Blunted natriuretic responses in normotensive men with positive family histories of hypertension.
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Blood Pressure↗
Biomedical subjects
O Kuchel
Publications and source records attributed to O Kuchel.
Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.
We studied the metabolic pathways of dihydroxyphenylalanine (DOPA) and dopamine as well as the cardiovascular and renal responses to a single administration of DOPA (500 mg orally) in stable essential hypertension. We found that after DOPA, stable hypertensive patients compared with controls showed more blood pressure decrease without reflex tachycardia, had lower creatinine clearance but a higher fractional excretion of sodium, and had lower plasma renin activity at the height of DOPA action. Hypertensive patients also showed increased plasma DOPA, the ratio of plasma DOPA to dopamine, and the sum of plasma DOPA and 3-O-methyl-DOPA, as well as increased urinary 3-O-methyl-DOPA and the plasma and urine dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. Finally, despite an augmented post-DOPA glomerular load of DOPA, the predominant source of urinary dopamine, the excretion rates of dopamine and its metabolites remained comparable in hypertensive patients to those in control subjects. These data suggest that, in stable hypertensive patients, exogenous DOPA is to a lesser degree decarboxylated to dopamine, which is more rapidly metabolized intraneuronally. Contrasting with this finding are the hyperdopaminergic features, such as hypernatriuresis with renin suppression and excessive blood pressure decline in the absence of reflex tachycardia. They may be due to an upregulation of renal, vascular, and brain dopaminergic receptors secondary to a preexisting dopaminergic deficiency in stable essential hypertension.
Administration, Oral↗
Distinct plasma atrial natriuretic factor, renin and aldosterone responses to prolonged high-salt intake in hypertensive and normotensive rats.
Five weeks of high (8%) sodium intake, resulting in a decline of plasma atrial natriuretic factor (ANF) in normotensive Wistar-Kyoto (WKY) and Wistar rats, did not affect plasma ANF in spontaneously hypertensive rats (SHR) which became severely hypertensive. Regardless of salt consumption, SHR presented more pronounced glomerular particulate guanylate cyclase activation after large ANF doses in vitro than normotensive rats. In response to salt loading, plasma renin activity (PRA) and plasma aldosterone unexpectedly increased in SHR, in contrast to their decrease in the normotensive strains. Thus, SHR fail to react to prolonged high-salt intake as do normotensive rats, i.e. by a fall in plasma ANF, PRA and plasma aldosterone, and have higher stimulated glomerular particulate guanylate cyclase activity. Thus, ANF and its target response in SHR, as well as the PRA-plasma aldosterone reaction to prolonged salt loading, are distinct from those in normotensive strains. Since the relatively increased ANF and its target action in SHR appear to be a reactive antihypertensive defense rather than a primary event, systems other than ANF probably play an important role in the high salt-induced accelerated hypertension of SHR.
Aldosterone↗
Dopaminergic abnormalities in borderline essential hypertensive patients.
To explore whether an altered metabolic pathway of dihydroxyphenylalanine (DOPA) may be related to some previously observed dopamine abnormalities in borderline hypertension, we measured basal and DOPA-induced (500 mg orally) changes in blood pressure and pulse rate as well as in three hourly plasma and urine samples. We found that borderline hypertensive patients compared with controls 1) showed a higher baseline urinary excretion of methoxytyramine, a marker of exocytotic dopamine release, with a greater DOPA-induced decrease of systolic blood pressure without reflex tachycardia; 2) had in response to DOPA a blunted plasma DOPA and free dopamine increase but an accentuated plasma dopamine sulfate and urinary DOPAC excretion; and 3) eliminated comparable quantities of dopamine in urine despite a lower rise in the glomerular DOPA load. Furthermore, although DOPA elicited natriuresis in both groups, its effect was greater in borderline hypertensive patients, who lacked the urinary sodium correlation with urinary dopamine excretion seen in control subjects. These data are compatible with increased basal exocytotic dopamine release and accelerated neuronal and renal (extraneuronal) dopamine generation from administered DOPA in borderline hypertension. The DOPA-induced hypernatriuresis exceeding augmented dopamine in borderline hypertensive patients, contrasting with the urinary sodium and dopamine correlation in control subjects, suggests that DOPA induced an additional natriuresis in borderline hypertensive patients by a decrease in renal sympathetic tone because of its central inhibition of sympathetic outflow, which also may account for the absence of reflex tachycardia.
Adult↗
High salt intake-induced changes in atrial natriuretic factor kinetics are mediated by clearance receptors.
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 (Vas) 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 less than 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 less than 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.
Analysis of Variance↗
Effect of atrial natriuretic factor and 8-bromo cyclic guanosine 3':5'-monophosphate on [3H]acetylcholine outflow from myenteric-plexus longitudinal muscle of the guinea pig.
We report that atrial natriuretic factor (ANF) inhibits electrically induced cholinergic twitches of longitudinal muscle in whole intestinal segments and myenteric-plexus longitudinal muscle (MPLM) strips from the guinea pig ileum. To elucidate the possible presynaptic mechanism of ANF's action, we studied spontaneous and stimulation-evoked radiolabeled acetylcholine (ACh) outflow from MPLM after incubation with [3H]choline. We developed a method of mounting and treating MPLM preparations, which allowed us, at the same time, to record isometric contractions and to determine [3H]ACh outflow upon electrical stimulation by a train of three pulses. ANF (5 x 10(-8) M), norepinephrine (2 x 10(-7) M) and 8-bromoguanosine 3':5'-cyclic monophosphate (10(-3) M) in nearly equieffective concentrations caused a similar inhibition of cholinergic twitches. However, ANF had no effect on [3H]ACh outflow, whereas norepinephrine was found to suppress [3H]ACh outflow and 8-bromoguanosine 3':5'-cGMP to enhanced [3H]ACh outflow. ANF (5 x 10(-8) M) caused a 7.0-fold increase of cGMP over control values, predominantly in muscle layers, whereas Escherichia coli heat-stable toxin (12.5 U/ml) elicited a 35-fold increment of cGMP in the extramuscular layer. Thus, ANF is able to elevate cGMP in intestinal smooth muscle and to inhibit cholinergic contractions of MPLM. This inhibition is mimicked by exogenous cGMP and by endogenously generated cyclic nucleotides. We suggest that the depressive action of ANF on cholinergic contractions of MPLM is mediated via its postsynaptic impact implicating elevation of cGMP in smooth muscle.
1-Methyl-3-isobutylxanthine↗
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 factor's 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.
Animals↗
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.
Animals↗
Atrial natriuretic peptide content in rat superior cervical ganglion after denervation and axotomy.
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Animals↗
Dissociation between right atrial pressure and plasma atrial natriuretic factor following prolonged high salt intake.
The influence of prolonged high salt intake on intravascular volume, right atrial pressure, plasma atrial natriuretic factor, and extra-atrial tissue (lung, kidney, and liver) COOH- and NH2-terminal atrial natriuretic factor content was investigated in normotensive rats. Despite prolonged high salt (8% NaCl) intake for 5 weeks, total intravascular volume was not impaired. However, right atrial pressure was increased by 54% (p less than 0.01) after salt loading. Although this increment in right atrial pressure should favor atrial natriuretic factor release after NaCl intake, plasma atrial natriuretic factor (COOH-terminal) concentrations markedly decreased from 97.8 +/- 27 to 38.9 +/- 8 pg/mL. Sodium and circulatory homeostasis was, however, well preserved. The lungs contained the highest levels of COOH- and NH2-terminal atrial natriuretic factor. Salt loading resulted in increased concentrations of low as well as high molecular weight atrial natriuretic factor in the lung but not in the kidney or the liver. Our study indicates a limited role of atrial natriuretic factor in adaptation to prolonged salt consumption in rats. Dissociation between right atrial pressure and plasma atrial natriuretic factor after salt intake implicates other factors regulating circulating peptide levels. Prolonged salt intake increases lung generation of atrial natriuretic factor.
Animals↗
ANF disappearance and tissue distribution in rats.
The disappearance of [125I]atrial natriuretic factor (ANF; Ser99-Tyr126) from the circulation and its tissue distribution with or without nonlabeled ANF pretreatment were investigated in normotensive Sprague-Dawley rats. Preadministration of the cold peptide increased plasma radioactivity levels for over 8 min following labeled ANF injection but did not change the half-life of circulating labeled ANF. The metabolic clearance rate (MCR) and volume of distribution in the first, second, and steady state phase were significantly decreased after cold ANF pretreatment. Circulating iodo-labeled ANF was taken up by several organs, even by tissues such as fat or bone, but its urinary excretion was very low. The highest uptake was found in the liver (16 +/- 1% of the injected dose), lung (14 +/- 1%), and kidney (12 +/- 1%), diminishing by 21, 89, and 59%, respectively, after cold ANF preinjection. The brain radioactivity was negligible implying an inability of [125I]ANF to cross the blood-brain barrier. Our data underscore the importance of the uptake-mediated, cold ANF preadministration suppressible clearance of ANF from the circulation, probably one of its basic elimination mechanisms. The liver, lung, and kidney are probably the most important participants in the MCR of ANF.
Animals↗
Effect of prolonged high salt diet on atrial natriuretic factor in rats.
Normotensive Sprague-Dawley rats were given 8% NaCl for 5 weeks. This salt load did not affect their blood pressure nor hematocrit, and plasma atrial natriuretic factor (ANF) showed no change at 3 weeks but decreased after 5 weeks of the experimental period when compared with control rats. The responsiveness of particulate guanylate cyclase and formation of cGMP in ANF target organs suggested an augmented baseline activity of the cGMP system but its relative hyporesponsiveness to exogenous ANF following prolonged salt loading. Decreased plasma ANF levels cannot be explained by its altered production since atrial levels of the peptide were comparable in rats with or without salt loading. Atrial ANF mRNA was unaffected by the salt regimen. This study demonstrates that plasma ANF does not increase during long-term NaCl loading and even decreases after 5 weeks of 8% NaCl. The changes in plasma ANF are associated with changes in the functional state of ANF receptors coupled to particulate guanylate cyclase, but in the opposite direction than expected from lowered plasma ANF. Thus, ANF may not play a significant role in the regulation of sodium excretion in response to prolonged high salt consumption or, if it does, it is not reflected by expected changes in its plasma levels.
Adrenal Cortex↗
Alternative catecholamine pathways after tyrosine hydroxylase inhibition in malignant pheochromocytoma.
A suppression of norepinephrine, epinephrine, and its metabolites in malignant pheochromocytoma by metyrosine was associated with an increase in tyrosine, plasma DOPA, and sulfate esters of DOPA and dopamine, followed, with continuing metyrosine administration, by a further rise of both DOPA sulfate and dopamine sulfate. Urinary dopamine progressively increased in the course of metyrosine treatment, and this, along with the increase of the dopamine metabolite, dihydroxyphenylethanol, and plasma dopamine sulfate, occurred in the absence of any change in plasma dopamine. The octopamine metabolite para-hydroxyphenylglycol, which was initially elevated at least 10-fold, also increased after metyrosine treatment. The unexpected increase of DOPA (progressively more converted toward DOPA sulfate) in the presence of tyrosine hydroxylase inhibition and increase in tyrosine may result from channeling the excess tyrosine toward DOPA and melanin through tyrosinase. Increases in plasma dopamine sulfate and urinary dopamine suggest that dopamine sulfate may be generated via DOPA sulfate and urinary dopamine may originate from circulating DOPA. Tyrosine hydroxylase inhibition may thus result in DOPA generation in non-catecholamine-producing tissues by an alternative pathway. The resulting progressive increase in DOPA and its sulfate may lead to increased urinary dopamine. DOPA sulfate may be an alternative source of dopamine sulfate.
Adrenal Gland Neoplasms↗
Peripheral dopamine in essential hypertension. An early defense against hypertension failing during its progression?
Measurements of dopamine (DA) and its metabolites in plasma (DA sulfate) and urine (homovanillic acid) as well as its urinary response to furosemide revealed two distinct patterns: a hyperdopaminergic state in borderline essential hypertension (EH) and a renal DA deficiency in stable EH. Long-term follow-up demonstrated that despite treatment, approximately 20% of borderline hypertensive patients became stable hypertensive within 12 years. Preliminary data on reinvestigation of these patients indicated that their dopaminergic indices also changed from those typical of borderline hypertension to those characteristic of stable hypertension, a finding compatible with the hypothesis that the hyperdopaminergic patterns in borderline hypertension represent an early antihypertensive defense response which progressively fails in patients who go on to develop stable hypertension.
Aging↗
Inhibitory action of atrial natriuretic factor on cholinergic and nonadrenergic, noncholinergic neurotransmission in guinea pig small intestine.
We studied the effect of synthetic rat atrial natriuretic factor (ANF) (Ser 99-Tyr 126) on the isolated guinea pig proximal ileum. This preparation contained about one-third of the endogenous tissue ANF content which, for the most part, comes from the blood. ANF inhibited, in a dose-dependent manner, cholinergic twitch contractions (EC50 = 4.2 nM), nonadrenergic, noncholinergic (NANC) primary and rebound contractions and histamine-induced sustained tonic contraction (but not carbachol induced contraction) of the longitudinal muscle. Ascending enteric reflex (AER) contractions of the circular muscle were inhibited though not dose-dependently. We suggest pre- and post-synaptic actions of sustained intestinal tissue and blood ANF levels which may play a role in regulating motor activity and muscle tone of the small intestine.
Animals↗
The heterogeneity of dopamine involvement in essential hypertension.
Compared to control subjects, patients with essential hypertension (EH) had a decreased urinary DA:NE ratio and an overall increase in the total (free + sulfated) plasma sum of NE, E and DA. With age-matching, this elevation was found to be due to augmented levels of DA sulfate. When subdivided into borderline (labile) and stable EH groups, only the borderline EH patients had heightened plasma DA sulfate levels, enhanced urinary homovanillic acid excretion and tended to have plasma NE and PRA increases. Patients with stable EH had a hyporesponsive urinary DA and Na+ excretion as well as reduced PRA levels at the height of furosemide-induced natriuresis. These data are compatible with a hyperdopaminergic component of the hyperadrenergic state, more or less affecting patients with borderline EH in contrast to the hypodopaminergic features of subjects evolving into stable EH in whom the neurogenic component subsides. In both EH subgroups, urinary DA lagged behind NE excretion. Dopaminergic tone may indirectly affect endogenous DA-modulated renal, adrenal and vascular synaptic processes as well as their responses to exogenous Angiotensin II and DA, respectively.
Blood Pressure↗
Cardiovascular, renal and endocrine responses to low doses of atrial natriuretic factor in mild essential hypertension.
The purpose of this study was to evaluate the cardiovascular, renal and endocrine effects of human atrial natriuretic factor (ANF), infused at a rate of 0.8 microgram/min (about 4 pmol/kg/min) for three hours in normal subjects and patients with essential hypertension. This infusion rate was chosen to obtain a range of plasma ANF levels which can be generated by physiological manoeuvres and to reduce the likelihood of hypotension. Five patients and six healthy volunteers participated in the study. The infusion had to be prematurely discontinued in one patient and in one control because of hypotension with relative bradycardia. Blood pressure otherwise remained unchanged during infusion whereas heart rate rose transiently. Plasma ANF levels increased similarly during infusion from 8.9 +/- 2.6 to 23.9 +/- 6.4 pmol/l in patients and from 3.7 +/- 0.7 to 25.4 +/- 6.9 pmol/l in the controls, remained stable during the infusion, and decreased similarly in both groups after the infusion, with a half-life of 7 min. Plasma guanosine cyclic phosphate (cGMP) was augmented by about four-fold in both groups. In both groups, plasma aldosterone levels fell whereas plasma noradrenaline increased. The diuretic effect of ANF was similar in both controls and patients (1354 +/- 161 vs 1542 +/- 116 ml/3 hrs respectively), whereas its natriuretic effect was exaggerated in hypertensive patients (90 +/- 11 vs 62 +/- 9 mmol/3 hrs, P less than 0.05). In conclusion, this low infusion rate of ANF produced similar changes in plasma ANF, cGMP, aldosterone and noradrenaline levels but patients with mild essential hypertension demonstrated an exaggerated diuretic and natriuretic response to ANF infusion.
Adult↗