Otto Kuchel

Gluco- and mineralocorticoids may regulate the natriuretic effect and the synthesis and release of atrial natriuretic factor by the rat atria in vivo

Adrenalectomy abolished the acute natriuretic effect of ANF which was partially restored to about 50% by combined therapy with gluco- and mineralocorticoids. It is suggested that the lack of effect of ANF may be due to a decreased renal vascular reactivity to the peptide in adrenalectomized animals. Simultaneous administration of Dexamethasone and Deoxycorticosterone acetate to adrenalectomized rats produced a marked increase in immunoreactive ANF in atrial tissue and plasma. The administration of NaCl to these animals produced a relatively lower concentration of atrial ANF and a further increase in plasma ANF. Our results suggest that glucocorticoids may regulate synthesis and release of ANF by the atria and mineralocorticoids may have a permissive role. Furthermore, the presence of steroids is necessary for the NaCl-stimulated ANF release.

ANF-like peptide(s) in the peripheral autonomic nervous system.

The recent demonstration of the atrial natriuretic factor (ANF) within the brain has been extended in the present study by the additional localization of ANF-like activity in the peripheral nervous structures. Using a sensitive radioimmunoassay, it was possible to detect ANF-like immunoreactive peptide(s) in crude and chromatographically separated extracts of parasympathetic rat ganglia. The partially purified ANF-like peptide exhibited a biological action similar to cardiac ANF. This finding supports a possible involvement of ANF in the regulation of both, central and peripheral neuronal activities.

Peripheral dopamine synthesis and metabolism in spontaneously hypertensive rats.

We have studied several parameters of peripheral dopamine synthesis and metabolism in spontaneously hypertensive rats during the development of hypertension. Compared to Wistar-Kyoto rats, there was an increased dopamine content in 8-week-old spontaneously hypertensive rats in the adrenals (1.6 +/- 0.1 vs. 1.2 +/- 0.1 nmol/pair in Wistar-Kyoto rats) and kidneys (97 +/- 12 vs. 63 +/- 7 pmol/g tissue in Wistar-Kyoto rats), but the dopamine content in peripheral organs from normotensive 4-week-old spontaneously hypertensive rats did not differ from Wistar-Kyoto rats. In the heart, the dopamine increase was observed in 14-week-old spontaneously hypertensive rats (systolic blood pressure: spontaneously hypertensive rats, 189 +/- 9; Wistar-Kyoto rats, 106 +/- 2 mm Hg;) in both atrium (spontaneously hypertensive rats, 133 +/- 14; Wistar-Kyoto rats, 86 +/- 20 pmol/g tissue) and ventricle (spontaneously hypertensive rats, 41 +/- 6; Wistar-Kyoto rats, 23 +/- 5 pmol/g tissue). Urinary free dopamine and dihydroxyphenylacetic acid, but not norepinephrine or normetanephrine, in spontaneously hypertensive rats significantly increased between the ages of 7 and 11 weeks, reflecting the dopamine changes in tissue and suggesting a selective increase of the rate of dopamine synthesis and release.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic Nervous System and Benign Essential Hypertension in Man

The clinical entity of benign essential hypertension is often subdivided into labile essential hypertension and stable essential hypertension. To establish less arbitrary limits between normotension and labile and stable benign essential hypertension, 70 subjects (56 with benign essential hypertension) were classified according to (a) the usual blood pressure index for each subject and (b) the upper limit of variation of the usual blood pressure indexes of a normotensive population. Catecholamines, plasma renin activity, and urinary creatinine, sodium, and potassium were measured in recumbent subjects who had received a controlled-sodium diet. Our findings suggest that (1) benign essential hypertension represents a heterogeneous entity and a continuous spectrum of clinical and biochemical changes when it is related to the level of blood pressure, (2) adrenergic involvement is more evident in labile hypertension, (3) regardless of the urinary excretion of catecholamines in subjects with benign essential hypertension the urinary ratio of dopamine to norepinephrine always remains lower, and (4) a negative correlation exists between urinary sodium excretion and usual blood pressure indexes.

Peripheral dopamine in pathophysiology of hypertension. Interaction with aging and lifestyle.

Dopamine, an ancestral catecholamine, is physiologically natriuretic and vasodilating, thus essentially protecting against hypertension. Its actions are overshadowed by the opposite effects of its main biological partner, norepinephrine, and this is accentuated with aging. Clinical observations combined with molecular biology approaches to catecholamine-synthesizing and catecholamine-metabolizing enzymes and receptors permit the identification of some inborn defects. Subtle changes in the dopamine-norepinephrine balance may account for the enhanced peripheral noradrenergic activity seen in the setting of decreased dopaminergic activity in advanced age. These changes may contribute to the diminished ability of the aged kidney to excrete a salt load, as well as to the finding that systolic blood pressure increases with age in populations with a high, but not in those with a low, intake of salt. The attainment of advanced age in Western societies with adverse lifestyle changes (mental rather than physical stress, excess salt intake, overeating, sedentarism) appears to facilitate the development of hypertension. The adaptation to all the preceding lifestyle changes necessitates an increased dopamine generation, which may initially compensate to maintain appropriate natriuresis and vasodilation since many patients with initial borderline essential hypertension express their sympathetic hyperfunction, in addition to increased norepinephrine release, by excessive dopamine release. However, the progression of hypertension is accompanied by a peripheral dopaminergic deficiency and diminished ability to excrete salt. This may represent an eventual inadequacy of a phylogenetically redundant system resulting in decreased natriuresis and vasodilation and may account for the responsiveness of established chronic hypertension to salt restriction, diuretics, and dopaminomimetic medication.

Presence of Conjugated Catecholamines in Rat Brain: A New Method of Analysis of Catecholamine Sulfates

Abstract: A new method of measuring catecholamine (CA) sulfate permitted us to detect its presence in rat brain for the first time. The procedure consisted of separating the CA sulfate from the free CA by alumina adsorption followed by passage through Dowex, and measuring the CA sulfate by a radioenzymatic assay in the presence of a sulfatase. This method permitted demonstration of the presence of dopamine sulfate, and occasionally, of norepinephrine and epinephrine sulfate in the hypothalamus, striatum, and hippocampus of rat brain.

The direct conversion of dopamine 3-0-sulfate to norepinephrine by dopamine-β-hydroxylase

Abstract Dopamine 3-0-sulfate is present in considerable amounts in mammalian plasma and peripheral tissues. Incubation of dopamine 3-0-sulfate (0.1 μmole) with purified bovine dopamine-β-hydroxylase resulted in the formation of free norepinephrine (7.3 × 10−3 μmole). The conversion to norepinephrine was inhibited by 0.6 mM of fusaric acid, an inhibitor of dopamine-β-hydroxylase. The reaction of dopamine 3-0-sulfate with dopamine-β-hydroxylase followed Michaelis-Menten kinetics. The calculated Km was 17 mM, different from the Km for free dopamine (0.1 mM). The incubation medium does not contain any sulfatase activity.

Effects of angiotensin II on steroid metabolism and hepatic blood flow in man.

SUMMARY Metabolic clearance rates (MCR) of aldosterone, cortisol, 11-deoxycorticosterone (DOC), corticosterone, and progesterone were simultaneously measured by constant infusion in eight control subjects before and during angiotensin II infusion in subpressor (3 ng/min per kg) and pressor (22 ng/min per kg) doses. Plasma levels of aldosterone and cortisol, the heat-labile protein-bound fraction of aldosterone, and hepatic blood flow (HBF) (as estimated by the fractional clearance of indocyanine green) were determined concomitantly. Angiotensin II in a subpressor dose produced a significant decrease of the MCR of aldosterone (by 23%), cortisol (by 16%), DOC (by 26%), corticosterone (by 14%) and progesterone (by 33%). The pressor dose further decreased the respective MCR by 37%, 21%, 40%, 28%, and 42% of the baseline value. Plasma aldosterone levels rose by 317% with subpressor and by 434% with pressor doses. HBF decreased by 18% with subpressor and by 33% with pressor doses of angiotensin II. Furthermore, there were significant negative correlations between the MCR of each steroid and the respective values of the fractional clearance of indocyanine green. We conclude that angiotensin II, by its vasoconstrictive action on the splanchnic vascular bed, decreases the MCR of aldosterone, cortisol, DOC, corticosterone, and progesterone. This decrease has to be taken into account when considering the stimulatory effect of angiotensin II on various plasma steroid concentrations.

Effects of atrial natriuretic factor on natriuresis and cGMP in patients with essential hypertension

Human atrial natriuretic factor (h-ANF) or its vehicle only, were infused at rates of 0.8, 1.6 and 3.2 μg/min over three successive 30-min periods, into five patients with mild essential hypertension and seven normotensive controls. Baseline (mean ± s.e.m.) plasma ANF levels were 13 ± 2 in patients and 8 ± 1 pg/ml in controls. During the first period, plasma ANF and cyclic guanosine monophosphate (cGMP) levels increased in both groups without significant alteration of blood pressure, heart rate, diuresis, natriuresis or cGMP excretion rate. During the second period of infusion, plasma ANF levels increased up to 179 ± 39 and 177 ± 30 pg/ml in patients and controls and plasma cGMP concentrations increased x 5.0 and x 4.9, respectively; natriuresis increased x 2.4 in patients and x 3.1 in controls while urinary cGMP increased x 10.9 in patients and x 10.5 in controls. During the last period, three controls became hypotensive while blood pressure remained stable in the other controls and in the patients with essential hypertension. During this period, the increases in plasma ANF concentration, diuresis, natriuresis and urinary cGMP excretion were similar in both groups. However, the mean plasma cGMP concentration after 90 min infusion was significantly higher in hypertensive patients than in control subjects (30.7 ± 3.3 versus 15.6 ± 3.4 pmol/ml, P < 0.05). The haif-life and clearance of plasma ANF, upon discontinuation of the infusion, were similar in both groups. Our data suggest that patients with mild essential hypertension have enhanced increases in plasma cGMP but normal increases in diuresis, natriuresis and cGMP excretion following infusion of h-ANF at pharmacological rates.

Inappropriate Response to Upright Posture: A Precipitating Factor in the Pathogenesis of Idiopathic Edema

Abstract The patterns of postural adaptation in 21 women suffering from idiopathic edema with elevated aldosterone excretion are compared with those in 21 healthy women. In the period free of edema...