Cyclic GMP in cell function.
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3',5'-Cyclic-GMP Phosphodiesterases↗
Biomedical subjects
P Hamet
Publications and source records attributed to P Hamet.
Plasma atrial natriuretic factor concentrations in essential and renovascular hypertension.
Plasma atrial natriuretic factor concentrations were measured in 44 patients with mild untreated essential hypertension and 48 normotensive controls. Mean venous plasma atrial natriuretic factor concentrations were 13.2 (SEM 1.5) and 13.0 (1.3) ng/l in the hypertensive patients and controls, respectively. Plasma atrial natriuretic factor concentrations were significantly correlated with age in both groups. Plasma atrial natriuretic factor concentrations were also measured during renal vein catheterisation in a group of 15 hypertensive patients; of these, eight had renovascular hypertension, and in all eight cases plasma atrial natriuretic factor concentrations were increased in the aorta and inferior vena cava. It is concluded that mild essential hypertension is not associated with increased plasma atrial natriuretic factor concentrations, whereas an age related increase in concentrations occurs in hypertensive and normotensive people.
Adult↗
The whole heart is an endocrine gland.
The relative contribution of atria and ventricles in the release of immunoreactive (IR-) atrial natriuretic factor (ANF) and in the eventual circulating levels of the peptide was evaluated in several situations. In situ, not only atrial but also ventricular cardiocytes contain IR-ANF although the amount present in ventricles is very low, particularly in the adult rat. In cardiomyopathic hamsters with heart failure, the amount of IR-ANF decreases constantly in the atria and increases in parallel in the ventricles so that the ratio of IR-ANF which is 114:1 in control animals becomes 3.9:1 in hamsters with severe heart failure. With the Langendorff preparation, the whole heart secretes much more IR-ANF than the isolated ventricles. From the latter, IR-ANF may originate from subendocardial cells of the conduction system and, more likely, from all ventricular cardiocytes where the peptide may be secreted by two pathways: one constitutive, the other regulated. These results are in agreement with clinical studies where circulating IR-ANF was measured in the same patients following catheterization of coronary sinus and great cardiac vein (draining the left ventricle). In this situation, it was found that while the levels of IR-ANF in the great cardiac vein are higher than in the general circulation, they are much lower than in the coronary sinus. All these results tend to indicate that IR-ANF is secreted by ventricular cardiocytes in relatively low amounts even in periods of intense stimulation.
Animals↗
Cardiac and renal hyperplasia in newborn spontaneously hypertensive rats.
Cardiac hyperplasia in newborn spontaneously hypertensive rats (SHR) has been noted by our group as well as by other investigators. The present study was designed to establish whether early (neonatal) hyperplasia is confined to the heart or is a generalized phenomenon in this hypertensive model. The ventricles, kidney and liver of newborn SHR, Wistar and Wistar-Kyoto (WKY) rats were analysed for their protein and DNA content. Total organ weight and the organ/body weight ratio of the heart and kidney but not of the liver were significantly greater in the SHR than in the control rats, irrespective of total body weight. The higher relative DNA content (per 100 mg of tissue or 100 g body weight) indicated that hyperplasia rather than hypertrophy was responsible for the enlarged heart as well as the kidney of newborn SHR. The cause of this selective cardiac and renal hyperplasia is not yet known: it may be due to putative 'haemodynamic growth stimuli', an intrinsic genetic abnormality of cells in the heart and kidney, circulating growth-promoting factors, or innervation.
Animals↗
Therapeutic modulation of growth-promoting activity in platelets from diabetics.
Proliferation of vascular smooth muscle is thought to be involved in the major diabetic complication atherosclerosis. We have previously reported an increase of growth-promoting activity (GA) in platelets from insulin-dependent diabetics. In this study, GA was measured in the platelet extract (PE) from eight diabetic patients who had been treated by conventional insulin therapy. Vascular smooth muscle cells from rat aorta were cultured and used as an assay system for GA. Incorporation of [3H]thymidine into DNA of cultured cells was stimulated by diabetic PE significantly more (P less than .05) than by normal PE. Diabetic PE incubated with cells for 4 days increased cell numbers significantly more (P less than .05) than normal PE. These abnormalities were corrected by long-term intensive insulin treatments (continuous subcutaneous insulin infusion and Pen infuser). The decrease of platelet extract GA appeared to correlate with the amount of insulin administered before meals as short-acting boluses, whereas the level of basal or long-acting insulin appeared to correlate with an increase of PE GA. Thus, the growth-promoting potential of platelets can be normalized by intensive insulin therapy. The relationship of insulin levels to this activity needs further evaluation.
Adult↗
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 micrograms/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 less than 0.05). The half-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.
Adult↗
Cushing syndrome with food-dependent periodic hormonogenesis.
Periodic hormonogenesis has been described in patients with ACTH-dependent hypercorticism, and fluctuations of cortisol secretion have also been observed in patients with adrenal tumors. In this report, we studied a 41-year-old white male who presented with hypertension, central obesity, and muscle weakness of 2-years duration. His plasma cortisol was low (4.5 micrograms) in the morning and high in the evening (29.3 micrograms). Urinary free cortisol was 750 micrograms/day. A 24-hour cycle demonstrated highest values at noon and in late afternoon. This pattern was not suppressed by dexamethasone. When the patient was kept fasting, plasma cortisol remained low all day, and became elevated immediately after meal administration overnight. A left-sided adrenal mass was demonstrated and removed. In vitro, the adenylate cyclase activity of tumor tissue demonstrated more significant response to vasopressin than to ACTH; other tested peptides were inactive. We propose that a humoral factor induced by eating was responsible for the periodic hormonogenesis, directly stimulating the adrenal secretion of cortisol.
17-Ketosteroids↗
[Physiological and physiopathological aspects of the atrial natriuretic factor].
The discovery of the atrial natriuretic factor (ANF) has opened a new field in modern biology. After rapid isolation and identification of this new peptide from atrial granules, it is now evident that this new hormone has a wide variety of actions with general implication in the control of vascular tone, sodium and water balance, hormonal secretion as well as neuronal functions. The major mode of action of this hormone is transmitted via its interaction with a membrane enzyme, particulate guanylate cyclase, leading to increases of cGMP levels. This nucleotide is a faithful marker of ANF action correlating with all functions ascribed to ANF up to date. Significant increases of ANF as well as of cGMP have been discovered in heart and renal failure, secondary hypertension and other states with altered salt-water balance, impairment of heart function and particularly increase of atrial pressure. The increases of levels and relative inefficiency of increased ANF have to be carefully interpreted in face of increased levels of cGMP. It can be expected that new pharmacological developments will occur in this area issuing from both our increasing knowledge concerning the peripheral mode of action of this hormone, its physiological implications as well as its pharmacological effectiveness in diseases with altered salt-water balance, cardiac function and blood pressure disregulation.
Atrial Natriuretic Factor↗
The atrial natriuretic factor in mild essential hypertension.
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Atrial Natriuretic Factor↗
Circulating forms and radioimmunoassay of atrial natriuretic factor.
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Animals↗
Atrial natriuretic factor (ANF) in experimental and human hypertension.
The plasma levels of immunoreactive (IR)-ANF have been evaluated by radioimmunoassay in several models of experimental hypertension and in human hypertension. In all models of experimental hypertension so far studied, the plasma levels of IR-ANF are consistently increased. This is accompanied by a decrease, at certain time intervals, of the IR-ANF levels in the left atrium. In human essential hypertension, the plasma levels of IR-ANF are not increased except in the severe form (diastolic blood pressure above 110 mmHg). In renovascular hypertension, the peripheral levels of IR-ANF are not different from the normal levels but are increased above normal in aortic blood.
Animals↗
ANF stimulation of detergent-dispersed particulate guanylate cyclase from bovine adrenal cortex.
Particulate guanylate cyclase from bovine adrenal cortex can be stimulated by ANF. A 2-fold stimulation of the enzyme was obtained with 100 nM ANF and a half-maximal stimulation, with a 5 nM dose. The stimulation by ANF persisted for at least 30 min. Various detergents, such as Triton X-100, Lubrol PX, cholate, CHAPS, digitonin and zwittergent, stimulated several-fold the activity of particulate guanylate cyclase. However, only Triton X-100 dispersed particulate guanylate cyclase without affecting its response to ANF. The dose-response curve of ANF stimulation of the particulate and the Triton X-100 dispersed enzyme was similar. The dispersion of a fully responsive guanylate cyclase to ANF will help us to uncover the type of interactions between guanylate cyclase and ANF. It will also be used as a first step for the purification of an ANF-sensitive particulate guanylate cyclase.
Adrenal Cortex↗
Enhanced DNA synthesis in heart and kidney of newborn spontaneously hypertensive rats.
Studies comparing relative organ weight (per gram of body weight) in spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar-Kyoto rats (WKY), have shown that the heart and kidney of SHR are enlarged at birth. In addition, higher DNA concentrations in these organs provide evidence of cardiac and renal cellular hyperplasia in newborn SHR. The rate of DNA synthesis was estimated with [methyl-3H]thymidine labeling in vivo for heart, kidney, liver, adrenals, and aorta of newborn WKY and SHR, and significantly higher relative organ weights, protein levels, and DNA contents were observed only for heart and kidney from SHR. In contrast, relative weight was significantly lower for liver from SHR and the same for adrenals from WKY and SHR despite lower adrenal protein and DNA contents for SHR. Relative weight and protein content of aorta were higher in SHR, possibly indicating hypertrophy of this organ. Several differences in [methyl-3H]thymidine labeling were observed in organs from SHR. Significantly higher organ accumulation (cpm/mg organ weight) was observed for heart from SHR (p less than 0.01), and higher incorporation into DNA (cpm/cpm) was observed for kidney and liver from SHR (p less than 0.001). Most significant was the finding of higher DNA specific activity for heart (+33%; p less than 0.05) and kidney (+39%; p less than 0.001) from SHR. These data provide evidence of enhanced DNA synthesis in the heart and kidney of newborn SHR.
Adrenal Glands↗
Atrial natriuretic factor: radioimmunoassay and effects on adrenal and pituitary glands.
A simple and sensitive radioimmunoassay was developed for measurement of immunoreactive atrial natriuretic factor (IR-ANF) in rat and human plasma and in rat atria. The two atria contain about 20 micrograms ANF per rat. The right atrium contained 2.5 times more ANF than did the left. Ether anesthesia and morphine markedly increased IR-ANF in rat plasma. The concentration of IR-ANF in plasma of clinically normal human subjects was 65.3 +/- 2.5 pg/ml. Paroxysmal tachycardia and rapid atrial pacing significantly increased IR-ANF in human plasma. Two- to seven-fold higher concentrations were found in coronary sinus blood than in the peripheral circulation. In the plasma of rats and humans, circulating ANF is probably a small-molecular-weight peptide. ANF acts on the adrenal and the pituitary. ANF inhibits aldosterone secretion from rat zona glomerulosa and steroid secretion by bovine adrenal zona glomerulosa and fasciculata. ANF stimulated the basal secretion of arginine vasopressin (AVP) in vitro and inhibited KCl-stimulated release of AVP.
Adenylyl Cyclase Inhibitors↗
Cyclic GMP as mediator and biological marker of atrial natriuretic factor.
Both our previous and the present studies established that increases in cyclic guanosine monophosphate (cGMP) reflect the activity of atrial natriuretic factor (ANF). The ANF message is transmitted by particulate guanylate cyclase, which appears to be in intimate contact with the ANF receptor since stimulation of particulate guanylate cyclase is observed even after dispersion of the membranes. The stimulation of smooth muscle and endothelial cells in culture leads to egression of cGMP to extracellular medium where it accumulates for over 2 h. The signal of the extracellular cGMP is magnified and prolonged compared to the intracellular signal. The stimulation of cGMP production by ANF in vascular smooth muscle and endothelial cells appears to be relatively irreversible and the responsiveness is down-regulated by prior exposure to low doses of ANF. Cyclic guanosine monophosphate can also serve as a marker for ANF action. Atrial natriuretic factor fragments of different potencies exert a biological activity that correlates with ANF-induced cGMP increases. In hypertensive rats and monkeys, where acute infusion of ANF leads to an exaggerated diuresis and natriuresis, urinary cGMP does not appear to be different. Overall, cGMP appears to be a mediator and a marker of ANF biological activity and may serve as a useful tool in the study of pathogenesis of hypertension.
Animals↗
Hypoglycemic effect of fenfluramine in insulin-treated diabetics.
In addition to its anorectic effect, fenfluramine has been demonstrated to decrease blood glucose levels in diabetics, independently of weight loss or the anorectic action. These studies have usually been performed in insulin-independent diabetics. We therefore undertook to investigate 8 non-insulin-dependent and 2 insulin-dependent patients receiving insulin, and noted a mean 21.1 +/- 3.8% decrease in blood glucose after 10 days of fenfluramine utilization. This parameter was diminished in all subjects in whom it had been elevated (greater than 120 mg/d1) during the placebo period of our double-blind, randomized study. Thus, fenfluramine apparently has the capacity to lower glucose in patients receiving insulin therapy.
Adult↗
The effects of sucrose meal on insulin requirement in IDDM and its modulation by acarbose.
The purpose of the present study was to evaluate the insulin requirement in response to sucrose meal in IDDM and its modulation by a disaccharidase inhibitor, Acarbose. After an overnight fast, the subjects (n = 9) were "hooked" to the artificial pancreas (Biostator) to maintain normoglycemia. Blood glucose and insulin requirement were recorded by the Biostator throughout the experiment. The patients were divided into two groups. In group I, five patients received increasing sucrose load (50, 75 and 100 g) with and without Acarbose 100 mg. After a 50 g sucrose meal with and without Acarbose, the peak postprandial (PP) blood glucose was 118 and 157 mg/dl and the insulin requirement was 3.9 and 7.8 units resulting in free plasma insulin peak of 34 and 59 microU/ml respectively. After a 75 g sucrose meal with and without Acarbose, the peak PC blood glucose was 134 and 166 mg/dl and the insulin requirement was 5.7 and 9.9 units resulting in free plasma insulin peak of 75 and 87 microU/ml. After a 100 g sucrose meal with and without Acarbose the peak PP blood glucose was 131 and 175 mg/dl and the insulin requirement was 6 and 12.8 units resulting in free plasma insulin peak of 50 and 69 microU/ml. In group II, four patients received increasing Acarbose dose with a fixed sucrose load (75 g). The PP blood glucose peaked at 161, 145, 120 and 102 mg/dl after 0, 50, 100, 200 mg of Acarbose respectively. The total insulin requirements were 12.9, 9.6, 4.3 and 3.1 units. The free plasma insulin was decreased by Acarbose treatment while plasma glucagon remained unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
Acarbose↗
Episodic dopamine discharge in paroxysmal hypertension. Page's syndrome revisited.
Dopamine concentration, a marker of the sympathetic discharge additional to norepinephrine and epinephrine levels, was determined in 31 patients. These patients, mostly women, had essential hypertension and hypertensive episodes that mimicked pheochromocytoma, except that the patients were rather plethoric (instead of pale) and often had associated nausea, epigastric discomfort, and polyuria. During and after hypertensive paroxysms, plasma free norepinephrine and epinephrine levels did not increase, but we found a mean eightfold and 16-fold increase of free and sulfated plasma dopamine levels, respectively, and similar although less marked dopamine level increases in the urine collected following the paroxysm. The hypertensive paroxysms, spontaneous or precipitated by stimulation of the autonomic nervous system, were similar to those described by Page as simulating diencephalic stimulation. Dopamine level may be a marker of the sympathetic discharge, undetected by measurements of free norepinephrine level, and may explain some clinical features of Page's syndrome.
Adrenal Gland Neoplasms↗