O. Kuchel

Hypertension with renal arterial stenosis: Humoral, hemodynamic and histopathologic factors☆

In 46 hypertensive patients with unilateral renal arterial stenosis, peripheral and renal venous plasma renin activity, juxtaglomerular cell count and granularity and systolic pressure gradient across the stenosis were determined. After corrective surgery and a mean postoperative observation period of 4.3 years, 18 patients were completely relieved of hypertension (good responders), 14 had a substantial reduction in arterial pressure (fair responders) and 14 remained hypertensive (poor responders). Analysis of plasma renin activity in both renal veins indicated that a ratio (stenotic/nonstenotic side) greater than 2.0 correctly predicted a favorable surgical result in all cases. Peripheral plasma renin activity was greater than normal in 65 percent of good responders, in 50 percent of fair responders and in one nonresponder. The prognostic accuracy of a pressure gradient greater than 40 mm Hg was 78 percent; no patient with a gradient of less than 40 mm Hg benefited from surgery. An increased juxtaglomerular cell count on the affected side predicted a successful operative result in 88 percent, as did increased granularity in 85 percent of cases. Renal venous renin ratio correlated positively (r =0.738, P less than 0.001) with the pressure gradient across the stenosis. The renal venous plasma renin activity of the affected side also correlated positively (r = 0.771, P less than 0.001) with the absolute count of granular cells in the juxtaglomerular apparatus. Plasma renin activity in both renal veins is the most reliable predictor of operative outcome. The addition of juxtaglomerular cell count or pressure gradient across the stenosis increases prognostic accuracy only slightly. The close mutual correlations between renal venous renin ratio, pressure gradient and juxtaglomerular cell count support the experimental evidence of a causal relation between the hemodynamic effects of the arterial lesion and the humoral and histologic changes observed in hypertension with renal arterial stenosis.

Atrial natriuretic factor is a new neuromodulatory peptide.

In this commentary, we will briefly discuss the potential regulatory role of atrial natriuretic factor in peripheral autonomic nervous system function. The focus will be on atrial natriuretic factors involvement in cardiovascular homeostasis through its peripheral effect on sympathetic nervous activity, which may complement its humoral role. [Kuchel et al. (1987) Life Sci. 40, 1545-1551; Lang et al. (1985) Nature 314, 264-266]. We will attempt to support the hypothesis of its neuromodulatory action on efferent autonomic outflow. Specifically, the role of atrial natriuretic factor in the regulation of the synthesis and release of neurotransmitters and in synaptic transmission at the level of the sympathetic ganglia will be outlined. Its potential usefulness in neurobiological studies will also be indicated.

The adrenal cortex and essential hypertension.

Publisher Summary This chapter presents views and findings concerning various aspects of the relationship of the adrenal cortex to hypertension. It reviews some aspects of the relationship of the adrenal cortex to hypertension: (1) disturbances in aldosterone regulation [plasma concentration, metabolic clearance rate (MCR), binding to a transcortin-like plasma protein fraction, hepatic blood flow, effects of adrenocorticotropin (ACTH) and angiotensin II on metabolic clearance rate and protein binding of aldosterone), (2) some aspects of low renin essential hypertension, (3) 18-hydroxy-11-deoxycorticosterone secretion rate in patients with mild, uncomplicated essential hypertension and its biological activity in dogs, (4) dehydroepiandrosterone, (5) adrenal isorenin, and (6) tonin. The chapter also outlines a few studies that have been done to understand these aspects, along with the methods applied and the patients taken as models for these studies. The chapter presents the overall results of plasma aldosterone concentration, measured in these studies by radioimmunoassay in 69 control subjects, 42 patients with mild, uncomplicated essential hypertension when in a normotensive phase, and 57 patients with stable mild essential hypertension.

A dissociated effect of Amino-Glutethimide on the mineralocorticoid secretion in man

Abstract Amino-Glutethimide (AG) decreases the secretion rates of aldosterone in control subjects. DOC secretory rate changes are less consistent (with an increase in 3 out of 5) and 18-OH DOC increases evidently in all 5 subjects where measured. Urinary sodium excretion increases after AG. With dexamethasone added to AG to suppress the compensatory increase in ACTH, the DOC and 18-OH DOC secretion rates decrease to the initial levels and further sodium diuresis occurs. Similar changes in urinary sodium excretion occurred in two hypertensive patients, but the blood pressure decreasing effect of AG was not consistent. These results indicate that zonal differences in the response of the adrenal cortex to AG probably exist. The zona glomerulosa, producing aldosterone, is more susceptible to the inhibitory action of AG, while other mineralocorticoids from the zona fasciculata (18-OH DOC and, in part, also DOC) increase as a consequence of the compensatory increase in ACTH. The combination of AG and dexamethasone may prove as a useful tool in suppressing the excessive mineralocorticoid secretion.

Atrial natriuretic factor constitutes an intrinsic functional unit within superior cervical ganglia of the rat

The molecular forms of atrial natriuretic factor were studied in the sympathetic ganglia of the rat. The peptide atrial natriuretic factor was also tested for its ability to induce intracellular changes in ganglionic elements. Chromatographic evaluation of extracted ganglionic atrial natriuretic factor revealed the presence of proatrial natriuretic factor together with lower molecular weight peptides. Atrial natriuretic factor induced a maximal six-fold increase of cGMP accumulation within ganglia in vitro, most probably in principal ganglionic cells. Its effect on cGMP was not mediated by acetylcholine or any other neurotransmitter because it persisted after muscarinic receptor blockade and in a calcium-free medium and was not affected by ganglia decentralization. Thus, atrial natriuretic factor appears to be produced by a structural neural component of ganglia (in preganglionic cholinergic neurons or small intensely fluorescent cells?) and has receptors at sites different from its source. It is suggested that atrial natriuretic factor may be locally involved in the process of neurotransmission and may be yet another peptide neurotransmitter and/or neuromodulator.

Effects and pharmacokinetics of bolus injections of atrial natriuretic factor in normal volunteers

The aim of this study was to examine the hemodynamic, renal, and endocrine effects of exogenous human atrial natriuretic factor (ANF), together with its pharmacokinetics, in healthy volunteers. Ten subjects participated in this study, in which the effects of a single bolus dose of ANF and of a matched vehicle injection were compared under a 135 mmol/day sodium intake. Doses of 3, 12.5, and 25 micrograms of ANF were given to 1 subject each, and doses of 50 and 100 micrograms were given to 4 and 3 subjects, respectively. Significantly, hemodynamic changes occurred at the 100 micrograms dose, when mean blood pressure decreased by 15% and heart rate increased reciprocally. Diuresis and natriuresis tended to increase following 50 micrograms but increased significantly and in a prolonged fashion following 100 micrograms of ANF. Atrial natriuretic factor did not cause significant changes in plasma catecholamine, renin activity, and aldosterone levels at any dose, although aldosterone tended to decrease. Plasma arginine-vasopressin concentrations decreased significantly following 100 micrograms. Plasma cyclic GMP levels increased in all subjects and in a dose-dependent fashion. Plasma ANF concentrations peaked 3-5 min following the bolus injection and returned toward baseline values within 10-60 min. Although with doses of less than or equal to 50 micrograms plasma ANF levels increased up to 8 to 50-fold, compared to baseline values, the only significant change was the increase in plasma cyclic GMP levels, perhaps because the effects of ANF were successfully masked by counter-regulatory mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor in sympathetic ganglia of the rat: Dependence on cholinergic innervation

Atrial natriuretic factor is detectable in the peripheral autonomic ganglia of the rat by radioimmunoassay and immunohistochemistry. In the present study, surgical and neurochemical methods were used to evaluate the source of this peptide in sympathetic ganglia. Decentralization of the ganglia and/or central administration of colchicine diminished the atrial natriuretic factor content in para- and prevertebral ganglia. Axotomy did not affect levels of ganglionic atrial natriuretic factor. A messenger ribonucleic acid species hybridizing with rat atrial natriuretic factor complementary deoxyribonucleic acid was not found within the total ribonucleic acid extracted from superior cervical ganglia. These results indicate a direct dependence of ganglionic atrial natriuretic factor on cholinergic innervation.

Effect of prolonged high salt intake on atrial natriuretic factor's kinetics in rats.

Abstract Plasma atrial natriuretic factor (ANF) paradoxically decreases after 5 weeks (but not after 3 weeks) of 8% NaCl intake in normotensive rats. As this phenomenon remains unaccounted for by changes in ANF production, we studied the disappearance of [ 125 I]ANF(99–126) from the circulation as an alternative explanation of plasma ANF decline. Following 5 weeks (but not 3 weeks) of an 8% NaCl diet, plasma concentrations of [ 125 I]ANF were significantly decreased and metabolic clearance rate and volume of distribution were increased compared to control rats fed a 0.8% NaCl diet. By studying [ 125 I]ANF tissue uptake we noted significantly greater peptide uptake after 5 weeks (but not after 3 weeks) of high salt consumption in several tissues. We hypothesize that prolonged (at least 5 weeks) 8% NaCl ingestion increases the density and/or affinity of ANF binding sites. These changes may be responsible for the previously observed decline in plasma ANF concentrations after a prolonged high salt intake.

High salt intake-induced changes in atrial natriuretic factor kinetics are mediated by clearance receptors.

Abstract We have reported a paradoxical plasma atrial natriuretic factor (ANF) decline following prolonged high salt intake that was attributed to an increased tissue uptake of circulating ANF, leading to its augmented distribution volume (Vss) and metabolic clearance rate (MCR) as compared with control rats on a standard diet. To explore this phenomenon further, we evaluated possible chronic salt-loading-induced changes in ANF clearance (C-ANF) receptors, which appear to play a major role in ANF removal from the circulation. We studied changes in plasma [125I]ANF(1–28) and its pharmacokinetics after preoccupation of C-ANF receptors by its specific ligand, C-ANF(4–23), in high-salt-treated rats and their controls. Following C-ANF(4–23) administration, we detected significantly higher circulating [125I]ANF levels throughout the study period (8 min) in high-salt-fed rats compared with the controls (280–470% vs 100–215% increase of basal values, P < 0.05). C-ANF(4–23) infusion caused a significantly greater decrease of the metabolic clearance rate and distribution volume of [125I]ANF in high-salt-fed rats than in control animals (74 ± 6% vs 41 ± 6% and 75 ± 4% vs 50 ± 5% of basal values, respectively; P < 0.05). These data suggest that a prolonged high salt diet may increase the availability of C-ANF receptors and, through this mechanism, may negatively modulate plasma ANF concentrations. C-ANF receptors may thus fulfill a regulatory function on circulating ANF during prolonged salt loading in rats.