Rainer Kolloch

Dopaminergic control of sympathetic tone and blood pressure: evidence in primary hypertension.

SUMMARY Bromocriptine (Br) was used to test the hypothesis that central dopaminergic mechanisms modulate sympathetic nerve tone, and that when dopaminergic control is deficient there may result enhanced noradrenergic activity and elevated blood pressure (BP) in some patients with primary hypertension. Seven hypertensive patients (age 29 ± 3 years) were studied after a single oral dose of Br (2.5-5.0 mg) and after 1 week of treatment with Br (5-15 mg/day). The data were compared to those obtained during respective placebo periods. The Br reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) during supine, sitting, and standing positions and mild mental stress but not during isometric handgrip exercise. Orthostatic hypotension occurred in all patients after the first dose of Br but was present only In one patient after 1 week of treatment. Pretreatment levels of plasma norepinephrine (NE) in supine and standing positions were elevated as compared to previously obtained data of normal controls. After 1 week of Br therapy, plasma NE was reduced 40% to 50% in supine, sitting, and standing positions, and during isometric handgrip exercise (p < 0.05). Plasma NE after a single dose of Br was not different from that found after 1 week of the drug. Excretion rates of urinary NE and normetanephrine (NM) were lower (p < 0.002 and p < 0.005 respectively) during Br as compared to pretreatment values. Sodium excretion tended to be higher and plasma renin activity (PRA) lower after 1 week of Br, but the differences were not significant. Dopaminergic stimulation by Br, probably central in location, reduces sympathetic outflow and thereby might contribute to lowering of BP in primary hypertension. These findings support the hypothesis that reduced central dopaminergic activity may be a factor in the cause and maintenance of primary hypertension.

Raised cerebrospinal fluid norepinephrine in some patients with primary hypertension.

SUMMARY To test whether central neurogenic factors participate in blood pressure elevation in primary hypertension, we studied the concentrations of: norepinephrine, epinephrine and dopamine-beta-hydroxylase (DBH) in cerebrospinal fluid (CSF); and norepinephrine, epinephrine, DBH and plasma renin activity (PRA) in plasma of 22 subjects (seven with primary hypertension, 11 normotensive patients with non-systemic neurological disorders, and four with secondary hypertension). Plasma and CSF norepinephrine (NE) were increased in primary hypertensives compared to normotensives. Cerebrospinal fluid norepinephrine was related to diastolic blood pressure, and systolic blood pressure when normotensive and primary hypertensives were taken together. The CSF norepinephrine of primary hypertensive patients was correlated with natural log PRA. The CSF norepinephrine was correlated inversely with age in primary hypertensive patients but not in the normotensive subjects. The low CSF norepinephrine and epinephrine, despite markedly increased plasma NE and epinephrine, in two patients with pbeochromocytoma, indicate a blood-brain barrier for these neurohormones. The observations support the view that the central sympathetic nervous system is involved in the pathogenesis of primary hypertension, particularly in younger patients.

Increased catecholamine excretion after labetalol therapy: A spurious effect of drug metabolites

Patients with essential hypertension were treated for four weeks with the alpha- and beta-adreno-receptor blocking agent labetalol. Urinary excretion of total catecholamines, metanephrine plus normetanephrine and vanillylmandelic acid was measured with various methods before and during treatment. An unidentified substance interfering with the fluorimetric method for catecholamines and the photometric assay for metanephrines caused falsely high values of those substances. Using appropriate methodology no changes of total catecholamines, metanephrine plus normetanephrine and vanillylmandelic acid excretion were found after labetalol therapy. Our findings are important in preventing errors in the diagnosis of pheochromocytoma as well as in the evaluation of the effects of labetalol on the sympathetic nervous system in man.

A radioenzymatic assay for plasma normetanephrine in man and patients with pheochromocytoma

Abstract We describe a radioenzymatic assay for plasma normetanephrine (NMN) based on the conversion of NMN to radio-labeled metanephrine (MN) by phenylethanolamine-N-methyl-transferase (PNMT, EC 1.1.1.28) and S-adenoslymethionine-methyl 3 H. The method consists on extraction of NMN by weak cation exchange resin column chromatography, enzymatic incubation and separation of radio-labeled MN by thin layer chromatography. This method is sensitive enough to detect 30 pg/ml of plasma NMN. The mean concentration of plasma NMN in nine normal volunteers was 64 ± 30 (mean ± SD) pg/ml. Values were greatly increased to levels of 2,100 to 6,150 pg/ml in three patients with surgically proven pheochromocytoma. This method provides a practical assessment of sympathetic function in man and patients with sympathetic nerve disorders.

Plasma normetanephrine: A biochemical marker of sympathetic nerve function in man

Abstract The concentration of the catecholamines in plasma are regarded by many investigators as biochemical markers of sympathoadrenal activity in man. This study was designed to: 1) assess the relationship of normetanephrine (NMN), the metabolite of norepinephrine (NE) most likely to represent degration of newly synthesized and released “active” norepinephrine, to that of norepinephrine in plasma of normal volunteers and 2) to determine regional variations in plasma normetanephrine concentrations at venous and arterial sites of patients undergoing cardiac catherization. The findings suggest that 1) plasma normetanephrine reflects sympathoadrenal activity and neurotransmitter production at both peripheral neuronal and adrenal medullary sites and 2) there is net removal of normetanephrine by liver and kidney. Plasma normetanephrine should provide assistance in the biochemical assessment of sympathoadrenal tone in man and in patients with various autonomic disorders.

A radioenzymatic assay for free and conjugated normetanephrine and octopamine excretion in man.

A radioenzymatic method for the measurement of free and conjugated normetanephrine (NMN) and octopamine (OCT) is described for human urine. The assay is based on the conversion of NMN or OCT to radiolabeled metanephrine (MN) or synephrine (SYN) by phenylethanolamine-N-methyl transferase (PNMT), using tritium-labeled S-adenosyl-methionine [3H]SAM as methyl donor. Thin-layer chromatographic separation yields an assay of high specificity. The sensitivity of the assay is 5 and 2.5 pg of NMN or OCT, respectively. The normal value of free and conjugated NMN was found to be 23 +/- 13 and 102 +/- 49 ng/mg creatinine. Four patients with pheochromocytoma had highly increased levels of free and conjugated NMN. The urinary excretions of free and total octopamine were 5.7 +/- 2.8 and 34.8 +/- 16.6 ng/mg of creatinine, respectively, in normal patients.

Central Noradrenergic Mechanisms in Hypertension and in Postural Hypotension

Recently, we described evidence implicating the central sympathetic nervous system in the pathogenesis of primary hypertension (1, 2). We have also reviewed reports of enhanced peripheral sympathetic tone in primary hypertension (3). Earlier, Ziegler and his colleagues (4) described low-plasma norepinephrine and a blunted norepinephrine response to postural stress in patients with orthostatic hypotension. When these patients assume an upright posture, they have a hemodynamic state that is, in some respects, opposite to that of some patients with primary hypertension (5). Herein, we report the concentrations of norepinephrine, in both plasma and spinal fluid while supine and in plasma while standing, and the magnitude of changes after standing, in patients with either primary hypertension or postural hypotension and compare them with respective values of normotensive patients.