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Biomedical subjects

P Hamet

Publications and source records attributed to P Hamet.

At least 307 records · Page 17Linked to original sources
PubMedDate not supplied

Once-daily dosing of acebutolol in hypertension.

Twenty-six patients with essential hypertension were admitted to a protocol comparing the efficacy of the once-a-day administration of acebutolol with twice-a-day administration. A placebo was substituted initially for their beta-blocker therapy. Other therapy was continued in 14 (11, diuretics alone; two, diuretics plus hydralazine or alpha-methyldopa; one, alpha-methyldopa alone). After 4 weeks, lying blood pressures were 160 +/- 16 (SD) mm Hg systolic, and 101 +/- 7 mm Hg diastolic. Incremental twice-a-day doses of acebutolol resulted in normotension (lying systolic, 131 +/- 12 mm Hg; diastolic, 84 +/- 5 mm Hg) in all 26 patients (eight on 400 mg, four on 600 mg, seven on 800 mg, one on 1,000 mg, and six on 1,200 mg/day). The same twice-a-day acebutolol dose was continued for two visits, 4 weeks apart, recording pressures at 8 a.m., 12 noon, 4 p.m., and 8 p.m.; followed by two visits, 4 weeks apart, while taking the total daily dose after the 8 a.m. recording. Blood pressures during once-a-day dosing were not different from those during twice-a-day dosing at any time. Highest pressures were at 8 a.m. and lowest were at 12 noon or 4 p.m. Variations during the day in both systolic and diastolic pressures were greater during once-a-day dosing. Plasma acebutolol and metabolite concentrations were proportional to the administered dose. Eighteen patients continued acebutolol for 1 year without adverse effects other than an asymptomatic positive antinuclear antibody test in six. Once-a-day dosing was as effective as twice-a-day dosing in this group of hypertensive patients.

Acebutolol↗
PubMedDate not supplied

The death of cardiotonic steroid-treated cells: evidence of Na+i,K+i-independent H+i-sensitive signalling.

Na/K-ATPase is the only known target of cardiotonic steroids (CTS) identified in plants, amphibians and later on in several mammalian species, including human. We focus our review on recent data implicating CTS in the tissue-specific regulation of cell survival and death. In vascular smooth muscle cells, CTS inhibited cell death triggered by apoptotic stimuli via a novel Na+i-mediated, Ca2+i-independent mechanism of expression of antiapoptotic genes, including mortalin. In contrast, exposure to CTS in vascular endothelial and renal epithelial cells led to cell death, showing combined markers of apoptosis and necrosis. This mode of cell death, termed oncosis, is caused by CTS interaction with Na/K-ATPase but is independent of the inhibition of Na/K-ATPase-mediated ion fluxes and inversion of the [Na+]i/[K+]i ratio. The intermediates of intracellular signalling involved in Na+i, K+i-independent oncosis of CTS-treated cells remain unknown. Recently, we found that this mode of cell death can be protected by modest intracellular acidification via the expression of H+i-sensitive genes. The molecular origin of intracellular Na+ and H+ sensor involvement in the development of apoptosis and oncosis is currently under investigation.

Apoptosis↗
PubMedDate not supplied

Regression of neointimal lesions in the carotid artery of nifedipine-treated SHR and WKY rats: possible role of apoptosis.

We previously observed that nifedipine reduces aortic hypertrophy in spontaneously hypertensive rats (SHR) partly by inducing smooth muscle cell (SMC) apoptosis. The present study examined nifedipine regulation of SMC apoptosis in carotids with or without a neointima. A neointima was produced by endothelial denudation of the left carotid of SHR and WKY rats. The contralateral carotid remained uninjured. Beginning at week 6 after injury, rats received nifedipine or placebo for 5 and 7 additional weeks. In situ terminal deoxynucleotidyl transferase (TdT)-mediated DNA labeling was used to mark apoptotic nuclei. Nifedipine reduced blood pressure in SHR but not WKY rats. Nifedipine had antihypertrophic effects in both SHR and WKY rats. In each strain, the greater reduction in cross-sectional area was seen in the neointima. In this tissue, nifedipine significantly increased TdT-positive SMC (4-fold at week 5 in SHR and 5-fold at week 7 in WKY rats) and reduced SMC number (70% in SHR and 29% in WKY rats) at week 7 compared to week 0. The effects were less pronounced in the injured and uninjured media. Thus, the antihypertrophic action of nifedipine is amplified in the neointima of SHR and WKY rat carotids, where histological evidence suggests SMC deletion via apoptosis.

Animals↗
PubMedDate not supplied

Dual effect of adenosine on vascular smooth muscle [(3)H]-thymidine DNA labeling: receptor-mediated modulation of DNA synthesis and inhibition of thymidine uptake.

This study examined the contribution of cAMP signaling to the modulation of vascular smooth muscle cell (VSMC) proliferation by adenosine. At a concentration of 1 mM, adenosine inhibited [(3)H]-thymidine uptake, measured as the initial rate of isotope influx, by 10-fold. Diminution of [(3)H]-thymidine uptake by adenosine was independent of the presence of A(1)- and A(2)-receptor antagonists, indicating that adenosine competes with thymidine for plasma membrane transporter-binding sites. Considering these results, in order to estimate [(3)H]-thymidine DNA labeling, VSMCs were preincubated with adenosine for 48 h, and adenosine was then omitted during the subsequent 2 h of incubation in [(3)H]-thymidine-containing medium. In serum-depleted VSMCs, preincubation with 100 microM or 1,000 microM adenosine augmented DNA synthesis by approximately 6- and 3-fold, respectively, whereas the increment of DNA synthesis triggered by serum was decreased in the presence of adenosine by 20-30%. Both cAMP production and inhibition of DNA synthesis by adenosine in serum-supplied cells were independent of the presence of the A(1)-antagonist 1,2-dipropyl-8-cyclopentylxanthine (DPCPX), but were abolished by the A(2)-antagonist 1,3-dimethyl-7-propylxanthine (DMPX). In contrast, the activation of DNA synthesis in serum-depleted cells by adenosine was decreased in the presence of DPCPX and DMPX by approximately 30 and 40%, respectively. Both in serum-supplied and -depleted VSMCs, dose-dependent elevation of cAMP production with an adenylate cyclase activator, forskolin, reduced DNA synthesis by up to 40-60%. Thus, our results show that in addition to suppressing thymidine uptake, adenosine depresses the DNA synthesis triggered by serum-derived growth factors and stimulates DNA synthesis in serum-depleted cells. These data also suggest that the inhibition of DNA synthesis is mediated by cAMP production where the activation of DNA synthesis is independent of cAMP signaling.

Adenosine↗
PubMedDate not supplied

Unconjugated hyperepinephrinemia: a hallmark of hypertension imitating pheochromocytoma?

Hypertensive patients with elevated and hyperresponsive plasma norepinephrine and epinephrine (NE + E) associated with low conjugated NE + E were previously identified by determination of the sum of NE + E. Because of their excessive E but not NE responses to glucagon and also hypertension corresponding to E excess, we explored whether an elevated unconjugated E resulting from a selective E conjugation defect could be obscured by the sum of NE + E. We found that nine patients with elevated E (reflected by the normal 4:1 ratio of plasma NE to E reversed in favor of E), had, when compared to 31 patients with plasma NE exceeding E:1) lower plasma conjugated E (mean 0.03 vs 0.27 ng/ml, p less than 0.01), lower degree of E conjugation (8 vs 51%, p less than 0.01), and a higher maximum systolic (p less than 0.05), pulse pressure (p less than 0.02) and higher pulse rates (p less than 0.04), but no differences in the unconjugated and conjugated proportions of plasma NE; and 2) an absence of conjugated E throughout the circulation and relative preponderance of E over NE at sampling points close to the peripheral venous blood (p less than 0.05). The absolutely and relatively decreased plasma conjugated E in patients with E exceeding NE (without difference in conjugated NE) is a preliminary indication that a selective sulfoconjugating defect of E results in plasma E higher than NE in accordance with the hyper-beta-adrenergic features of their hypertension. Epinephrine, a circulating hormone, is more dependent on conjugated E reflect better this defect than those measuring the sum of NE and E.

Adolescent↗
PubMedDate not supplied

Prazosin plasma concentration and blood pressure reduction.

Prazosin was administered to 16 patients with essential hypertension in an initial dose of 0.5 mg, after which the blood pressure (BP), pulse, and plasma concentrations of prazosin were measured at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours. The dose of prazosin was then increased over 16 to 20 weeks, and similar sequences of measurements were obtained twice. Eleven patients completed the 20-week course. All patients did not respond in a similar way; two distinct patterns of BP and pulse response emerged, although there was no significant difference in the pharmacokinetic parameters, namely, absorption rate constant (Ka), maximum plasma concentration (Cpmax), time to reach the maximum concentration (Tmax), prazosin plasma half-life (T 1/2), elimination rate constant (kel), prazosin plasma concentration-time curve (AUC), and clearance. Patients in Group 1 had a marked reduction (52/30 mm Hg) of BP after the first dose of prazosin, no pulse increase, and needed a small dose of prazosin to maintain an adequate BP response. Patients in Group 3 had a minimal reduction in BP (14/13 mm Hg) after a first dose, a significant pulse increase, and needed a high dose of prazosin to control their BP. We conclude that this effect might be due to a different drug-receptor interaction, and the BP response and dose could be predicted from the response of the first dose of prazosin.

Blood Pressure↗
PubMedDate not supplied

Dopamine surges in hyperadrenergic essential hypertension.

From a total of 61 referred hypertensive patients, 21 were clinically suspected of pheochromocytoma but in none was this diagnosis confirmed. Instead we found nine of the 21 patients had surges of conjugated dopamine during hyperadrenergic periods unaccounted for by rise in norepinephrine (NE) or epinephrine (E). Overall, essential hypertensive (EH) patients had in plasma (ng/ml) higher conjugated dopamine (DA) (2.3 +/- 0.2 vs 1.0 +/- 0.1, p less than 0.01), increasing with age (p less than 0.01), lower conjugated NE + E (0.6 +/- 0.1 vs 1.2 +/- 0.2, p less than 0.01), and higher free E (p less than 0.007), lower urinary free DA and total DA but higher free NE + E excretions (each p less than 0.05) than 24 control subjects. Following the DA surges, a short-lived urinary overflow of total DA occurred. The patients with DA surges were older, had a higher incidence of low conjugated NE + E (less than 0.23 ng/ml), a higher proportion of arterial free DA, and higher venous baseline conjugated plasma DA than the rest of the patients. Patients with low conjugated NE + E had in turn higher plasma DA concentrations at several regional sampling sites than patients with normal conjugated NE + E. High conjugated DA in EH probably results from pulsatile DA surges leading to a rise of baseline plasma conjugated DA. In the short run DA pulses can result in temporary alpha- and beta-adrenergic actions of huge arterial free DA concentrations prior to DA conjugation; in the long run the excessive high affinity DA conjugation may take preference to the lower affinity NE and lowest affinity E conjugation and free E increases. Both result in an acute or chronic increase of sympathetic tone.

Adolescent↗
PubMedDate not supplied

Regional sources of free and sulfoconjugated catecholamines in hypertension.

To elucidate the sources of free catecholamines (CA) and their sulfates in hyperadrenergic essential hypertensives (EH), their arteriovenous differences were determined radioenzymatically and by sulfatase hydrolysis (with correction for cross-contamination) across several organs and regions in 16 hyperadrenergic essential hypertensive patients. Comparison with arterial concentrations showed that: the adrenal venous outflow contains 240 times more free epinephrine (E), 55 times more free norepinephrine (NE), and 7 times more free dopamine (DA) concentrations, but E, NE, and DA sulfates are not different; free E concentrations are lower in the peripheral venous blood; NE sulfate concentrations are higher in the superior vena cava (p less than 0.05 for all differences noted). The data suggest the following conclusions for hyperadrenergic EH patients: with the exception of NE sulfate added into the superior vena cava region, no other organ or region can be associated with a net DA or NE sulfate release. The proportional adrenal vein concentrations of DA:NE:E are approximately 1:10:50, which are very close to those seen in other studies performed under different degrees of stress. Free E is extracted in peripheral tissues. The DA surges in hyperadrenergic EH patients probably result from the pulsatile, predominantly adrenal, release of free DA.

Arteries↗
PubMedDate not supplied

Abnormalities of platelet function in hypertension and diabetes.

The increased frequency of hypertension in diabetes and of abnormalities of carbohydrate metabolism in hypertension are now well established. It is conceivable that the high coincidence of the two diseases is based on a common metabolic defect. Studies of platelets permit the evaluation of the stimulatory, phosphoinositol-linked and the inhibitory, cyclic adenosine 3',5'-monophosphate-dependent pathways of cell activation. Furthermore, platelets may be relevant for the development of angiopathy through their contents of growth factors. Abnormalities of platelet aggregation have been demonstrated in hypertension and diabetes. They are accompanied by exaggerated stimulation of adenylate cyclase in hypertension and abnormal activity of cyclic guanosine 3',5'-monophosphate phosphodiesterase in diabetes. Defective function of platelets is also observed in patients and animals when the two diseases are present at the same time. Both increased and decreased aggregation have been described in these two diseases in the literature. The apparent discrepancies may be due to different types of platelet preparation, evaluation of aggregation, evolution of defect with age, and form of the disease. Integrated studies of biochemical mechanisms responsible for cell activation are needed to characterize the exact defect present in diabetes and hypertension in platelets.

Adenylyl Cyclases↗
PubMedDate not supplied

Effects of continuous subcutaneous insulin infusion versus multiple injections on insulin receptors in insulin-dependent diabetics.

We compared continuous subcutaneous insulin infusion (CSII) versus multiple injections (MI) in the treatment of insulin-dependent diabetes mellitus (IDDM) to assess the effect of glucose control on monocyte insulin receptors. Each IDDM patient (n = 8) was treated for 2 mo by MI (HS Ultralente and AC boluses of regular insulin) and for 2 mo by CSII in a randomized fashion. Prestudy preprandial/postprandial blood glucose levels were 199 +/- 33/261 +/- 28 mg/dl and improved to 124 +/- 12/156 +/- 13 mg/dl during MI and to 115 +/- 11/151 +/- 11 mg/dl during CSII. Glycosylated hemoglobin before the study was 10.1 +/- 0.5% and decreased to 8.8 +/- 0.4 and 8.3 +/- 0.3% during MI and CSII, respectively. The specific 125I-labeled insulin binding to circulating monocytes in a group of nonobese controls (n = 17) was 4.6 +/- 0.2%. In our poorly controlled diabetics during conventional therapy, the 125I-insulin binding was decreased to 3.7 +/- 0.3 (P less than .025). This was not significantly affected by MI despite good glucose control (4.0 +/- 0.3%). With CSII, however, good glucose control was associated with normalization of 125I-insulin binding to monocytes (4.7 +/- 0.27%). The affinity of the insulin receptors was normal before the study and was not affected by either MI or CSII. In conclusion, these observations demonstrate that in IDDM, intensive therapy by MI and CSII resulted in similar good glucose control, but only CSII resulted in normalization of insulin receptors on circulating monocytes.

Adult↗
PubMedDate not supplied

Patient self-management of continuous subcutaneous insulin infusion.

Continuous subcutaneous insulin infusion (CSII) is one of the ways to control blood glucose for prolonged periods. This study was undertaken to establish the long-term feasibility and efficacy of CSII with patient self-management. Patients were instructed to maintain their calorie and carbohydrate intake. Basal infusion of insulin, representing 50% of the total pre-CSII dose, was supplemented by boluses of insulin based on carbohydrate intake for each meal. With this type of regimen, blood glucose and M-values were easily normalized during the physician-directed periods. This study demonstrated that near-normalization of blood glucose, M-values, and glycosylated hemoglobin was maintained after a 1 1/2-yr period of patient self-management. We attributed this successful management in part to the protocol used, in which boluses were related solely to carbohydrate intake while basal insulin was adjusted according to fasting blood glucose. The chronic normalization of blood glucose resulted in improvement of platelet function as witnessed by responsiveness to antiaggregating (PGE1) and aggregating (epinephrine) agents. An improvement was noticed in doppler measurement of ankle-arm blood pressure and a near-normalization of nerve latency and conductivity was observed.

Adult↗
PubMedDate not supplied

Continuous subcutaneous insulin infusion (Mill-Hill Infuser) versus multiple injections (Medi-Jector) in the treatment of insulin-dependent diabetes mellitus and the effect of metabolic control on microangiopathy.

The present study was designed to compare continuous subcutaneous insulin infusion (CSII) using the Mill-Hill Infuser (Muirhead Medical Products Ltd., London, England) with multiple injections (MI) using the Medi-Jector (Derata Corporation, Minneapolis, Minnesota) in the treatment of insulin-dependent diabetes mellitus (IDDM), and to assess the effect of glucose control on diabetes complications. Twelve diabetic subjects were treated 3 mo with CSII and 3 mo with MI (bedtime ultralente and premeal boluses of regular insulin) in a randomized fashion. Prestudy preprandial/postprandial glucose levels were 147-215 mg/dl and improved to 108-138 mg/dl during CSII, and to 115-139 mg/dl during MI with glycosylated hemoglobin of 12.9%, 9.1%, and 8.7%, respectively. This improved glucose control with either CSII or MI was associated with an increase in sural nerve conductivity from 42.9 to 45 m/s and a decrease in proteinuria from 1.9 to 0.5 g/24 h. The 24-h insulin dose consisted of 45 U before the study, 44 U during CSII, and 56 U during MI. After the study, seven patients opted to continue with the Mill-Hill Infuser, and five with the Medi-Jector. We conclude the following: (1) treatment with both the Mill-Hill Infuser and the Medi-Jector was well accepted by the patients and resulted in similar improvement in measured blood glucose and glycosylated hemoglobin; (2) this improved metabolic control was associated with an increased nerve conductivity and a decreased protein excretion; and (3) MI required 20% more insulin than CSII to achieve similar glycemic control.

Adult↗
PubMedDate not supplied

Abnormal expression and function of hormone receptors in adrenal Cushing's syndrome.

The initial description of GIP-dependent Cushing's syndrome suggested that abnormal or ectopic expression of adrenal receptors for various ligands may underlie other cases of ACTH-independent hypercortisolism. GIP-dependent Cushing's syndrome has been described in patients with unilateral adenomas or bilateral ACTH-independent macronodular adrenal hyperplasia (AIMAH) and results from the adrenal overexpression of non-mutated GIP receptor. In AIMAH, other patients were identified in whom regulation of cortisol production resulted from an abnormal adrenocortical response either to vasopressin, beta-adrenergic receptor agonists, hCG/LH, or serotonin 5-HT-4 receptor agonists. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists of the abnormal receptor.

Adrenal Cortex↗
PubMedDate not supplied

Environmentally-regulated genes of hypertension.

Several monogenetic causes of hypertension have recently been identified, but for the most part, the disease is of polygenic and possibly heterogenous character. The environmental impact, representing about 2/3 of blood pressure variance, is usually thought to be exerted at the level of phenotypic modification, additive to the effect of genetic loci determining blood pressure. The concept presented here is that for a significant part, the environment interacts with genes, influencing their expression. Of particular interest are stress genes expressed differentially in human and experimental hypertension. They may constitute candidate genes of blood pressure and heart weight, influenced by environmental stressors at the level of gene expression.

Animals↗
PubMedDate not supplied

Genes and hypertension: where we are and where we should go.

Our understanding of the genetics of hypertension is incomplete. A great deal has, however, been learned about the role of several < > genes by altering their expression in transgenic and knockout models. Crosses of inbred strains, analyzed in F2 generations, have demonstrated consistent quantitative trait loci, particularly on chromosomes 1, 2 and 10, suggesting significant contributions of some genes in distinct models of rodent hypertension. The effect of these loci has been tested in congenic strains and their interaction underlined in double congenics. The weakness of testing individual animals from F2 crosses is overcome in recombinant inbred strains. In humans, Mendelian models of hypertension have contributed to progress in our understanding of this disease, but have not yet revealed any major gene of essential hypertension. Many association as well as linkage studies of humans have provided useful though somewhat contradictory data. Our renewed effort is oriented towards the discovery of genetic determinants of environmental interaction in hypertension as well as towards the future of pharmacogenomics. This progress will be the basis of future individualized treatment and prevention.

Animals↗