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P Korner

Publications and source records attributed to P Korner.

At least 37 records · Page 2Linked to original sources
PubMed1984

Measurement of total and organ-specific norepinephrine kinetics in humans.

A variety of biochemical tests, most notably measurement of the plasma concentration of norepinephrine, have been used to quantify overall sympathetic nervous system activity in humans. Plasma norepinephrine values provide a fallible index of sympathetic activity in that they are dependent in part on the rate of removal of norepinephrine from plasma. Measurement of the rate of release of norepinephrine to plasma is a better guide to overall sympathetic nervous tone because it avoids this confounding influence of norepinephrine plasma clearance. The overall norepinephrine spillover measurement, however, suffers from one major limitation: the sources of the released norepinephrine are not identified. Recently developed radiotracer techniques allow the estimation of regional sympathetic nervous activity from measurements of the organ-specific norepinephrine spillover rate. We find that the lungs are the main source of norepinephrine release to plasma, with mean pulmonary norepinephrine spillover of 159 ng/min constituting 40% of total norepinephrine release. Pulmonary norepinephrine release exceeded the combined norepinephrine spillover from the heart (3%), kidneys (17%), and hepatomesenteric circulation (8%).

Humans↗
PubMed1984

Redevelopment of essential hypertension after cessation of long term therapy; preliminary findings.

We have previously found that the vascular hypertrophy that accounts for the maintenance of a substantial fraction of the elevation of the total peripheral resistance index (TPRI) in essential hypertension can be almost completely reversed by one years antihypertensive treatment (1). On ceasing treatment, blood pressure returns rapidly to pretreatment values suggesting that the original cause of the hypertension is still present. In the present study, 7 patients stopped a standard regimen for 10 weeks after at least 2 years of normotension. In the first week, standing and lying blood pressure increased related to rise in supine cardiac index and TPRI. Thereafter standing pressures, supine systolic blood pressure and cardiac index (CI) increased further, but supine diastolic blood pressure and TPRI did not alter. Changes in measurements of resting sympathetic activity, plasma volume or renin-angiotensin did not account for these observations. The return of hypertension after stopping effective therapy has some features previously described in borderline hypertension, particularly increasing systolic blood pressure, CI and postural blood pressure responses. Some of the changes may reflect the relative preponderance of cardiac and vascular amplifiers.

Blood Pressure↗
PubMed1984

Total, and organ-specific, noradrenaline plasma kinetics in essential hypertension.

We have developed radiotracer techniques, based on measurement of the rate of spillover of noradrenaline to plasma, to simultaneously estimate total, and organ-specific, sympathetic nervous activity in humans. In 27 unmedicated subjects without renal or liver disease, or cardiac failure, regional noradrenaline spillover rates were as follows: lungs 33% of total noradrenaline release to plasma, kidneys 22%, skeletal muscle 20%, hepatomesenteric 9%, skin 5%, and heart 3%. These findings have relevance to numerous previous studies on the importance of the sympathetic nervous system in the pathogenesis of human essential hypertension. The indices of overall sympathetic nervous tone which have been used, such as measurements of plasma noradrenaline concentration or total NA release to plasma, are seen to be not sufficiently specific, since the organs and regions thought to be central to hypertension pathogenesis (kidney, heart, splanchnic circulation) are responsible for no more than 35% of all noradrenaline released to plasma. Organ-specific noradrenaline spillover measurements are better suited to the elucidation of any sympathetic nervous system pathophysiology in human hypertension. Early results point to an increase in renal sympathetic tone in young patients with essential hypertension.

Humans↗
PubMed1983

Cardioselectivity of prenalterol and isoproterenol.

We examined the hemodynamic effects and kinetics of prenalterol, a new beta-adrenoceptor agonist, in 10 normal subjects. There is some doubt whether prenalterol is selective for beta 1 adrenoceptors in animals; therefore, we also compared its cardioselectivity with that of the nonselective agonist, isoproterenol, with respect to heart rate (HR) and blood pressure (BP) responses after inhibition of cardiovascular reflexes with atropine, clonidine, and phentolamine. After intravenous (2.5 mg) and oral (10 mg and 100 mg) dosing, t 1/2 beta was 2 to 3 hr. Oral bioavailability averaged 33% and was independent of dose. Oral prenalterol, 10 mg and 100 mg, increased resting HR, systolic BP, and cardiac index by up to 27% but had no significant effects during graded exercise. Prenalterol infusions were calculated to attain steady-state plasma concentrations of 10, 20, and 40 ng/ml. HR and BP effects of the levels (10.8, 23.6, and 47.4 ng/ml) were compared with those of 0.5, 1.5, and 2.5 micrograms isoproterenol. Before autonomic block, prenalterol increased HR by 10 bpm at the highest dose and mean arterial pressure (MAP) by 10 mm Hg. In contrast, HR rose and MAP fell after isoproterenol. After block, at the highest doses of prenalterol and isoproterenol, there was an average rise in HR of 42 and 27 bpm; BP was almost maintained after the former but fell by 33 mm Hg after the latter. Prenalterol is an inotropic drug that has the effects of a full cardioselective beta-adrenoceptor agonist. Its inotropic effects are evident at doses that have little effect on HR because of the modifying effect of cardiovascular reflexes. The hemodynamic effects are most obvious at rest when sympathetic tone is low.

Administration, Oral↗
PubMed1982

Biochemical quantification of sympathetic nervous activity in humans using radiotracer methodology: fallibility of plasma noradrenaline measurements.

We have developed radiotracer techniques for studying noradrenaline kinetics, to assess better sympathetic nervous system function in humans. Tritiated l-noradrenaline was infused intravenously (0.35 microCi/m2/min) to plateau plasma concentration. Noradrenaline plasma clearance was calculated from plasma tritiated noradrenaline concentration at steady state, and the rate of spillover of noradrenaline to plasma derived from plasma noradrenaline specific radioactivity. Mean noradrenaline spillover at rest in 34 normal subjects was 0.33 micrograms/m2/min (range 0.17-0.61 micrograms/m2/min). Predictably, noradrenaline spillover was reduced in patients with subnormal sympathetic nervous system activity, 0.16 +/- 0.09 micrograms/m2/min in eight patients with idiopathic peripheral autonomic insufficiency, and 0.11 +/- 0.07 micrograms/m2/min (mean +/- SD) in six patients with essential hypertension treated with clonidine (0.45 mg daily). Noradrenaline line plasma clearance in normal subjects was 1.32 +/- 0.28 L/m2/min. Clearance fell with age, causing the previously described rise in plasma noradrenaline concentration with aging. Unexpected effects of drugs were encountered, for example chronic beta-adrenergic blockade in patients with essential hypertension reduced noradrenaline clearance. Plasma noradrenaline concentration measurements were not in agreement with noradrenaline release rate values, and do not reliably indicate sympathetic nervous system activity, in instances such as these where noradrenaline clearance is abnormal.

Humans↗
PubMed1981

Effect of norepinephrine uptake blockers on norepinephrine kinetics.

We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 +/- 0.22 to 1.08 +/- 0.19 l/m2/min (p less than 0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, 0.27 +/- 0.07 to 0.15 +/- 0.04 micrograms/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half-time of the rapid-removal phase (t1 1/2) = 2.0 +/- 0.4 min and half-time of the second exponential (t2 1/2) = 34 +/- 10 min. The rapid-removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1 1/2 being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1 1/2 value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations.

Adult↗
PubMed1981

Age-dependence of noradrenaline kinetics in normal subjects.

1. The influence of age on the rate of spillover of noradrenaline into plasma, clearance of noradrenaline from plasma, and plasma noradrenaline concentration at rest was studied in 34 healthy subjects aged 20--69 years. 2. The plasma concentration of noradrenaline was dependent on age, values being higher in older subjects. 3. This age-dependence of plasma noradrenaline concentration was due principally to a reduced clearance of noradrenaline from the circulation in older subjects. 4. The rate of spillover of noradrenaline into plasma was little influenced by age. The higher plasma noradrenaline values found in older subjects do not seem to be due to an increase in sympathetic nervous system tone with aging.

Adult↗
PubMed1981

Cardiac beta adrenoceptors and adenylate cyclase in normotensive and renal hypertensive rabbits during changes in autonomic activity.

The effects of hypertrophy and alterations in cardiac autonomic activity on left ventricular (LV) beta adrenoceptors and adenylate cyclase were measured in rabbits. Normotensive and renal hypertensive animals were exposed to three levels of chronic sympathetic activity: (i) "normal" activity; (ii) reduced activity after 2 weeks treatment with guanethidine; (iii) 2 weeks increased sympathetic activity following sino-aortic denervation. In hypertensive animals with "normal" activity LV beta receptor sarcolemma concentration was reduced by 36+ compared with the normotensive subgroup whilst total LV receptor numbers were unaltered. Isoprenaline activated adenylate cyclase was similarly affected whilst other sarcolemma marker enzymes were unaffected. Chronic guanethidine administration to normotensive rabbits increased beta receptor concentration (16%, P less than 0.05), basal and isoprenaline activated meters were unaffected. Sino-aortic denervation did not significantly affect beta receptor concentration in either group. The small changes in beta receptor concentration during alterations in sympathetic activity suggest that only a small proportion of LV beta receptors appear to be innervated. The reduction in sarcolemma beta receptor concentration in hypertensive animals appears to be a specific effect due to hypertrophy of the cardiocyte.

Adenosine Triphosphatases↗
PubMed1980

Determination of noradrenaline uptake, spillover to plasma and plasma concentration in patients with essential hypertension.

1. The rates of entry of noradrenaline to plasma and of removal of noradrenaline from plasma, and plasma noradrenaline concentration, were determined in normal subjects and in patients with essential hypertension. Neuronal uptake of noradrenaline was assessed from the plasma tritiated noradrenaline disappearance curve, after infusion to steady state. 2. Noradrenaline disappearance was biexponential. Rapid removal was dependent on neuronal uptake, being slowed if neuronal noradrenaline uptake was reduced, either by desipramine in normal subjects, or in patients with sympathetic nerve dysfunction (autonomic insufficiency). 3. In 10 of 41 hypertensive patients the t 1 1/2 similarly was prolonged, presumptive evidence of a defect in neuronal noradrenaline uptake. Endogenous noradrenaline escaping uptake after release, and spilling over into plasma, and plasma noradrenaline concentration, were increased in these patients. 4. Defective neuronal uptake of noradrenaline, by exposing adrenoreceptors to high local transmitter concentration, may be important in the pathogenesis of essential hypertension in some patients.

Adult↗
PubMed1980

Norepinephrine kinetics in patients with idiopathic autonomic insufficiency.

The rates of norepinephrine release into plasma and removal from plasma were studied in patients with idiopathic peripheral autonomic insufficiency (sympathetic neuronal dysfunction), as it was thought that plasma norepinephrine concentration alone inadequately quantifies the degree of sympathetic nervous underactivity in this disorder. In four patients with autonomic insufficiency, clearance of norepinephrine from the circulation was slowed, 1.69 +/- 0.44 liters/min, compared with 2.80 +/- 0.73 liters/min in 10 normal subjects (P less than 0.05). As a consequence, despite a 60% lower norepinephrine apparent secretion rate, 0.19 +/- 0.12 microgram/m2 per min vs. 0.54 +/- 0.20 microgram/m2 per min, the plasma norepinephrine concentration was near normal. The plasma concentration of neurotransmitter does not provide a valid index of sympathetic nervous tone in this disorder in which removal of norepinephrine from the circulation is slowed.

Dysautonomia, Familial↗
PubMed1979

Comparison of effectiveness of timolol administered once a day and twice a day in the control of blood pressure in essential hypertension.

The effects of a single dose and of two equally divided doses of timolol were compared in a double-blind trial in 15 patients with essential hypertension. The amount of timolol per day remained constant for each patient, but individual patients received different amounts (from 10 mg to 30 mg/day). Timolol combined with a diuretic produced similar lowering of blood pressure in patients who required 10 mg, 20 mg or 30 mg of timolol per day when given either as one dose or in two equal doses. Plasma concentrations of timolol were high enough to be a major contributing factor to the long duration of the hypotensive response.

Adult↗
PubMedDate not supplied

Adverse effects limit the usefulness of fluvoxamine for the treatment of alcoholism.

Open-label and placebo-controlled trials of fluvoxamine, a selective, serotonergic antidepressant, were conducted as an adjunct to relapse prevention psychotherapy in alcoholics. In the open trial, 16 inpatient alcoholics began a 12-week treatment program, with 10 patients dropping out during the first 4 weeks of treatment. In the controlled trial, 8 of 10 patients on fluvoxamine dropped out during the first 4 weeks of treatment, compared with only 1 of 9 patients on placebo. Baseline patient characteristics did not appear to explain the differential attrition in the controlled trial, although the placebo-treated patients were more alcohol dependent. In both trials, patients on fluvoxamine complained of a variety of adverse effects, which they often identified as the basis for early termination of treatment. These adverse effects appear to limit the usefulness of the medication for the treatment of alcoholism.

Adult↗