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Biomedical subjects

M Esler

Publications and source records attributed to M Esler.

At least 55 records · Page 3Linked to original sources
PubMed1993

Cyclosporine therapy after cardiac transplantation causes hypertension and renal vasoconstriction without sympathetic activation.

BACKGROUND: Hypertension frequently complicates the use of cyclosporine A (CyA) therapy, and it has been suggested that sympathoexcitation may be the underlying mechanism in this form of hypertension. METHODS AND RESULTS: To further investigate the possibility of a neurogenic mechanism for this hypertensive effect, we studied the effects of CyA on renal blood flow (n = 11), forearm blood flow (n = 8), and sympathetic nervous system activity, assessed by renal and whole-body radiolabeled norepinephrine plasma kinetics and muscle sympathetic nerve firing (using microneurography) in cardiac transplant recipients receiving CyA and a reference group of healthy age-matched control subjects (n = 17). In 11 cardiac transplant patients (2 hours after cyclosporine dose), renal blood flow was significantly lower than that in 8 control subjects (680 +/- 88 vs 1285 +/- 58 mL/min, P < .001). In 5 of these transplant patients, renal blood flow was measured before and for 2 hours after oral cyclosporine and fell progressively over this period, by 37% (P < .01). Total body and renal norepinephrine spillover rates in transplant patients were similar to those in control subjects (3070 +/- 538 vs 2618 +/- 313 pmol/min and 579 +/- 124 vs 573 +/- 95 pmol/min, respectively), and there was no progressive effect in the 2 hours after cyclosporine dosing. Forearm blood flow was increased 2 hours after CyA administration (1.74 +/- 0.31 to 3.12 +/- 0.50 mL x 100 mL-1 x min-1, P < .001), whereas mean arterial blood pressure and noninvasively determined cardiac output (indirect Fick method) were unchanged. Muscle sympathetic nerve discharge rates recorded in 6 of these transplant patients were not different from those in 9 healthy control subjects (37.9 +/- 10.1 vs 41.3 +/- 2.3 bursts per 100 beats per minute). During 90 to 120 minutes of recording after cyclosporine dosing, nerve firing rates remained unchanged. CONCLUSIONS: CyA therapy causes acute renal vasoconstriction without accompanying systemic hemodynamic effects. These renal effects are nonneural, not being attributable to sympathoexcitation.

Cyclosporine↗
PubMed1993

Functional and neurochemical evidence for partial cardiac sympathetic reinnervation after cardiac transplantation in humans.

BACKGROUND: The presence of cardiac reinnervation in humans after cardiac transplantation has been widely debated, based on the application of differing methods for the assessment of neuronal function. Some of these techniques have been rather indirect; consequently, the time course and extent of cardiac reinnervation remains uncertain. METHODS AND RESULTS: To test for the presence of cardiac reinnervation after transplantation, we examined neurochemical (radiolabeled norepinephrine [NE] kinetics) and functional markers (power spectral analysis, heart rate response to exercise) of cardiac sympathetic nerve integrity in 15 cardiac transplantation recipients and 25 healthy control subjects of similar age. Cardiac transplantation subjects were studied 9 weeks to 8 years after cardiac transplantation (10 "early" patients < 18 months and 5 "late" patients > 2 years after cardiac transplantation). At rest, cardiac NE spillover was markedly attenuated early after transplantation (11.2 +/- 18.3 pmol/min) compared with subjects late after transplantation (105 +/- 11 pmol/min, P < .01) or in healthy control subjects (103 +/- 15 pmol/min, P < .01). Heart rate variability (measured by total spectral power) was significantly reduced in cardiac transplantation recipients compared with control subjects (59.4 +/- 30 vs 1673 +/- 516 milliseconds squared; P < .05), with evidence of a trend toward increasing spectral power late after transplantation. During exercise, the cardiac NE spillover was significantly lower in early cardiac transplantation recipients when compared with control subjects (163 +/- 50 vs 1876 +/- 418 pmol/min, P < .01). Late cardiac transplantation subjects showed a response intermediate (1080 +/- 254 pmol/min) between that of the early cardiac transplantation and control groups. However, measurements of the neuronal reuptake process for NE (assessed by the fractional extraction of plasma labeled NE across the heart and tritiated dihydroxyphenylglycol release) were significantly depressed in both early and late cardiac transplantation subjects. CONCLUSIONS: The present study demonstrates a partial restoration of cardiac sympathetic nerve function in humans up to 8 years after heart transplantation.

Blood Pressure↗
PubMed1992

Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis.

OBJECTIVE: To study disturbances in sympathetic nervous system function in patients with alcoholic cirrhosis and the effect of clonidine on such disturbances. DESIGN: Cross-sectional physiologic and neurochemical evaluation of patients with cirrhosis and of healthy controls; an uncontrolled trial of intravenous clonidine in the cirrhotic patients. PATIENTS: Forty-four hospitalized patients with biopsy-proven alcoholic cirrhosis and 31 healthy controls. INTERVENTIONS: Intravenous clonidine. MAIN OUTCOME MEASURES: Radiotracer-derived measures of norepinephrine release to plasma, central hemodynamics, wedge hepatic vein pressure, and measures of renal function. MAIN RESULTS: In patients with cirrhosis, clonidine reduced previously elevated norepinephrine overflow rates for the whole body, kidneys, and hepatomesenteric circulation. This sympathetic inhibition was accompanied by the following potentially clinically beneficial effects: the lowering of renal vascular resistance (median reduction, 24%; 95% CI, 14% to 31%), the elevation of glomerular filtration rate (median increase, 27%; CI, 14% to 39%), and the reduction of portal venous pressure (median reduction, 25%; CI, 18% to 32%). The norepinephrine and hemodynamic responses to graded clonidine dosing (1, 2, and 3 micrograms/kg body weight intravenously) indicated that the sympathetic outflow to the hepatomesenteric circulation was more sensitive to pharmacologic suppression with clonidine than was the sympathetic outflow to the systemic circulation. CONCLUSIONS: The sympathetic nerves to the kidneys, heart, and hepatomesenteric circulation are stimulated in patients with cirrhosis. Clonidine inhibits these activated sympathetic outflows differentially, which could possibly provide a basis for the selective pharmacologic treatment of portal hypertension in patients with cirrhosis.

Adult↗
PubMed1992

The autonomic nervous system and cardiac arrhythmias.

Disturbed autonomic nervous 'balance' of the sympathetic nervous and vagal outflows to the heart potentiates the experimental development of ventricular arrhythmias in laboratory animals. For some time the best evidence for the occurrence of a similar phenomenon in humans was provided by the long QT interval syndrome, sufferers of which are very prone to develop serious ventricular arrhythmias and in whom evidence exists of abnormal anatomy and function of the cardiac sympathetic nerves. Recently the case for disturbed autonomic function causing clinical arrhythmias has become more broadly based. Reduced baroreflex sensitivity after myocardial infarction, and low heart rate variability, both of which rest largely on vagal underactivity, have been shown to be associated with substantially increased risk of subsequent sudden death. A second observation is that patients having recovered from unexpected ventricular tachycardia or ventricular fibrillation have markedly increased cardiac sympathetic activity compared with appropriate reference groups, based on measurements of the rate of spillover of the sympathetic neurotransmitter, noradrenaline, from the heart to plasma. These clinical findings support a role for cardiac autonomic dysfunction, specifically sympathetic activation and vagal withdrawal, in arrhythmogenesis. These observations are timely, given the recent demonstration that most conventional anti-arrythmics are of little benefit in preventing sudden death. A reappraisal of the anti-arrhythmic activity of beta-adrenergic blocking drugs, and evaluation of potential benefits of other pharmacological and non-pharmacological means of favourably altering cardiac autonomic function is now needed.

Animals↗
PubMed1992

Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans.

1. Muscle sympathetic nerve activity (MSA) was recorded in the peroneal nerve at the knee by microneurography in ten healthy subjects and determinations were made simultaneously of intra-arterial blood pressure, and whole-body and cardiac noradrenaline spillover to plasma. Measurements were made at rest, during isometric handgrip at 30% of maximum power and during stress induced by forced mental arithmetic. 2. At rest there were significant positive correlations between spontaneous MSA (expressed as number of sympathetic bursts min-1) and both spillover of noradrenaline from the heart and concentration of noradrenaline in coronary sinus venous plasma. 3. Both isometric handgrip and mental arithmetic led to sustained increases of blood pressure, heart rate and MSA. Plasma concentrations of noradrenaline and spillover of noradrenaline (total body and cardiac) increased. In general the effects were more pronounced during handgrip than during stress. 4. When comparing effects during handgrip and stress the ratio between the fractional increases of MSA and cardiac noradrenaline spillover were significantly greater during handgrip. 5. The data suggest (a) that there are proportional interindividual differences in the strength of resting sympathetic activity to heart and skeletal muscle which are determined by a common mechanism and (b) that handgrip and mental stress are associated with differences in balance between sympathetic outflows to heart and skeletal muscle.

Adult↗
PubMed1991

Is adrenaline released by sympathetic nerves in man?

Radiotracer methods were used to measure the rates of regional release of adrenaline and noradrenaline into plasma in man. This was done as a partial test of a theory of essential hypertension pathogenesis which envisages an important cotransmitter function for neuronally released adrenaline. In healthy resting men no release of adrenaline could be detected from the heart, lungs or liver. Adrenaline was released into the right renal vein but an adrenal medullary source is suspected. With the relatively limited activation of the cardiac sympathetic outflow which accompanied mental challenge and isometric exercise, cardiac adrenaline release remained undetectable. During supine bicycle exercise, which increased cardiac noradrenaline release 10-30 fold, to a mean value of 197 ng/min, cardiac adrenaline release averaged 2.36 ng/min. In two clinical conditions associated with persistently elevated plasma adrenaline concentrations, cardiac failure and adrenaline-secreting phaeochromocytoma, regional release of adrenaline was clearly evident. Thus, in normal man during exercise, and in patients with cardiac failure at rest, adrenaline is released from non-adrenal sources, and probably from sympathetic nerves. Whether neuronal adrenaline release of the degree found would be sufficient to facilitate noradrenaline release, augment sympathetically-mediated cardiovascular responses and contribute to the development of arterial hypertension remains to be tested.

Adrenal Gland Neoplasms↗
PubMed1991

Evidence for a role for the cardiovascular amplifiers in human primary hypertension.

1. Hypertrophy of vascular and cardiac smooth muscle is present in human primary hypertension. The amplifier properties associated with hypertrophy play a major role in maintaining hypertension. 2. Long-term antihypertensive drug therapy causes substantial regression of the structural changes, assessed by the non-autonomic component of vascular resistance, and by left ventricular mass. The latter occurs more slowly. 3. The more complete the reversal of left ventricular hypertrophy, the more slowly hypertension redevelops if long-term antihypertensive therapy is discontinued. 4. Subjects who redevelop hypertension more rapidly tend to have higher cardiac output, suggesting that the cardiac amplifier may play a role in the pathogenesis. 5. Studies of small arteries and of veins from patients with primary hypertension suggest that there may be a general disturbance of vascular smooth muscle function, independent of the mechanical effects of elevated systemic blood pressure.

Antihypertensive Agents↗
PubMed1991

Adrenaline release by the human heart.

1. Radiotracer methods were used to measure the rates of regional release of adrenaline and noradrenaline to plasma in humans. 2. No release of adrenaline could be detected from the heart, lungs, liver and kidneys at rest. 3. With the relatively mild activation of the cardiac sympathetic outflow associated with mental challenge and isometric exercise, cardiac adrenaline release remained undetectable. 4. During supine bicycle exercise, which increased cardiac noradrenaline release 10-20 fold, to a mean value of 128 ng/min, cardiac adrenaline release averaged 1.63 ng/min. 5. Whether neuronal adrenaline release of this degree in the heart is sufficient to facilitate noradrenaline release and to augment sympathetically mediated cardiac responses remains to be tested.

Epinephrine↗
PubMed1991

Biochemical evidence of sympathetic hyperactivity in human hypertension.

Radiotracer measures of norepinephrine overflow to plasma are well suited for studying both human sympathetic nervous system responses to mental stress and sympathetic nervous pathophysiology in human hypertension. With an experimental laboratory stressor (cognitive challenge), we noted a preferential activation of the cardiac sympathetic outflow; however, in fainting reactions ("vasovagal syncope"), which occur infrequently during the course of central venous catheter placement under local anesthesia, the converse was seen--an almost total withdrawal of cardiac sympathetic activity. In primary human hypertension (particularly in younger patients), a differentiated activation of the sympathetic outflow to the heart and kidneys is present, based on measurements of norepinephrine spillover to plasma. It is uncertain whether this is attributable to behavioral factors and represents a component of the defense reaction. We previously reported overflow of norepinephrine into the cerebrovascular circulation (with high internal jugular venous sampling) in humans. Because this is resistant to ganglion blockade, brain neurons--not the cerebrovascular sympathetics--are the presumed source. In a preliminary study, we found higher rates of norepinephrine spillover into the cerebrovascular circulation in patients with essential hypertension than in healthy subjects, suggesting that an underlying increase in central nervous system norepinephrine turnover may be the basis for the increased sympathetic outflow.

Brain↗
PubMed1990

Evidence for increased renal norepinephrine overflow during sodium restriction in humans.

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organ's fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.

Adult↗
PubMed1990

Increased regional sympathetic nervous activity in human hypertension: causes and consequences.

Biochemical, electrophysiological, pharmacological and haemodynamic findings provide evidence for the existence of sympathetic nervous system activation in some patients with primary human hypertension, particularly younger ones. Sympathetic activation has been shown to involve neural outflows to the heart, kidneys and skeletal muscle. This sympathetic nervous stimulation, the cause of which remains obscure, appears to be commonly important in the pathogenesis of the hypertension. Whether the sympathetic overactivity has adverse effects in addition to its effect on blood pressure, by promoting left ventricular hypertrophy, cardiac arrhythmias and atherogenesis, is at present uncertain.

Blood Pressure↗
PubMed1989

Measurement of overall and cardiac norepinephrine release into plasma during cognitive challenge.

Measurements of plasma norepinephrine concentrations and norepinephrine spillover into plasma were used to gauge sympathetic nervous system activation during cognitive challenge (forced mental arithmetic) in 12 human subjects. Norepinephrine levels were influenced by the sampling site, with the fractional increase being greatest for norepinephrine spillover from the heart (where norepinephrine release almost trebled), intermediate for the arterial plasma norepinephrine concentration and total body norepinephrine spillover (50-70% increase), and inconsequential for antecubital venous plasma norepinephrine levels (less than 20% increase). These findings are explained by patterning of the sympathetic response, which only minimally involves the sympathetic outflow to the skeletal muscle of the forearm but preferentially involves the heart. Antecubital venous plasma norepinephrine levels are not sufficiently sensitive to allow satisfactory monitoring of the sympathetic neural outflow to organs, such as the heart, which are selectively activated in the response to mental challenge.

Adult↗
PubMed1989

Noradrenaline release and the pathophysiology of primary human hypertension.

Measurements of the overflow of norepinephrine to plasma from individual organs (using radiotracer methodology) were used to delineate the pattern of sympathetic nervous system activation present in primary human hypertension. Mean total norepinephrine (NE) spillover in hypertensive patients was 418 ng/min, 42% (124 ng/min) higher than in subjects with normal blood pressure (BP)(P less than .05). Norepinephrine spillover among hypertensive patients was a function of age, only being elevated in patients under 40 years of age. Half of the excess in total norepinephrine release in hypertensive patients was accounted for by increased cardiorenal spillover. Mean renal norepinephrine spillover was 120 ng/min, compared with 69 ng/min in healthy subjects (P less than .02). Renal spillover was highest in younger patients. Corresponding cardiac norepinephrine spillover values were 12.6 ng/min and 5.1 ng/min (P less than .01). The balance of the excess total norepinephrine spillover comes from undetermined sites, but not the lungs or hepatomesenteric circulation. These measurements of regional norepinephrine overflow suggest that sympathetic nervous outflow to the kidneys and heart is selectively activated in early hypertension.

Humans↗
PubMed1989

Regional norepinephrine turnover in human hypertension.

Overall and regional rates of norepinephrine overflow to plasma were measured in 55 untreated patients with primary hypertension and in 40 healthy subjects, to study sympathetic nervous pathophysiology in human hypertension. Total norepinephrine spillover was increased in primary hypertension, particularly in patients aged less than 40 years, largely due to higher rates of renal and cardiac norepinephrine overflow. Renal renin release, and arterial plasma renin activity, were highest in these younger patients with increased renal sympathetic nervous activity. In older patients sympathetic activity and norepinephrine release was typically normal. A selective increase in the sympathetic nervous outflow to the heart and kidneys is commonly present in young patients with primary hypertension, and probably contributes materially to the early pathogenesis of the hypertension.

Female↗
PubMed1989

Renal catecholamine metabolism.

Renal catecholamine metabolism encompasses: (1) catecholamine metabolism within the kidney intrinsic to renal sympathetic nervous function and renal tubular production of dopamine; (2) the overflow of catecholamines, released within the kidney, into the renal vein; (3) the excretion into urine of catecholamines and catecholamine metabolites, and (4) the extraction of catecholamines from plasma by the kidney. Study of these elements of catecholamine metabolism by the kidney provides a theoretical underpinning for the use of biochemical methodology in the experimental and clinical investigation of the properties of the renal sympathetic nerves.

Catecholamines↗
PubMed1988

In vivo measurement of neuronal uptake of norepinephrine in the human heart.

Neuronal uptake (Uptake-1) of the sympathetic neurotransmitter norepinephrine from the circulation in the human heart was assessed in vivo with three techniques. 1) Cardiac removal of intravenously infused tracer-labeled norepinephrine was measured before and after Uptake-1 blockade with desipramine; 2) the difference between the fractional extraction of radioactive norepinephrine and of radioactive isoproterenol, which is not a substrate for neuronal uptake, was used to estimate the removal of norepinephrine by Uptake-1 in the heart compared with other vascular beds (arm, leg, brain, and lungs); and 3) regional arteriovenous differences in radioactive and endogenous dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, were compared in these beds. In untreated patients, cardiac removal of radioactive norepinephrine averaged 79%, whereas in desipramine-treated patients, cardiac removal of radioactive norepinephrine averaged 19%, a value similar to that of isoproterenol in untreated patients (14%), confirming that in the heart the non-neuronal removals of isoproterenol and norepinephrine were similar. In the heart, 69% of delivered norepinephrine was estimated to be removed by Uptake-1, a much higher percentage than that in the arm (14%), leg (7%), brain (10%), and lungs (4%). The cardiac arteriovenous increment in endogenous DHPG (137%) far exceeded that of the other beds (49%, 26%, 39%, and -19%, respectively), and radioactive DHPG in the great cardiac vein exceeded arterial levels by 113%, whereas in the other beds, arterial radioactive DHPG exceeded venous levels. The results indicate that the human heart is exceptionally dependent on neuronal uptake for in vivo removal of circulating norepinephrine.

Desipramine↗