma.

The autonomic nervous system is divided into the parasympathetic and sympathetic systems, with three types of adrenergic receptors: alpha (smooth muscle contraction), beta1 (cardiac acceleration and fatty acid mobilization) and beta2 (smooth muscle relaxation). Substances affecting the function of the adrenergic system are the agonists or stimulators, which mimic the effects of endogenous norepinephrine or epinephrine, and antagonists or blockers, which block the receptors and prevent stimulation by the agonists. Autonomic stimulation in the eye mediates various changes which apparently affect outflow facility and rate of formation of aqueous humor. Alteration of either or both of these factors by autonomic agonists or antagonists may have a direct or an indirect effect on intraocular pressure. Beta-adrenergic blocking substances have been used to treat a variety of diseases. Some of the effects of these drugs are attributable to properties other than beta blockade, such as intrinsic sympathomimetic activity and local anaesthetic activity. Side effects of this class of drugs require caution in cases of congestive heart failure and in asthmatics. Autonomic agents used in the treatment of ocular hypertension and glaucoma include pilocarpine, a chilinergic agonist, epinephrine, an adrenergic agonist, and various beta adrenergic blockers or antagonists including propranolol, atenolol and timolol. The physico-chemical properties and pharmacokinetics of timolol are reviewed. Data showing a significant reduction in intraocular pressure as a result of ocular instillation of timolol are presented. Reduction of the rate of aqueous formation appears to be the mechanism of action. A low incidence of non-serious side effects is reported.

Adrenergic beta-Antagonists

Interrelations of dietary and hormonal effects in aging.

A model system is proposed which suggests that aging involves a genetically programmed process encoded within specific regions of the central nervous system and is characterized by a gradual ascendency of inhibitory over excitatory influences. The resulting neural suppression reduces tonic stimulation to the hypothalamus-pituitary-endocrine axis, the autonomic nervous system and the spinal cord, and promotes the secretion of inactive pituitary hormone, the involution of the somatic musculature (smooth, cardiac and striated) and the compromise of secretomotor function. Experimental observation from nutritional restriction studies which include the prolongation of the life-span and delays in reproductive and homeostatic aging, degenerative coat changes and the appearance of neoplasia, are considered from the perspective of this hypothesis.

Aging

Effect of anesthetics on the heart.

In man, high doses of the "group 1" inhalation anesthetics (diethylether, cyclopropane, and fluroxene) produce relatively minor depression of ventricular function, although it is possible to depress the heart if the dose is great enough. The "group 2" drugs (halothane, methoxyflurane, etc.) produce dose-related depression in cardiac function, but reasonable caridac outputs and blood pressure can be maintained at light anethetic levels. Much the same can also be said for the intravenous barbiturates and other hypnotics. If ventilation is supported and hypovolemia avoided, large doses of the narcotic analgesics appear to produce minimal cardiac effects. The only intravenous drug which stimulates the heart is the dissociative anesthetic ketamine, and this is probably an autonomic, reflex phenomenon (as with group 1 inhalation anesthetics). Regional anesthesia and the neuromuscular blocking drugs appear to have relatively little effect on ventricular function. Most of the work in man on the effect of anesthetics has been in healthy patients or volunteers. The effects on patients with severe heart or other systemic disease may well be different. In fact, low concentrations of fluroxene have been shown to produce significant depression of stroke volume in patients with aortic vavular disease in contrast to the effects on healthy volunteers. All potent central nervous system depressant drugs possess the potential for significant cardiac depression. If such depression is undersirable in a particular patient, the only safe way to administer anesthesia is by careful titration of the dose against the best measurement of cardiac function which is available. At the present time, this would mean measuring at least direct arterial pressure, central venous pressure, and a continuous electrocardiogram. The optimal management would prpbably include recording systolic time intervals, pulmonary capillary wedge pressure, and some measure of cardiac output as well. All the skill and pharmacologic knowledge available connot substitute for vigilant monitoring and carful tiration of drug dose in the clinical situation.

Adrenergic beta-Agonists

Synaptic organization and acetylcholine sensitivity of multiply innervated autonomic ganglion cells.

The principal cells of the mudpuppy cardiac ganglion receive synapses from three sources: vagal axons, interneurons and axon collaterals from other principal cells. The simplicity of the structural organization and the visual clarity in the living preparation provide favorable conditions for examining the function of these synapses and how different classes of synapses on the same cell influence its function. We have studied the sensitivity of the principal cells to iontophoretically applied acetylcholine--the transmitter at synapses made by the vagal axons and by postganglionic axon collaterals from other principal cells. In normal ganglia, the ACh sensitivity on the cell surface is highest at the region of synapses. Partial denervation, produced by severing the vagus nerves, results in an increased ACh sensitivity in nonsynaptic areas but does not appear to affect synaptic transmission at the remaining synapses.

Acetylcholine

Medication safety in older adults in India: an integrative PhD synthesis of direct evidence and contextual implementation evidence.

BACKGROUND: Unsafe medication practices among older adults are an important global health concern, particularly in low- and middle-income countries where multimorbidity, fragmented care, self-medication, and informal healthcare provision intersect. OBJECTIVE(S): To synthesize direct evidence on medication safety among older adults in India and contextual evidence on deprescribing and community-level provider interventions relevant to safer medication use. METHODS: This PhD synthesis integrates four studies: a record-based cross-sectional study on polypharmacy and cardiovascular autonomic function in Kolkata; a six-city community study of 600 Indian older adults; a systematic review and meta-analysis on deprescribing preventive medications in frail or end-of-life older adults; and a systematic review of informal healthcare provider interventions in low- and middle-income countries. Studies I-II provided direct Indian older-adult evidence, while Studies III-IV provided indirect contextual evidence for their optimization and implementation. RESULTS: Polypharmacy was associated with higher anticholinergic burden and numerically higher cardiac autonomic neuropathy although residual confounding limits causal interpretation. In the multicity study, one-third had polypharmacy, while potentially inappropriate medications, prescribing omissions, and self-medication were common. Risks were higher with multimorbidity, recent hospitalization, care transitions, or living alone. Deprescribing showed no statistically significant increase in mortality, hospitalization, or major cardiovascular events, but heterogeneity was high and certainty low to very low. Informal-provider interventions showed the potential to improve knowledge, referral, case management, and medication-related practices. CONCLUSIONS: Medication safety among older adults in India requires an integrated continuum approach, but direct evidence supports only some components and implementation strategies that need prospective evaluation.

Humans

Autonomic function in hemodialyzed patients.

The authors have studied the autonomic function in a group of 34 regular hemodialyzed patients and in a group of 24 normal volunteers with simple, non-invasive and repeteable techniques. To evaluate autonomic function Valsalva manoeuvre, cold pressor test, mental stress test, tilt test, diving reflex test, systolic-time intervals and plasma catecholamines levels were used in all subjects. Uremic patients on maintenance hemodialysis were studied the day after hemodialysis. The response to cold pressor test, mental stress test, tilt test and plasma catecholamines levels resulted normal in all uremic patients, even if 17 out of 34 patients showed an abnormal response to the Valsalva manoeuvre (Valsalva ratio lesser than 1.40). In these patients an alteration of diving reflex and/or a pathological systolic-time interval was found. The authors suggest that sympathetic function is normal in regular hemodialyzed patients and that the abnormal response to the Valsalva manoeuvre is probably due to a defect in the vagal control of the heart and/or an alteration of cardiac performance.

Adolescent

Catecholamine release-inhibitory peptide catestatin (chromogranin A(352-372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension.

BACKGROUND: Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. METHODS AND RESULTS: Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by approximately 47%) and downward deflections (by approximately 44%), increased cardiac parasympathetic index (by approximately 2.4-fold), and decreased cardiac sympathetic index (by approximately 26%). Renal norepinephrine excretion was diminished by approximately 26% and epinephrine excretion by approximately 34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to approximately 70,000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by approximately 5 to 6 mm Hg, and the polymorphism accounted for approximately 1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. CONCLUSIONS: The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

Amino Acid Sequence

Inotropic responses to digoxin during hypoxia and autonomic blockade.

Inotropic responses to digoxin (0.08 mg/kg) were studied in dogs and compared with responses during hypoxemia and autonomic blockade. Changes in left ventricular contractility (VC) were assessed by constructing function curves relating left ventricular (dP/dt)max and stroke volume to end-diastolic pressure. Augmentation of VC was observed 20 min after digoxin infusion and continued to increase until termination of the experiment after 60 min. In animals subjected to autonomic blockade with practolol, TEAC, and atropine, the increases in VC after digoxin were substantially greater. Equally large increases occurred in blocked dogs during sustained hypoxia (Pao2 = 28 mmHg). However, in animals without blockade there was a progressive fall in VC during hypoxia despite digoxin infusion, although less than in those not given digoxin. Serum digoxin levels were measured by radioimmunoassay and did not differ significantly in blocked compared to unblocked dogs or in hypoxic compared to nonhypoxic animals. These findings indicate that digoxin protects the heart from the decrease in myocardial contractility which occurs during extended hypoxia. This protective effect is more pronounced in animals deprived of autonomic function, possibly reflecting the elimination of reflex sympathetic withdrawal ordinarily induced by digitalis.

Adrenergic beta-Antagonists

Left ventricle contractile function in trained dogs with cardial hypertrophy.

Eight mongrel dogs exercised for 8 weeks by treadmill running at 20 per cent incline 20 to 25 minutes twice daily, 4-5 days/week. Another eight dogs which were kept in the cages for a similar period served as controls. The exercise program was effective in inducing myocardial hypertrophy since the ratio left ventricular weight/body weight was significantly (P less than 0.001) higher in the trained dogs (5.04 g/kg) than in the sedentary animals (3.83 g/kg). In morphine-chloralose anesthesia the dogs were studied by left heart catherization and cineangiography at spontaneous heart rate (run I), at paced heart rate (run II), at paced heart rate following cardiac autonomic nervous blockade by bilateral vagotomy and the administration of propranolol (run III) and during acute pressure loading with methoxzmine at constant heart rate (run IV). Intergroup comparison yielded no significant difference in any hemodynamic or volumetric parameter throughout the entire study. However, with intragroup comparisons between run III and run IV a less significant increase in left ventricular end-diastolic pressure (from 5 to 15 mm Hg; P less than 0.05) was observed in the trained animals than in the control dogs (from 6 to 25 mm Hg; P less than 0.001). Left ventricular end-diastolic volume increased significantly only in the control dogs during acute pressure loading. Mean aortic pressure and left ventricular peak dP/dt increased to a similar extent in both groups. Since in the trained dogs the left ventricle encroaches less on the Frank-Starling mechanism than in normal animals for overcoming an acute pressure burden it is concluded that the development of hypertrophy concomitant with chronic exercise represents an adaptive mechanism with evidence of beneficial consequences for the intrinsic contractile function of the myocardium.

Animals