Biomedical subjects

I T Meredith

Publications and source records attributed to I T Meredith.

66 records · Page 4Linked to original sources

PubMed1991

Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias.

BACKGROUND: Although enhanced efferent cardiac sympathetic nervous activity has been proposed as an important factor in the genesis of ventricular arrhythmias and sudden cardiac death, direct clinical evidence has been lacking. METHODS: We measured the rates of total and cardiac norepinephrine spillover into the plasma, which reflect respectively overall and cardiac sympathetic nervous activity, in 12 patients who had recovered from a spontaneous, sustained episode of ventricular tachycardia or ventricular fibrillation outside the hospital 4 to 48 days earlier. The results were compared with those from three age-matched reference groups without a history of ventricular arrhythmias: 12 patients with coronary artery disease, 6 patients with chest pain but normal coronary arteries, and 12 healthy, normal subjects. RESULTS: The patients who had had ventricular arrhythmias had reduced left ventricular ejection fractions, as compared with the patients with coronary artery disease or chest pain (mean [+/- SE], 46 +/- 3 percent vs. 58 +/- 4 percent and 69 +/- 5 percent, respectively; P less than 0.003). The rates of total norepinephrine spillover into the plasma were similar in the three reference groups, but 80 percent higher in the patients with ventricular arrhythmias (P less than 0.005). The rate of cardiac norepinephrine spillover was 450 percent higher in these patients (176 +/- 39 pmol per minute, as compared with 32 +/- 8 pmol per minute in the normal subjects; P less than 0.001), a disproportionate increase relative to the increase in total spillover, which indicated selective activation of the cardiac sympathetic outflow. This increase in cardiac norepinephrine spillover was probably caused by a reduction in left ventricular function. CONCLUSIONS: These results suggest that in some patients major ventricular arrhythmias are associated with and perhaps caused by sustained and selective cardiac sympathetic activation. We speculate that depressed ventricular function was present before the ventricular arrhythmia occurred, and that this resulted in reflex cardiac sympathetic activation, which in turn contributed to the genesis of the arrhythmia.

Angina Pectoris↗

PubMed1991

Biochemical evidence of sympathetic denervation of the heart in pure autonomic failure.

Primary autonomic failure is a heterogenous group of diseases with evidence for lesions in both the central and peripheral elements of the autonomic nervous system. We determined the extent of peripheral sympathetic dysfunction in six patients with primary autonomic failure without clinical evidence of central nervous system involvement (pure autonomic failure) using biochemical methods for studying regional noradrenaline spillover and removal. The results were compared with those from 14 age-matched normal subjects, seven of whom were studied before and after pharmacological neuronal uptake-blockade with desipramine. Total, cardiac and renal noradrenaline spillover to plasma were 78%, 98% and 66% lower respectively in pure autonomic failure than in normal subjects (p less than 0.001). Total noradrenaline plasma clearance was 20% lower in pure autonomic failure (p less than 0.005) than in normal subjects and similar to the level observed in normal subjects following neuronal noradrenaline uptake-blockade with desipramine, mean transcardiac extraction of tritiated noradrenaline was 74% in normal subjects and 20% in pure autonomic failure, identical to the value post-desipramine in normal subjects. Cardiac spillover of the noradrenaline precursor, dihydroxyphenylanine, and the primary intra-neuronal metabolite dihydroxyphenylglycol, were 78% and 94% lower respectively in pure autonomic failure than in normal subjects (p less than 0.001). These data indicate a marked reduction in the apparent release rate and neuronal uptake of noradrenaline in the hearts of patients with pure autonomic failure, and provide biochemical evidence of almost total postganglionic sympathetic denervation in this condition.

Aged↗

PubMed1991

Neuronal re-uptake of noradrenaline by sympathetic nerves in humans.

1. Plasma concentrations of [3H]dihydroxyphenylglycol, the intraneuronal metabolite of noradrenaline, were examined during intravenous infusion of [3H]noradrenaline in 43 subjects, to assess the nature of its formation. Noradrenaline re-uptake by sympathetic nerves was estimated in 11 subjects from the effects of neuronal uptake blockade with desipramine on noradrenaline clearance and plasma concentrations of [3H]dihydroxyphenylglycol and endogenous dihydroxyphenylglycol. In seven subjects noradrenaline re-uptake and spillover into plasma were examined before and during mental arithmetic or handgrip exercise. 2. During infusion of [3H]noradrenaline, plasma [3H]dihydroxyphenylglycol increased progressively, indicating its formation from previously stored [3H]noradrenaline leaking from vesicles as well as from [3H]noradrenaline metabolism immediately after removal into sympathetic nerves. Thus, to estimate noradrenaline re-uptake, the amount of [3H]dihydroxyphenylglycol derived from [3H]noradrenaline metabolized immediately after removal into the sympathetic axoplasm must be isolated from that derived from [3H]noradrenaline sequestered into vesicles. 3. At rest in the supine position the rate of noradrenaline re-uptake was 474 +/- 122 pmol min-1 kg-1, 9.5-fold higher than the rate of spillover of noradrenaline into plasma (49.6 +/- 6.4 pmol min-1 kg-1). Noradrenaline re-uptake and spillover into plasma were both increased during mental arithmetic and isometric handgrip exercise.

Adult↗

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

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

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↗

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↗

PubMedDate not supplied

Long-term oestrogen therapy is associated with improved endothelium-dependent vasodilation in the forearm resistance circulation of biological males.

1. The aim of the present study was to determine the effects of long-term oestrogen on resistance vessel reactivity in biological males. 2. Recent studies have demonstrated that long-term oestrogen therapy favourably alters the lipid profile and improves vasodilator function in the conduit arteries of biological males. Whether a similar benefit is exerted on the resistance circulation is not known. Therefore, we examined the effects of long-term oestrogen therapy on skeletal muscle resistance vessel function in biological males and the potential mechanisms by which it may exert its effects. 3. Forearm blood flow (FBF) and resistance were compared in 15 male-to-female transsexuals being prescribed oestrogen, with 14 age-matched healthy males, at rest and in response to the endothelium-dependent nitric oxide (NO) vasodilator acetylcholine (ACh), the endothelium-independent but NO-mediated vasodilator sodium nitroprusside (SNP), the endothelium-independent and non-NO-mediated vasodilator verapamil (VER) and the endothelium-independent vasoconstrictor phenylephrine (PE). 4. Basal blood flows were similar in the two groups. However, the male-to-female transsexuals had a significant upward and leftward shift in FBF responses to ACh compared with males, with a 52% increase in FBF responses at the highest dose of ACh used. Forearm blood flow in transsexuals rose from a mean (+/- SEM) baseline level of 3.02 +/- 0.25 to a maximum of 19.5 +/- 2.59 mL/min per 100 mL forearm tissue (compared with 3.24 +/- 0.41 and 9.43 +/- 1.97 mL/min per 100 mL forearm tissue, respectively, in males) with the highest dose of ACh (+2.73 micrograms/min per 100 mL; P < 0.0005). Forearm vascular resistance was also significantly reduced in transsexuals compared with males (P < 0.05). Vasodilator responses to SNP, VER and PE were similar in both groups. 5. There were no differences observed in total cholesterol and low-density lipoprotein-cholesterol levels. However, male-to-female transsexuals had 20% higher high-density lipoprotein-cholesterol levels compared with males (1.57 +/- 0.11 vs 1.26 +/- 0.08 mmol/L, respectively; P < 0.05) and 47% higher triglyceride levels (P < 0.005). Serum testosterone levels (an index of oestrogen therapy) was a predictor of responses to endothelium-dependent vasodilation (rs = -0.50; P < 0.01). 6. Long-term oestrogen therapy enhances endothelium-dependent vasodilation in the skeletal muscle microcirculation of biological males. The effects appear to be selective because endothelium-independent vasodilation and vasoconstriction are not altered.

Acetylcholine↗

PubMedDate not supplied

Effect of anti-oxidant treatment and cholesterol lowering on resting arterial tone, metabolic vasodilation and endothelial function in the human forearm: a randomized, placebo-controlled study.

1. The aim of the present study was to determine whether anti-oxidant therapy with vitamin E and/or cholesterol-lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia. 2. Endothelium-dependent and -independent, nitric oxide (NO)-mediated vasodilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies suggest that vascular function may be improved with anti-oxidant or cholesterol- lowering therapy, although these treatments may be synergistic. 3. We compared FBF at rest, in response to isotonic exercise, the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator sodium nitroprusside (SNP) and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in 26 young, otherwise healthy volunteers (mean (+/-SD) age 29+/-7 years; 14 female, 12 male) with hypercholesterolaemia, before and after 6 months treatment with vitamin E, simvastatin and/or placebo. Treatment was randomized, double-blinded in a 2 x 2 factorial design. Forearm blood flow was measured using venous occlusion plethysmography. 4. Vitamin E therapy increased plasma alpha-tocopherol from 39.5+/-9.6 to 75.7+/-33.8 micromol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9+/-1.7 to 4.9+/-0.8 mmol/L and low- density lipoprotein (LDL) from 4.8+/-1.7 to 3.0+/-0.7 mmol/L (both P < 0.001), although total and LDL-cholesterol also decreased slightly in the placebo group. Vitamin E increased resting FBF from 2.1+/-0.3 to 2.4+/-0.3 mL/100 mL per min (P = 0.04) and decreased resting forearm vascular resistance from 42.1+/-4.2 to 36.1+/-3.4 units (P = 0.01), but the reduction in resting FBF with L-NMMA was not affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin and in the combined vitamin E-simvastatin groups. NG-Monomethyl-L-arginine infusion reduced resting FBF and functional hyperaemia in response to exercise and these responses were not altered by treatment. 5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subjects, these effects may not be via NO-dependent pathways. Metabolic vasodilation and responses to the NO-mediated vasodilators ACh and SNP were not favourably affected by anti-oxidant or cholesterol-lowering therapy, either alone or in combination.

Adult↗

PubMedDate not supplied

Cellular adhesion molecules and cardiovascular disease. Part II. Their association with conventional and emerging risk factors, acute coronary events and cardiovascular risk prediction.

The role of cellular adhesion molecules in the patho-genesis of atherosclerosis has now been clearly demonstrated. Plasma levels of adhesion molecules, which have been shed from the cell surface, have also been associated with the presence of clinical atherosclerotic disease, cardiovascular risk factors and acute coronary syndromes. However, there is little consensus in the literature, including between the large well-designed population studies. This may be explained either by unrecognized confounding factors or, alternatively, by the unpredictable relationship between cell surface expression and activity of cellular adhesion molecules and their shedding into the plasma under different circumstances. Probably for the latter reasons, there is at present little evidence that the measurement of circulating adhesion molecules is likely to offer any additional benefit for individual patients above the assessment of conventional cardiovascular risk factors in the assessment of either the extent of, or future risk from, cardiovascular disease.

Antioxidants↗