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Biomedical subjects

J Tremblay

Publications and source records attributed to J Tremblay.

At least 109 records · Page 6Linked to original sources
PubMed1992

Accelerated entry of aortic smooth muscle cells from spontaneously hypertensive rats into the S phase of the cell cycle.

The present study was designed to characterize the growth kinetics of the exaggerated proliferative response to mitogens of vascular smooth muscle cells from spontaneously hypertensive rats compared with cells from normotensive Wistar-Kyoto controls. Cellular DNA content, analyzed by flow cytometry, demonstrated a 4-h accelerated entry into the S phase of the cell cycle of vascular smooth muscle cells from spontaneously hypertensive rats; the significant (4.5-fold) increase in the percentage of cells in the S phase occurred between 8 and 12 h after calf serum stimulation. A 3.9-fold increase of cells in the S phase was seen in the normotensive controls only between 12 and 16 h. Transit through the cell cycle was quantitated by flow cytometry using the Hoechst 33,342--bromodeoxyuridine substitution technique. Vascular smooth muscle cells from spontaneously hypertensive rats went through the cell cycle 4 h ahead of cells from normotensive Wistar-Kyoto rats. This accelerated transit of spontaneously hypertensive rat cells was mostly due to an earlier entry into the S phase. Persistence of this new intermediate phenotype in cell culture suggests its primary pathogenetic role in spontaneous hypertension.

Animals↗
PubMed1992

Enhanced growth-dependent expression of TGF beta 1 and hsp70 genes in aortic smooth muscle cells from spontaneously hypertensive rats.

Enhanced proliferation of vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) as compared with Wistar-Kyoto rats (WKY) persists in long-term culture and is characterized by an accelerated entry of these cells into the synthetic S phase of the cell cycle and a higher specific growth rate, particularly evident at high cell density. In the present study, we investigated by Northern blot experiments the expression of genes putatively involved in the regulation of VSMC growth. One of them is the transforming growth factor beta 1 gene (TGF beta 1), a bifunctional modulator of cell growth whose action is dependent on cell density. The accumulation of TGF beta 1 mRNA was enhanced in growing SHR cells at every density studied as early as 24 h after inoculation with a further increase at later times. Protooncogenes c-fos and c-myc, which have been implicated in G1/S phase transition, have also been investigated in VSMC by Northern blot analysis. At low cell density, calf serum stimulated c-fos and c-myc mRNA expression was comparable in WKY and SHR cells whereas at high cell density, c-fos induction was higher in VSMC from SHR. SHR VSMC respond more to mitogenic stimulation and to environmental (e.g., heat) stress, particularly when growing near saturation density. hsp70 constitutes a gene family responsive to environmental stimuli (heat) and to mitogenic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Restriction fragment length polymorphism of hsp70 gene, localized in the RT1 complex, is associated with hypertension in spontaneously hypertensive rats.

Previous studies from our laboratory have demonstrated that the intermediate phenotype of thermosensitivity is present in hypertensive mice and rats. Increased expression of hsp70 caused by increased transcription rate was demonstrated in vivo, in organs, and in cultured cells from spontaneously hypertensive rats and hypertensive mice. In this study, a polymorphism of this gene was revealed with BamHI enzyme by using a human hsp70 probe. A 4.4-kb fragment was visualized in normotensive rats (Brown-Norway BN.lx and Sprague-Dawley), and a 3.0-kb fragment was found in spontaneously hypertensive rats (SHR) of three different origins and in Wistar and Buffalo rats. Both fragments were present in the Wistar-Kyoto rat strain. The present study mapped the polymorphism of hsp70 into the RT1 complex in BN.1K and SHR.1N congenic strains. The hsp70 restriction fragment length polymorphism is associated with a blood pressure difference of 15 mm Hg in recombinant inbred strains. These results justify the search for a mechanism by which hsp70 could influence blood pressure.

Animals↗
PubMed1991

Characterization of the functional domains of the natriuretic peptide receptor/guanylate cyclase by radiation inactivation.

Radiation inactivation has been used to evaluate the molecular size of domains responsible for atrial natriuretic peptide (ANP)-binding and cyclase functions of the ANP receptor/guanylate cyclase. Two types of inactivation curves were observed for cyclase function in both adrenal cortex and aortic smooth muscle cells: 1) biphasic with enhanced guanylate cyclase activity after exposure to low radiation doses and 2) linear after preincubation of membrane proteins with 0.5 microM ANP or solubilization with Triton X-100. The existence of an inhibitory component was the simplest model that best explained the types of radiation curves obtained. Activation of guanylate cyclase by ANP or Triton X-100 could occur via the dissociation of this inhibitory component from the catalytic domain. On the other hand, the loss of ANP-binding activity was linear with increasing radiation exposures under basal, ANP treatment, and Triton X-100 solubilization conditions. Radiation inactivation sizes of about 30 kDa for cyclase function, 20 kDa for ANP-binding function, and 90 kDa for inhibitory function were calculated. These studies suggest that the ANP receptor/guanylate cyclase behaves as a multidomain protein. The results obtained by radiation inactivation of the various biological functions of this receptor are compatible with the hypothesis of an intramolecular inhibitory domain repressing the guanylate cyclase catalytic domain within its membrane environment.

Adrenal Glands↗
PubMed1991

Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension.

The increased growth potential of vascular smooth muscle cells (VSMCs) represents one of the crucial anomalies responsible for the development of essential hypertension, diabetic macroangiopathy, and atherosclerosis. The exaggerated response to growth factors of VSMC from spontaneously hypertensive rats (SHRs) persists in culture when compared with normotensive Wistar-Kyoto control rats, indicating an intrinsic defect in the hypertension-producing mechanism. This greater proliferation is characterized by two intermediate phenotypes: (1) accelerated entry into the S phase of the cell cycle, which results from hyperresponsiveness to epidermal growth factor and platelet-derived growth factor, and (2) abnormal contact inhibition. The enhanced expression of transforming growth factor beta 1 (TGF-beta 1) messenger ribonucleic acid in SHRs precedes this altered contact inhibition, and only VSMCs from SHRs respond to exogenously added TGF-beta 1 at a high cell density, which suggests that abnormal TGF-beta 1 autoregulation may be implicated in the second phenotype. Platelets contain major growth factors for VSMC. Platelet extracts from hypertensive and diabetic patients present augmented growth-promoting activity on VSMCs, which is most evident when both diseases occur simultaneously. Growth-promoting activity may be further influenced by antihypertensive therapy. This growth-promoting activity is increased by hydrochlorothiazide but not by indapamide, atenolol, or captopril in diabetic hypertensive and nondiabetic hypertensive patients. In conclusion, VSMCs in hypertension manifest an intrinsic growth defect that is modulated by extrinsic platelet growth factors and antihypertensive drugs.

Animals↗
PubMed1991

Influence of environmental temperature on the blood pressure of hypertensive patients in Montréal.

To assess the influence of environmental temperature on blood pressure, we analyzed 42,813 readings of systolic and diastolic blood pressures in recumbent and upright positions in 2,000 hypertensive patients in our clinic in correlation to noon temperature and mean daily temperature in Montréal. The sample comprised 860 men and 1140 women with an average age of 55 years. Analysis of variance showed highly statistically significant negative correlations for all blood pressure values between different noon temperature, as well as mean daily temperature, groups. The greatest difference for systolic blood pressure was 7 mm Hg, and for diastolic blood pressure it was 3 mm Hg, within the -24 degrees C to 27 degrees C temperature range. The same relationship between blood pressure and different environmental temperatures was also seen when the blood pressure recordings were divided between temperature below 0 degree C and above 0 degree C, ie, within the winter or summer months. This environmental effect may have a clinically significant impact because thermosensitivity appears to be related to hypertension.

Adult↗
PubMed1991

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↗
PubMed1991

Evidence for atrial natriuretic peptide (ANP) synthesis and the presence of ANP-transducing receptors in the rat olfactory bulb.

This study demonstrates the presence of both atrial natriuretic peptide (ANP) precursor and ANP transcripts in the rat olfactory bulb (OB), a key brain structure involved in the generation of olfaction-dependent behavior. In addition to synthesizing ANP, the OB contains ANP-transducing receptors coupled to the guanylate cyclase system but it is devoid of ANP "clearance receptors." The characterization of biologically active ANP receptors and the evidence for in situ ANP synthesis in this region of the CNS adds credence to the hypothesis that the peptide plays a putative role in olfaction.

Animals↗
PubMed1991

Effects of ANP, angiotensin, vasopressin, and endothelin on ANP receptors in cultured rat vascular smooth muscle cells.

Some evidence suggests homologous and heterologous regulation of atrial natriuretic peptide (ANP) receptors. We have examined the effects of exposure to ANP, angiotensin II (ANG II), arginine vasopressin (AVP), and endothelin (ET), on binding of ANP to cultured rat vascular smooth muscle cells (VSMC) and on guanylate cyclase-coupled and -uncoupled ANP receptors. The latter were studied by examining production of guanosine 3',5'-cyclic monophosphate (cGMP) in response to ANP and binding of ANP to Triton X-100-solubilized VSMC membranes, irreversible cross-linking with disuccinimidyl suberate, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in presence of dithiothreitol, followed by radioautography. Exposure to 100 nmol/l ANP for 18 h reduced ANP sites to 43% of control. However, if acid wash of VSMC membranes at pH 5.0 was performed before binding, no decrease in density of ANP binding sites was detected. On SDS-PAGE, a 130-kDa band bound 42 vs. 46% of 125I-labeled ANP in acid-washed membranes from control vs. cells exposed to ANP; the remainder was bound to a 67-kDa band. ANG II (100 nmol/l), AVP (1 mumol/l), or ET-1 or ET-3 (100 nmol/l) did not produce changes in density of ANP sites or in binding to the 130- and 67-kDa bands. cGMP production in response to ANP showed exaggerated response in ANG II but not in AVP- or ET-treated VSMC. Effect of ANG II was abolished by the ANG II antagonist [Sar1-Ile8]ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1991

Cell biology of atrial natriuretic peptide.

Atrial natriuretic peptide (ANP) exhibits a wide spectrum of cardiovascular, endocrine, metabolic and renal actions. cGMP is the major mediator of ANP at the cellular level and only tissues possessing particulate guanylate cyclase appear to present ANP-induced actions. Three types of ANP receptors have recently been cloned. Two of them (A and B receptors) are homologous and contain guanylate cyclase catalytic domains. The C receptor could possibly regulate the metabolic fate of ANP. Data obtained by the radiation inactivation method suggest the presence of an inter- or intramolecular inhibitory component of nearly 90 kilodaltons that represses the catalytic activity of guanylate cyclase within its membrane environment. The mechanism of guanylate cyclase stimulation by ANP could involve this inhibitory component. Preliminary data suggest that the hyperresponsiveness of the particulate guanylate cyclase/cGMP system in hypertension occurs through modulation of the inhibitory component.

Animals↗
PubMed1991

Transforming growth factor beta 1 expression and effect in aortic smooth muscle cells from spontaneously hypertensive rats.

Previous studies demonstrated that in addition to an increased response to growth factors, cultured vascular smooth muscle cells derived from spontaneously hypertensive rats (SHRs) grow to a greater density than cells from normotensive Wistar-Kyoto (WKY) rats. Transforming growth factor beta 1 (TGF-beta 1) has a bimodal effect on vascular smooth muscle cell growth, depending on cell density. The present study investigated the relation between cell density and expression of the proto-oncogene c-fos and TGF-beta 1 in cells from WKY rats and SHRs. The results demonstrate an increased accumulation of c-fos mRNA in calf serum-stimulated SHR cells but only at a high cell density. The expression of TGF-beta 1 mRNA was enhanced in growing SHR cells at every density studied as early as 24 hours after inoculation, with a further increase at later times. The effect of exogenous TGF-beta 1 on new DNA synthesis was evaluated by [3H]thymidine incorporation. At a low cell density, TGF-beta 1 had no effect on DNA synthesis in either WKY or SHR vascular smooth muscle cells. At a high cell density, there was a significant increase of DNA synthesis in response to TGF-beta 1 in SHR cells without any effect in WKY cells. In conclusion, contact inhibition of vascular smooth muscle cells from SHRs at a higher cell density is accompanied by an earlier expression of the marker gene c-fos and preceded by an exaggerated expression of TGF-beta 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cyclic nucleotides and calmodulin-phosphodiesterase activator: potential biochemical markers of salt sensitivity.

Salt sensitivity affects a fraction of hypertensive and normotensive subjects, but biochemical markers that target salt-sensitive individuals are not available at present. The aim of these studies was to establish if calmodulin-phosphodiesterase (CaM-PDE) activator (J Clin Invest 82: 276, 1988) and platelet cyclic nucleotides could serve as potential markers of salt sensitivity. The results demonstrated that CaM-PDE activator was increased in the heart of Dahl salt-sensitive rats (DS/JR) compared to Dahl salt-resistant (DR/JR) animals fed a 1% sodium diet. Normotensive male Wistar rats given a low (0.15%) or high (3.5%) sodium diet from age 7 weeks to 11 weeks presented significant increases (p less than 0.01) of three parameters: blood pressure (from 106 +/- 4 to 128 +/- 8 mmHg); platelet aggregation in response to ADP and thrombin; and CaM-PDE activator levels (from 1.57 +/- 0.14 to 2.8 +/- 0.18). Basal as well as stimulated cyclic nucleotide levels were significantly reduced in rats fed the high sodium diet. Since the degree of stimulation by the agonists was unaltered, the results are compatible with augmented PDE activity. These preliminary data suggest that CaM-PDE activator should be explored as a potential marker of salt sensitivity.

Animals↗
PubMed1991

Intrinsic factors involved in vascular smooth muscle cell proliferation in hypertension.

The exaggerated response to growth factors of vascular smooth muscle cells from spontaneously hypertensive rats when compared to cells from normotensive control Wistar-Kyoto rats persists in culture, indicating an intrinsic/genetic defect. The time course of 3H-thymidine incorporation shows that synchronized vascular smooth muscle cells from spontaneously hypertensive rats start to synthesize new DNA earlier after mitogenic stimulation than cells from normotensive rats. Flow cytometry demonstrates that in cell populations growing in 10% calf serum for three d there is a higher proportion of cells from spontaneously hypertensive rats in the S phase of the cell cycle. The same proportions in the G2 + M phase of growing, as well as synchronized cells from normotensive and hypertensive rats indicate no difference in polyploidy. Forward light scatter analysis reveals no difference in cell size. These results suggest that the growth kinetic of vascular smooth muscle cells from normotensive and spontaneously hypertensive rats are different. Since the defect seems to be in the prereplicative phase of the cell cycle susceptible to regulation by extrinsic factors, we studied the effect of the calmodulin inhibitor, W-7, on DNA synthesis. The comparable IC50 of W-7 to inhibit cell growth of vascular smooth muscle cells of both origins indicates that the defect may not be due only to calmodulin, and furthermore suggests the involvement of a previously-reported calmodulin activator in hypertension.

Animals↗