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Biomedical subjects

P Hamet

Publications and source records attributed to P Hamet.

At least 109 records · Page 6Linked to original sources
PubMed1996

Cell volume in vascular smooth muscle is regulated by bumetanide-sensitive ion transport.

Vascular smooth muscle cells (VSMC) exhibit shrinkage-induced bumetanide-inhibited 86Rb influx and ethylisopropylamiloride (EIPA)-inhibited 22Na influx. In this study, we examined the role of these transport pathways in volume adjustment of VSMC after isosmotic and hyperosmotic shrinkage. Cell volume was assessed by measurement of [14C]urea distribution. An initial 18-20% cell volume decrease in isosmotically shrunken VSMC was followed by a regulatory volume increase (RVI). RVI was completely abolished by bumetanide but not by EIPA. No RVI was noted in hyperosmotically shrunken VSMC. The initial rate of bumetanide-inhibited 86Rb influx was two- to threefold higher in isosmotically shrunken VSMC than with hyperosmotic shrinkage. Hyperosmotic shrinkage of VSMC was accompanied by a three- to fourfold increase in the rate of bumetanide-inhibited 86Rb efflux, whereas isosmotic shrinkage augmented this component by only 20-30%. In contrast to bumetanide-inhibited 86Rb influx, isosmotic shrinkage slightly increased the rate of EIPA-sensitive 22Na influx. Hyperosmotic shrinkage led to transient activation of EIPA-inhibited 22Na influx, which was completely abolished in 15 min. Activation of adenosine 3',5'-cyclic monophosphate (cAMP) signaling with isoproterenol arborized VSMC and decreased their volume by approximately 15%. A similar volume decrease was seen in VSMC treated with the microfilament-disrupting compound, cytochalasin B. The isoproterenol-induced cell volume decrease was prolonged by the addition of bumetanide. Unlike isoproterenol, agents that raise intracellular Ca2+ (A-23187 and angiotensin II) did not modify VSMC volume. Thus our data demonstrate involvement of cAMP signaling in the regulating of VSMC volume and a key role of bumetanide-inhibited ion transport in the RVI after isosmotically induced shrinkage.

Animals↗
PubMed1996

cAMP signaling inhibits dihydropyridine-sensitive Ca2+ influx in vascular smooth muscle cells.

This study examines the role of the cAMP signaling pathway in the regulation of 45Ca influx in cultured vascular smooth muscle cells from the rat aorta. K+o-induced depolarization of smooth muscle cells increased the rate of 45Ca uptake by twofold to threefold. This effect was completely abolished by the dihydropyridine derivatives nifedipine and nicardipine, with a Ki of 3 and 10 nmol/L, respectively. Activators of cAMP signaling (isoproterenol, forskolin, cholera toxin) increased cAMP content by 50- to 100-fold and decreased voltage-dependent 45Ca uptake by 50% to 70%. Neither the dihydropyridines nor the cAMP activators affected basal 45Ca influx. Direct addition of the protein kinase inhibitor H-89 to the incubation medium in the 1- to 10-micromol/L range did not alter basal 45Ca uptake but completely abolished voltage-dependent Ca2+ transport. Preincubation of cells for 1 hour with 10 micromol/L H-89 did not modify basal and depolarization-induced 45Ca uptake in H-89-free medium but prevented forskolin-induced inhibition of voltage-dependent Ca2+ influx. The addition of cytoskeleton-active compounds reduced voltage-dependent Ca2+ transport and completely abolished its regulation by cAMP. Activation of cAMP signaling decreased the volume of smooth muscle cells by 12% to 15%. The same cell volume diminution in hyperosmotic medium did not alter voltage-dependent 45Ca uptake. Thus, data obtained in this study show that in contrast to cardiac and skeletal myocytes, in vascular smooth muscle cells, 45Ca influx, putatively due to L-type channels, is inhibited by cAMP. This regulatory pathway appears to be mediated via protein kinase A activation and cytoskeleton reorganization.

Animals↗
PubMed1996

Apoptosis and vascular wall remodeling in hypertension.

Vascular structure plays a key role in the pathogenesis of hypertension. Because it is less readily reversible than protein accumulation, DNA accumulation in the arterial wall may be considered as a record of past episodes of vascular growth, contributing to the persistence of the vascular disease. Apoptosis, a ubiquitous and highly regulated form of programmed cell death that is involved in tissue morphogenesis and homeostasis as the essential counterpart of cell replication, is potentially involved in the regulation of vascular structure, via the deletion of cells in the vessel wall. We discuss how the current knowledge on apoptosis may provide insights into the pathogenesis of vascular wall remodeling, with an emphasis on the biology of vascular smooth muscle cells. Evidence suggests that heightened cell replication rates are often associated with increased apoptosis, as for smooth muscle cells in genetic hypertension or in arterial repair after injury. However, apoptotic cell death may also be regulated independently of cell growth. The triggering of apoptosis depends on a balance of environmental cues that are not specific to apoptosis. However, there is a common set of key biochemical events mediating apoptosis (i.e., committing the cell to die), thus providing a basis for the design of novel pharmacological strategies specifically targeting apoptotic cell death. The identification of biochemical markers of apoptosis and other methodological advances will ultimately help in understanding the role of apoptotic cell death in vascular remodeling and hypertensive end-organ damage.

Animals↗
PubMed1996

HSP27 locus cosegregates with left ventricular mass independently of blood pressure.

Left ventricular hypertrophy remains a significant clinical problem and a predictor of fatal outcome in hypertension. Blood pressure per se and environmental modifiers including stress affect cardiac mass. Heat shock proteins are involved in the stress response as well as in the regulation of cardiac growth and cytoprotection. The present study evaluates heat shock protein 27 as a locus marker or candidate gene of cardiac hypertrophy in hypertension. The spontaneously hypertensive rat allele of heat shock protein 27 was associated with about a 6% increase in relative left ventricular weight (P = .0112) in 30 recombinant inbred strains from crosses of Brown Norway and spontaneously hypertensive rats. In 336 F2 crosses of spontaneously hypertensive and Wistar-Kyoto rats, the hypertensive allele was dominant and cosegregated with a similar 6% increase in the ratio of left ventricular weight to body weight (P = .0058) in rats fed a normal salt diet, but its contribution to left ventricular weight decreased in rats kept on a high salt diet. The contribution of the heat shock protein 27 allele was independent of blood pressure. We suggest that heat shock protein 27 represents a candidate gene/locus marker of cardiac hypertrophy in hypertension.

Alleles↗
PubMed1996

How to translate science into community action.

For the most part, scientific knowledge originates at the level of basic research, which is then tested at the level of clinical research before being translated into community action. The argument is debated that there is a multilateral interaction between basic research, clinical research and community action. The main players, at all three levels, are academia, government and industry. The case is made for integrated action at these three levels and among the three players. Although at the present time community action is based on accumulated knowledge proven by clinical research and tested at the community level, more targeted intervention is foreseeable in high risk groups with a shortened time of transition for genetically-determined markers which are predicted to be used both in prevention and treatment.

Community Health Services↗
PubMed1996

The time window of apoptosis: a new component in the therapeutic strategy for cardiovascular remodeling.

APOPTOSIS AND EXPERIMENTAL HYPERTROPHY: Apoptosis (programmed cell death) is a physiological counterpart of cell replication with shared as well as specific pathways. Our initial studies have demonstrated increased apoptosis in the heart, kidney and brain of spontaneously hypertensive rats (SHR) and mice, persisting in cultured vascular smooth muscle cells. In these target organs of hypertension, programmed cell death paralleled the well known hypertrophy/hyperplasia. We also observed that the two processes can be dissociated in time, as in experimental hypertrophy of the heart induced by pressure overload. In this context, only a short-lived apoptotic window precedes the overt development of cardiac hypertrophy. EFFECTS IN HYPERTENSION: We now propose that a more prolonged apoptotic window is present in hypertension. Apoptosis seems to be significantly reduced during the first weeks of life in SHR, possibly contributing to the early cardiac hyperplasia. However, increased apoptosis is clearly evident thereafter throughout the development of hypertension and fades below the levels observed in normotensive animals after the age of 24 weeks. ANTIHYPERTENSIVE THERAPY AND APOPTOSIS: In addition to the apoptotic windows that suggest a dynamic regulation of this process in disease states, antihypertensive therapy with angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and calcium channel blockers can also modify the contribution of apoptosis, independently of the blood pressure fall. We propose that the presence of apoptotic windows and the involvement of this biological process as a primary or secondary event in cardiovascular remodeling should be taken into account when designing innovative therapeutic approaches.

Animals↗
PubMed1995

The influence of dairy products on plasma uric acid in women.

Elevated levels of plasma uric acid have been linked to increased risk of cardiovascular diseases and their complications. As dairy proteins have been found to decrease plasma uric acid without increasing glomerular filtration rate, a sample of postmenopausal women living in Montreal was studied to investigate the nature of this relationship. Participants (158 Roman Catholic nuns) were randomly assigned to one of two test diets for a period of four weeks: the dairy foods group (n = 81) consumed approximately 30 grams of dairy protein daily and the dairy-free diet group (n = 77) ate no dairy foods at all. Subjects completed two one-day food records, a core questionnaire and a dairy foods diet history; blood specimens were obtained, and blood pressure, height and weight were measured. Average nutrient intakes differed as a consequence of the test diets, with significantly greater intakes of protein, fat, saturated fat, monounsaturated fat, potassium and calcium (p < 0.01) in the dairy group after the study period, and lower dietary levels of protein, cholesterol, calcium and retinol (p < 0.01) in the dairy-free group. Plasma uric acid was unchanged after the dietary intervention in the dairy group, but increased by 7.8 mumol/l (p = 0.03) in subjects on the dairy-free diet; however, diastolic blood pressure decreased in response to calcium (beta = -22.9, SE = 10.0, p = 0.02) among those whose diet included dairy foods.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Distribution↗
PubMed1995

Plasma atrial natriuretic peptide during spontaneous bronchoconstriction in asthmatics.

The aim of this work was to establish the role of endogeneous ANP during a spontaneous asthma attack. Forced expiratory lung volume in 1 s (FEV1), cardiovascular parameters, and plasma ANP, cAMP, and cGMP were measured for 60 min before and 10 min after treatment with a bronchodilator in 10 asthmatics. The results show that in the presence of moderate bronchoconstriction, FEV1 was 54 +/- 3% (+/-SE); ANP levels initially were slightly elevated at 47 +/- 10 pg/ml and decreased to 26 +/- 3 pg/ml (p < 0.05) over 60 min, with no change in FEV1. Following salbutamol inhalation, FEV1 increased to 77 +/- 4% with no change in ANP. We conclude that endogenous ANP does not act as a bronchodilator in asthmatics with moderate bronchospasm.

Acute Disease↗
PubMed1995

Altered beta-adrenergic regulation of Na-K-Cl cotransport in cultured smooth muscle cells from the aorta of spontaneously hypertensive rats. Role of the cytoskeleton network.

To verify the hypothesis of Na-K-Cl cotransport (COTR) involvement in ion transport abnormalities as revealed in vascular smooth muscle cells (VSMC) of spontaneously hypertensive rats (SHR), we compared the rate of ouabain-insensitive, bumetanide-inhibited 86Rb influx in quiescent and growing cultures of VSMC from the aorta of SHR and normotensive (BN.lx) rats and its regulation by the cAMP signaling system. Basal COTR was not altered in quiescent cells from SHR but was decreased by 30% to 40% (P < .02) in growing SHR VSMC as compared to BN.lx rats. In quiescent BN.lx VSMC, isoproterenol inhibited COTR by 50% and induced cell shape transition of > 90% of cells, resulting in the appearance of rounded VSMC with arborized cytoplasms. In contrast, isoproterenol elicited cell shape transition in only 50% of quiescent SHR VSMC and did not modify COTR. In growing cells, it decreased COTR by 85% to 95% and altered cell morphology in > 95% of VSMC without differences between SHR and BN.lx rats. Neither inhibitors of protein kinase A (H-89 and KT-5720) nor an inhibitor of phosphoprotein phosphatase (okadaic acid) affected cell shape transition and COTR suppression in isoproterenol-treated VSMC. The COTR suppression and cytoplasm arborization was also demonstrated by the addition of cytochalasin B, a disintegrator of microfilament bundles, and staurosporine, an inhibitor of protein kinase C. The effects of these compounds on COTR and SHR and BN.lx VSMC morphology were not different. The calmodulin antagonist R24571 decreased COTR by 60% to 70% in quiescent BN.lx VSMC and did not modify this carrier in SHR VSMC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1995

Alternative splicing of natriuretic peptide A and B receptor transcripts in the rat brain.

1. In the present study we searched for variants of alternative splicing of guanylyl cyclase A and B mRNA in rats in vivo. 2. Guanylyl cyclase A2 and guanylyl cyclase B2 isoforms of guanylyl cyclase produced by alternative splicing leading to the deletion of exon 9 of both transcripts were quantified in several rat organs. 3. Only one alternative splicing was found in the regulatory domain, encoded by exons 8-15. 4. Quantification of the guanylyl cyclase B2 isoform in different rat organs and in cultured aortic smooth muscle cells showed that this alternative splicing was tissue-specific and occurred predominantly in the central nervous system where the alternatively spliced variant represented more than 50% of the guanylyl cyclase B mRNA. 5. The same alternative splicing existed for guanylyl cyclase A mRNA but at very low levels in the organs studied. 6. Alternative splicing of guanylyl cyclase B exon 9 in the brain may play an important role in signal transduction, since the expressed protein possesses a constitutionally active guanylyl cyclase acting independently of C-type natriuretic peptide regulation.

Alternative Splicing↗
PubMed1995

Apoptosis in target organs of hypertension.

Apoptosis or programmed cell death frequently parallels abnormalities in cell proliferation and differentiation. As hypertrophy/hyperplasia or remodeling occurs in organs affected by hypertension, we evaluated the degree of apoptosis in the heart, kidney, and brain in situ in genetically hypertensive mice and rats as well as in cultured vascular smooth muscle cells. Apoptosis was characterized by morphological features, DNA fragmentation, and laddering as well as by terminal deoxynucleotidyl transferase labeling of the 3' OH ends of both extracted DNA and tissue sections. The present report provides the first evidence of increased apoptosis in whole organs of genetically hypertensive rat and mouse strains: in the heart of spontaneously hypertensive rats (SHR) and in the heart (ventricular cardiomyocytes), kidney (inner cortex and medulla), and brain (cortex, striatum, hippocampus, and thalamus) of spontaneously hypertensive mice, with a higher effect of apoptotic inducers in cultured aortic smooth muscle cells derived from SHR. Both types of known apoptotic processes, oligonucleosomal cleavage and large DNA fragmentation, were observed in vascular smooth muscle cells, but only the former appeared to be increased in SHR. This study underlines the importance of cell death dysregulation in hypertension, reveals a new route for investigation of the pathogenesis of hypertension, and suggests novel targets of therapeutic intervention.

Animals↗
PubMed1995

Genes of intracellular calcium metabolism and blood pressure control in primary hypertension.

In the last two decades, major progress has been made in understanding the role of calcium (Ca) metabolism in blood pressure (BP) control. This article discusses the intracellular Ca handling systems that could potentially be involved in the pathogenesis of primary hypertension. We begin by reviewing our current knowledge of intracellular Ca handling, alterations of intracellular Ca metabolism in primary hypertension, and possible mechanisms of BP control. We have analyzed data on the structure and alternative splicing of major genes controlling intracellular free Ca concentration, ie, genes encoding intracellular Ca-binding protein (calmodulin, calbindin, plasma membrane Ca2+ pump, Na+/Ca2+ exchanger, and voltage-dependent Ca channels). Data are presented on the relationship of gene polymorphism and alternative splicing with membrane architecture and the function of gene products. Numerous observations on abnormalities of these gene products in primary hypertension are summarized. Studies on the polymorphism of genes regulating intracellular Ca in hypertension are only now being performed.

Animals↗
PubMed1995

Environmental stress and genes of hypertension.

1. Genetic, common household and non-familial environmental factors contribute about 33, 15 and 50% of blood pressure (BP) variance, respectively. Although usually considered to be additive, the environmental impact on the expression of hypertension may also interact with genetic components. Even factors such as gender and age may exert an additive (subtractive) or interactive effect. These interactions usually lead to phenotypic amplification. 2. In some instances, the environmental impact is allele-dependent (putative locus of salt-sensitivity), and there are other occasions when phenotypic expression may be environmentally dependent. Environmental temperature appears to be another environmental modifier of BP. 3. Increased sensitivity to this environmental factor has been observed in hypertension, and a locus of thermosensitivity segregates with BP in mice. Candidate genes of environmental susceptibility are proposed to include tumour necrosis factor and the heat shock protein (HSP) family. An abnormal accumulation of HSP27 and HSP70 messenger RNA has been described in rodent (mice, rat) models of hypertension as well as in human subjects. Segregation of the HSP27 and HSP70 polymorphism with BP has been determined in at least some crosses. 4. These candidate genes of environmental susceptibility may also be involved in determining heart weight in addition to BP.

Animals↗
PubMed1994

Effect of intravenous atrial natriuretic peptide on gas exchange in humans.

The aim of this work was to establish whether a physiological increase in atrial natriuretic peptide (ANP) plasma levels affects pulmonary gas exchange in humans. Ten volunteers received an infusion of either ANP (4 pmol.kg-1.min-1) or physiological saline, for 60 min. Baseline measures of the alveolar-arterial PO2 difference and of the physiological dead space were within normal limits and remained stable during and after the infusion of ANP or saline, although plasma ANP and cGMP rose significantly (p < 0.01) (mean +/- SEM: ANP: 13.4 +/- 3.9 to 56.0 +/- 10.4 pmol/l; cyclic GMP: 3.8 +/- 0.3 to 17.0 +/- 3.8 nmol/l). We conclude that a physiological increase in plasma ANP does not affect pulmonary gas exchange significantly in humans.

Adult↗