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Biomedical subjects

M D Esler

Publications and source records attributed to M D Esler.

At least 109 records · Page 6Linked to original sources
PubMed1991

Central sympathoinhibition and peripheral neuronal uptake blockade after desipramine in rabbits.

Peripheral- and central nervous system (CNS)-mediated effects of desipramine (Des) on sympathetic nerves and the contribution of alpha 2-adrenoceptors to these effects were studied in conscious rabbits. Blood pressure, renal sympathetic nerve activity (SNA), and norepinephrine (NE) reuptake and spillover into plasma were measured before and after intracisternal (ic) or intravenous (i.v.) administration of Des. In other animals, NE spillover responses to i.v. Des were examined before and after alpha 2-adrenoceptor blockade with i.v. idazoxan. Treatment with i.v. Des blocked neuronal reuptake and decreased renal SNA but did not alter blood pressure or NE spillover. Decreased NE release by sympathetic nerves after i.v. Des was reflected by a decrease in the combined rate of NE reuptake and spillover. Treatment with ic Des (at 1.7% of the i.v. dose) decreased blood pressure and renal SNA and produced equivalent falls in NE reuptake and spillover, indicating little peripheral effect of centrally administered Des on the efficiency of neuronal reuptake. Thus Des had two distinct actions: the drug blocked neuronal reuptake by direct actions on nerve endings and reduced SNA by actions within the CNS. After ic Des, decreased SNA produced parallel falls in NE reuptake, spillover, and blood pressure. After i.v. Des, blockade of neurotransmitter reuptake increased NE concentrations at sympathoeffector junctions offsetting the fall in SNA, so that there was little change in NE spillover or blood pressure. However, after alpha 2-adrenoceptor blockade with i.v. idazoxan, NE spillover increased in response to i.v. Des. Thus the Des-induced decrease in NE release was partly mediated by an action of raised intrasynaptic NE concentrations on inhibitory alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1991

Neuronal reuptake of norepinephrine and production of dihydroxyphenylglycol by cardiac sympathetic nerves in the anesthetized dog.

BACKGROUND: Reuptake of norepinephrine by cardiac sympathetic nerves before and during two levels of electrical stimulation of the left ansa subclavia was estimated in anesthetized dogs from the cardiac production of dihydroxyphenylglycol (DHPG), the intraneuronal metabolite of norepinephrine. METHODS AND RESULTS: The method depended on the effects of neuronal uptake blockade with desipramine on the cardiac production of [3H]DHPG from intravenously infused [3H]norepinephrine. The ratio of the desipramine-induced decrease in the cardiac extraction of [3H]norepinephrine to the production of [3H]DHPG was used to transform the cardiac production of DHPG from recaptured norepinephrine into a rate for norepinephrine reuptake. Cardiac spillover of norepinephrine into plasma increased from 49 +/- 12 to 205 +/- 40 and 451 +/- 118 pmol/min during sympathetic activation. Cardiac DHPG production increased from 108 +/- 18 to 166 +/- 34 and 240 +/- 47 pmol/min. Desipramine decreased resting cardiac DHPG production by 20% and completely blocked the stimulation-induced increase. Thus, most (80%) cardiac DHPG produced at rest was derived from norepinephrine leaking from storage vesicles. This amount remained constant, and that derived from recaptured norepinephrine increased during sympathetic activation. The cardiac extraction of [3H]norepinephrine (126,000 dpm/min) and production of [3H]DHPG (3,790 dpm/min) were decreased by 55-57% after desipramine. Thus, only 3% of the norepinephrine recaptured by cardiac sympathetic nerves appeared in plasma as DHPG. The remainder was sequestered into storage vesicles (more than 94%) or ultimately formed metabolites other than DHPG (less than 3%). Reuptake of norepinephrine by cardiac sympathetic nerves was 1,188 +/- 476 pmol/min and increased in parallel with cardiac norepinephrine spillover to 4,182 +/- 1,982 and 6,594 +/- 2,241 pmol/min during sympathetic stimulation. CONCLUSIONS: Of the norepinephrine released by cardiac sympathetic nerves, 16-fold more was recaptured than entered plasma. Combined estimation of norepinephrine reuptake and spillover offers an approach to assess the efficiency of neuronal reuptake in disorders of cardiac function.

Animals↗
PubMed1991

Exercise training lowers resting renal but not cardiac sympathetic activity in humans.

Endurance exercise training has previously been shown to reduce the plasma concentration of norepinephrine. Whether reduction in sympathetic activity is responsible for the blood pressure-lowering effects of exercise training is unknown. Using a radiotracer technique, we measured resting total, cardiac, and renal norepinephrine spillover to plasma in eight habitually sedentary healthy normotensive men (aged 36 +/- 3 years, mean +/- SEM) after 1 month of regular exercise and 1 month of sedentary activity, performed in a randomized order. One month of bicycle exercise 3 times/wk (40 minutes at 60-70% maximum work capacity) reduced resting blood pressure by 8/5 mm Hg (p less than 0.01) and increased maximum oxygen consumption by 15% (p less than 0.05). The fall in blood pressure was attributable to a 12.1% increase in total peripheral conductance. Total norepinephrine spillover to plasma was reduced by 24% from a mean of 438.8 ng/min (p less than 0.05). Renal norepinephrine spillover fell by an average of 41% from 169.4 ng/min with bicycle training (p less than 0.05), accounting for the majority (66%) of the fall in total norepinephrine spillover. Renal vascular conductance was increased by 10% (p less than 0.05), but this constituted only 18% of the increase in total peripheral conductance. There was no change in cardiac norepinephrine spillover. The reduction in resting sympathetic activity with regular endurance exercise is largely confined to the kidney. The magnitude of the fall in renal vascular resistance, however, is insufficient to directly account for the blood pressure-lowering effect of exercise, although other effects of inhibition of the renal sympathetic outflow may be important.

Adult↗
PubMed1991

Increased plasma dihydroxyphenylalanine during sympathetic activation in humans is related to increased norepinephrine turnover.

Plasma concentrations of dihydroxyphenylalanine (DOPA) were measured before and during isometric handgrip exercise or mental stress and after coffee drinking or intravenous infusion of desipramine to examine the influence of sympathetic nervous activity on DOPA formation. Sympathetic activity was assessed by the spillover of norepinephrine into plasma. Turnover of norepinephrine was assessed by the plasma concentration of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG). In normal subjects the resting plasma concentration of DOPA was 6.05 +/- 0.16 nmol/L (n = 42). Plasma DOPA level was increased by stimulation of the sympathetic nervous system; handgrip exercise caused a 0.49 +/- 0.07 nmol/L increase (n = 15), mental stress a 0.25 +/- 0.10 nmol/L increase (n = 34), and coffee drinking a 0.85 +/- 0.19 nmol/L increase (n = 9). Desipramine decreased plasma DOPA level by 0.25 +/- 0.06 nmol/L (n = 23). The small but consistent changes in plasma DOPA level during manipulations of sympathetic activity were positively correlated with changes in norepinephrine spillover (r = 0.55, n = 81) and plasma DHPG level (r = 0.66, n = 81). Percentage increases in plasma DOPA level during sympathetic activation were similar to those in plasma DHPG but were a sixth of the percentage increases in norepinephrine spillover. The similar increases in plasma DOPA and DHPG levels indicated that production of DOPA was related to the turnover of norepinephrine in sympathetic nerves. The smaller percentage increases in plasma DOPA (smaller than those in norepinephrine spillover) were consistent with the partial contribution of exocytotic neurotransmitter release to the turnover of norepinephrine in sympathetic nerves.

Adult↗
PubMed1990

Parallel increases in noradrenaline reuptake and release into plasma during activation of the sympathetic nervous system in rabbits.

Rates of noradrenaline reuptake and spillover into plasma were examined in conscious rabbits before and during activation of the sympathetic nervous system to determine whether neuronal reuptake varies disproportionately or in parallel with increases in noradrenaline release. The sympathetic nervous system was stimulated by nitroprusside-induced hypotension, 2-deoxyglucose-induced glucopenia or intravenous infusion of isoprenaline before and after administration of desipramine to block neuronal uptake. Spillover of noradrenaline into plasma was estimated from the dilution of intravenously infused 3H-noradrenaline with endogenous plasma noradrenaline. The amount of dihydroxyphenylglycol (DHPG) in plasma that was derived from metabolism of recaptured noradrenaline, together with the desipramine-induced decreases in clearance from plasma of 3H-noradrenaline and appearance in plasma of 3H-DHPG, were used to estimate the rate of neuronal reuptake of noradrenaline. The mean (+/- SEM) resting noradrenaline reuptake rate (n = 28) was 0.62 +/- 0.04 nmol kg-1 min-1, 5-fold greater than the rate of its spillover into plasma (0.12 +/- 0.02 nmol kg-1 min-1). Intravenous infusion of nitroprusside at 3 rates titrated to cause graded increases in heart rate caused 74%, 129% and 240% increases in noradrenaline spillover into plasma and 66%, 104% and 198% increases in noradrenaline reuptake. At 15-30 min after intravenous injection of 2-deoxyglucose (500 mg/kg) there was a 106% increase in noradrenaline spillover and a 93% increase in noradrenaline reuptake. Infusion of isoprenaline (0.25 micrograms kg-1 min-1) caused a 102% increase in noradrenaline spillover and a 130% increase in noradrenaline reuptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Simultaneous determination of plasma noradrenaline and adrenaline kinetics. Responses to nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia in the rabbit.

Liquid chromatographic fractionation and detection of exogenous radiolabelled and endogenous catechols was used to examine simultaneously the plasma kinetics of noradrenaline and adrenaline in the conscious rabbit. Plasma clearances and release of noradrenaline and adrenaline into plasma were compared before and during nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia, stimuli purported to differentially affect catecholamine release from sympathetic neurons and the adrenal medulla. Plasma concentrations of dihydroxyphenylglycol (DHPG) were also measured to assess presynaptic sympathetic function. Plasma clearances of adrenaline correlated with, but were significantly less than those of noradrenaline. Plasma clearances of both catecholamines showed significant decreases during nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia. Glucopenia and hypotension increased the release into plasma of noradrenaline and adrenaline, but the adrenaline response relative to the noradrenaline response was greater during glucopenia than during hypotension. Plasma DHPG concentrations increased during glucopenia and hypotension, consistent with increased neuronal reuptake of noradrenaline and therefore a neuronal source--as opposed to an adrenal source--of most of the noradrenaline appearing in plasma during the stimuli. The increase in plasma DHPG relative to that of noradrenaline was greater after 2-deoxyglucose than after nitroprusside suggesting that the presynaptic handling of noradrenaline during glucopenia was different from that during hypotension or that the two stimuli released DHPG from regionally distinct sources.

Animals↗
PubMed1990

Time-course of the antihypertensive and autonomic effects of regular endurance exercise in human subjects.

To assess the role of different factors on the long-term antihypertensive effect of regular exercise we examined the time course of changes in haemodynamics, oxygen consumption and plasma noradrenaline in 10 normal healthy subjects. For 12 weeks, subjects performed alternating months of training and detraining in a random order. Training involved 40 min of bicycle exercise three times per week at 60-70% of maximum work. Steady-state changes at the end of 1 month's exercise were: (1) falls in resting blood pressure when supine and erect by 8/5 and 10/6 mmHg, respectively (P less than 0.01); (2) a reduction in the total peripheral resistance index of 14%; (3) an increase in maximum oxygen consumption of 14% (P less than 0.005); and (4) a fall in plasma noradrenaline of 21% (P less than 0.05). A significant fall in blood pressure occurred at the third training bout (P less than 0.005), at the beginning of the second week, and no further reduction occurred beyond the fourth bout of exercise. The reduction in plasma noradrenaline concentration was confined to the second half of the month in which exercise took place and lagged behind the blood pressure changes. There were significant differences between the rates of the initial fall of blood pressure and noradrenaline, and the times taken for the maximum changes to occur (P less than 0.05). During detraining, blood pressure remained low for 1-2 weeks after cessation of exercise, as did plasma noradrenaline. Both then rose gradually towards the initial sedentary levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Altered venous responses to vasoconstrictor agonists and nerve stimulation in human primary hypertension.

The reactivity of human veins, biopsied from the forearms of 15 patients with untreated primary hypertension and 14 normotensive subjects, was studied in vitro. Veins of hypertensive patients were less distensible since the slope of their wall tension-circumference relationships was steeper than in normotensive subjects. There was no difference between the groups with regard to their sensitivity (location of the concentration corresponding to 50% of the maximum response) or their normalized maximum contractile force (Fmax/unit radius) in response to potassium or serotonin. However, veins from hypertensive subjects were less sensitive to noradrenaline and the selective alpha 2-adrenoceptor agonist UK14304, and showed a fall in normalized Fmax with all alpha-adrenoceptor agonists. In contrast, in veins from hypertensive subjects, normalized Fmax was 3.7 times higher in response to angiotensin II than in veins from normotensive subjects. Despite the reduced responses to exogenous alpha-adrenoceptor agonists, contractile responses to transmural field stimulation were enhanced in veins from hypertensive patients. There was no evidence of medial hypertrophy in the veins of hypertensive subjects. The effect of selective alpha 2-adrenoceptor blockade suggested a decrease in prejunctional autoinhibition, while the effect of desipramine on field stimulation and tritiated noradrenaline efflux suggested a decreased neuronal amine uptake in veins of hypertensive subjects. We conclude that veins in hypertension are stiffer, have reduced alpha-adrenoceptor responsiveness, and generate a greater Fmax in response to angiotensin II and nerve stimulation when compared with veins from normotensive subjects.

Adult↗
PubMed1990

Differences in the neuronal removal of circulating epinephrine and norepinephrine.

Neuronal uptake is an important mechanism for the removal of norepinephrine, but its contribution to the removal of epinephrine is unknown. This study compared the neuronal removal of circulating epinephrine and norepinephrine by examination of the cardiac extractions or plasma clearances of [3H]norepinephrine and endogenous or 3H-labeled epinephrine in healthy subjects, patients with cardiovascular disorders, and subjects administered desipramine to block neuronal uptake. In rabbits the plasma clearances of [3H]epinephrine and [3H] norepinephrine by neuronal uptake and the formation of dihydroxyphenylglycol (DHPG) from simultaneously infused [3H] norepinephrine and epinephrine were compared. In normal patients 51 +/- 3% of plasma epinephrine was extracted during one pass through the coronary circulation, significantly less than the cardiac extraction of [3H]norepinephrine (78 +/- 1%). In patients with cardiovascular disorders extractions of epinephrine (34 +/- 3%) remained lower than those of [3H]norepinephrine (63 +/- 2%). After desipramine, cardiac extraction of epinephrine was reduced to 12 +/- 2% and [3H]norepinephrine to 20 +/- 3%. In subjects infused simultaneously with [3H]epinephrine and [3H] norepinephrine, desipramine reduced the cardiac extraction of [3H]epinephrine by 28 +/- 6%, significantly less than the 49 +/- 7% reduction in [3H]epinephrine extraction; the plasma clearance of [3H]epinephrine was reduced by 4 +/- 5%, significantly less than the 20 +/- 6% reduction in [3H]norepinephrine clearance. In rabbits desipramine reduced the plasma clearance of [3H] epinephrine by 18%, significantly less than the 42% reduction in [3H]norepinephrine clearance; production of DHPG from epinephrine was less than half the production of [3H]DHPG from [3H]norepinephrine. The above differences indicated that epinephrine was removed 44-64% less avidly than norepinephrine by uptake into and metabolism within sympathetic neurons.

Animals↗
PubMed1990

Effect of endurance exercise on cardiac secretion and renal clearance of atrial natriuretic peptide in normal humans.

Previous work from our laboratory has shown that (i) regular endurance exercise lowers blood pressure (BP), and (ii) acute exercise increases circulating levels of atrial natriuretic peptide (ANP). We hypothesised that increased ANP release may contribute to the antihypertensive effect of regular exercise. Using arterial and selective venous (coronary sinus and renal vein) catheterization and sampling, we measured cardiac secretion and renal clearance of ANP at rest in 7 normal healthy males (mean age 36 years), before and after 4 weeks of training. Body weight and haematocrit remained unchanged. Systolic BP fell by 10 mmHg with training (p = 0.008), diastolic BP fell by 6 mmHg (p = 0.006) and heart rate decreased by 9 beats/minute (p = 0.002), but central venous pressure remained unchanged. Arterial, coronary sinus and renal vein ANP concentrations did not change with training. There was no significant rise in cardiac secretion of ANP with training (sedentary: 42.6 +/- 13.2 ng/ml, trained: 47.4 +/- 17.9 ng/ml, p n.s.). Renal extraction of ANP was 72 +/- 4% before training, and unchanged (66 +/- 5%) after the exercise period. Renal clearance of ANP was also unaltered by training (514.2 +/- 48.4 ml/min before, and 508.9 +/- 74.8 ml/min after training, p n.s.). We conclude that as ANP release is not increased by training, the peptide does not account for the anti-hypertensive effect of endurance exercise. Other humoral and/or neural mechanisms possibly mediate the beneficial haemodynamic effects of training.

Adult↗
PubMed1990

Circulatory regulation at rest and exercise and the functional assessment of patients with congestive heart failure.

Congestive heart failure occurs when myocardial dysfunction is advanced. Although clinical manifestations and diminished functional capacity can be traced back to the poor cardiac contractile state, there are major modifying influences from a complex series of compensatory responses. These particularly involve the heart, vessels, kidneys, sympathetic nervous system, the renin-angiotensin system, and other hormone systems. Functional capacity is, therefore, determined by the sum of the effects of the original cardiac insult and the effects, beneficial and adverse, of the secondary events. Functional capacity relates closely to prognosis only in the most severely disabled patients. The latter is mainly related to the extent of ventricular dysfunction, and there can be independent contributions from arrhythmias and sympathetic activity. Measures of resting parameters of cardiac contractility, hemodynamics, or neurohumoral responses are, therefore, of no value in predicting functional capacity but can be useful in examining outlook or examining mechanisms of disease and therapy. Exercise measurements are necessary because adequate resting performance can disguise major limitations in cardiac reserve. Measurement of functional capacity can be used to quantify the effects of therapy on daily living and to give an indication of the overall response of the body to major cardiac inadequacy. Limitation of exercise capacity, the earliest symptom of heart failure, can be quantified during a graded exercise test. Measurements of cardiac output and hemodynamic variables during exercise quantify the extent to which the cardiovascular system can increase performance to meet the demands of exercise. Work capacity and maximum oxygen capacity indicate the limits of physical performance, whereas determination of the anaerobic threshold indicates the highest level of exercise at which cardiorespiratory mechanisms are able to provide adequate oxygen supply to maintain aerobic metabolism in working skeletal muscle.

Autonomic Nervous System↗
PubMed1989

Cardiac secretion and renal clearance of atrial natriuretic peptide in normal man: effect of salt restriction.

1. Previous studies of endogenous atrial natriuretic peptide (ANP) in humans have examined changes in plasma levels, rather than regional secretion and clearance of the peptide. Using arterial and selective venous catheterization and sampling, and measurement of regional organ flow, we measured haemodynamics, cardiac secretion of ANP and renal clearance of ANP in six healthy volunteers at rest, on a normal sodium diet. 2. Salt restriction decreases plasma concentrations of ANP. We assessed the contribution of the heart and kidney to this decrease, by measuring cardiac secretion and renal clearance of ANP at the termination of a low salt diet. 3. Twenty-four hour urinary sodium excretion fell on the low salt diet from 163 to 29 mmol/day [standard error of the difference (SED)+/- 14, P less than 0.001]. Body weight decreased on salt restriction from 76.4 to 75.4 kg (SED +/- 0.33, P less than 0.05). Brachial mean arterial pressure fell by 6% (P less than 0.05), but right atrial pressure was unchanged. Renal vein plasma renin activity increased by 56% with sodium restriction (P less than 0.01), whereas arterial ANP concentrations fell by 39% (P less than 0.05). 4. Coronary sinus ANP levels fell from 417 to 268 pg/ml (SED +/- 74, P less than 0.05), whereas renal vein concentrations were unaltered. There was a 47% decrease in cardiac secretion of ANP in the low salt state (P less than 0.05). Net extraction of ANP across the kidney (about two-thirds) and renal clearance of ANP were unchanged on the low salt diet. Thus decreased plasma ANP with sodium restriction is due to reduced cardiac secretion.

Adult↗
PubMed1989

Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.

Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED +/- 3.4, p less than 0.01), associated with an increased cardiac output (5.85-7.73 l/min, SED +/- 0.46, p less than 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED +/- 1.03, p less than 0.05). Resting forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED +/- 6.4, p less than 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/min) was also significantly greater after hydrocortisone, increasing from an average of 14.9 +/- 2.4 R units before treatment to 35.1 +/- 5.5 R units after hydrocortisone (SED +/- 6.0, p less than 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Release of noradrenaline into the cerebrovascular circulation in patients with primary hypertension.

The conventional view is that a 'blood-brain barrier' prevents the passage into the bloodstream of noradrenaline released as a transmitter in the brain. When we tested directly for noradrenaline spillover, sampling via high right and left internal jugular venous catheters in 22 untreated patients with primary hypertension, release of noradrenaline into the cerebrovascular circulation was detected. The concentration of noradrenaline was 14.8% (mean 0.29 nmol/l) higher in right jugular venous than arterial plasma, and 29.8% (mean 0.55 nmol/l) higher in left (both P less than 0.02, Student's paired t-test). Asymmetry in the cerebral venous drainage pattern (right jugular typically largely represents cortical flow, left jugular subcortical flow) and flow rate (usually lower on the left) may underlie the higher venoarterial plasma concentration gradient on the left. Cerebral noradrenaline overflow was calculated from the cerebral plasma flow, the venoarterial noradrenaline plasma concentration gradient across the brain and transcerebral extraction of radiolabelled noradrenaline. Mean cerebral noradrenaline spillover was 220 pmol/min, accounting for 9.1% of total noradrenaline release to plasma (determined by isotope dilution). Since the ganglionic blocker arfonad reduced whole-body noradrenaline spillover (principally derived from sympathetic nerves), but not cerebral spillover, the noradrenaline overflow appears to originate from brain neurones and not cerebrovascular sympathetic nerves. Jugular venous noradrenaline measurements may provide a direct 'window' into noradrenergic brain mechanisms in primary hypertension, with bilateral sampling perhaps allowing differentiation of cortical from subcortical neurotransmitter function.

Blood-Brain Barrier↗
PubMed1988

Norepinephrine spillover to plasma during steady-state supine bicycle exercise. Comparison of patients with congestive heart failure and normal subjects.

This study was performed to determine the relative contributions of plasma norepinephrine clearance and norepinephrine release to the increase in plasma norepinephrine concentration that occurs during exercise and to determine whether the high rates of cardiac norepinephrine release from the heart and kidney in patients with heart failure are associated with diminished reserve for regional sympathetic nervous stimulation. During supine steady-state bicycle exercise at 50% of maximum voluntary exercise capacity, the plasma norepinephrine concentration of six patients with congestive heart failure rose from 385 +/- 88 to 2,200 +/- 497 pg/ml, whereas that of nine normal subjects rose from 208 +/- 21 to 882 +/- 257 pg/ml. The change in plasma concentration in both groups was due to an increase in norepinephrine spillover to plasma without a change in plasma norepinephrine clearance. In patients with heart failure, cardiac spillover increased from 80 +/- 26 to 528 +/- 265 ng/min during exercise, and renal spillover rose from 146 +/- 71 to 418 +/- 69 ng/min. In the normal subjects, cardiac spillover rose from 5 +/- 2 to 73 +/- 23 ng/min, and renal spillover increased from 76 +/- 27 to 275 +/- 106 ng/min. There is no evidence of a reduced reserve for overall or regional sympathetic stimulation in patients with heart failure. Reduced reflex responses in these patients are more likely due to end-organ refractoriness than to inadequate stimulation.

Bicycling↗
PubMed1987

The cardiovascular amplifiers in human primary hypertension and their role in a strategy for detecting the underlying causes.

The present review considers evidence that in chronic hypertension, hypertrophy of the muscles of the resistance vessels and left ventricle (LV) accounts for their intrinsic properties as haemodynamic amplifiers. In spontaneously hypertensive rats (SHR) there is early hypertrophy of both vessels and LV, suggesting that they may initiate hypertension; slow development of alpha-adrenoceptors may contribute to the early preponderance of the LV amplifier. In human hypertension LV hypertrophy occurs in most patients, including a high proportion of mild hypertensives. In Goldblatt one-kidney hypertension the stenosis resistance, which is the initiating cause, accounts for 25% of the rise in blood pressure throughout, with 75% initially due to systemic constrictor action of angiotensin II and later due to the amplifier properties of the hypertrophied heart and vessels. The cardiovascular amplifiers must be important in all chronic hypertension, so that if hypertrophy can be reversed, detection of the initiating mechanism should be easier. Studies in patients indicate that drug therapy can reverse hypertrophy and that subsequent redevelopment of hypertension is markedly slowed. We postulate an intrinsic disturbance of muscle performance in all primary hypertension, which may be triggered through the sympathetic nervous system in some patients and through altered cation transport in others.

Animals↗
PubMed1987

A new approach to the identification of pathogenetic factors and to therapy in human primary hypertension.

In experimental studies on renovascular hypertension, we found that the amplifier properties of the hypertrophied heart and resistance vessels contributed considerably more to the maintenance of the elevated blood pressure (BP) during the chronic phase of the disorder than the basic underlying cause. This must also occur in chronic primary hypertension. Accordingly, we hypothesized that after reversal of hypertrophy by antihypertensive medication, the cause(s) of hypertension should be easier to detect during the redevelopment of hypertension once medication was stopped than in the chronic phase of the disorder. We have studied three groups of patients with moderate/severe hypertension in whom BP was controlled for 1 month; 1 year; 15 months to 5 years. The rate of subsequent redevelopment of hypertension between the series was inversely related to the duration of therapy, which was mostly with beta blockers and diuretics. The differences in the rate of redevelopment of hypertension between series 2 and 3 suggest that, with the drugs used, reversal of vascular hypertrophy is quicker than reversal of left ventricular hypertrophy (LVH). In series 3, we observed an inverse relationship between LV mass and duration of therapy. Redevelopment of hypertension was slowest after obtaining regression of both vascular hypertrophy and LVH. Preliminary findings suggest that sympathetic overactivity is present during the redevelopment phase in the majority of patients. Our findings have suggested a new therapeutic strategy, where the effectiveness of nonpharmacological methods of controlling BP is enhanced by first causing regression of cardiovascular hypertrophy by drug treatment followed by a non-drug phase of maintaining normal BP. We have found moderate regular exercise one of the most effective nonpharmacological antihypertensive methods and have now maintained five patients with moderate hypertension at normal BP for 1 year, following an initial period of drug treatment.

Animals↗