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Biomedical subjects

J Lemay

Publications and source records attributed to J Lemay.

18 recordsLinked to original sources
PubMed2006

Evidence for the homeostatic regulation of induced beta cell mass expansion.

AIMS/HYPOTHESIS: Diabetes results from an insufficient insulin-secreting beta cell mass. Restoration of beta cell mass through pharmaceutically induced endogenous beta cell mass expansion may revolutionise diabetes therapy. However, it remains to be determined whether the induced beta cell mass expansion is under homeostatic regulation. METHODS: Beta cell mass expansion rates were derived from three separate studies of continuous stimulation of islet neogenesis, including the partial duct obstruction of euglycaemic Syrian hamsters, administration of a pentadecapeptide with the same amino acid sequence as residues 104-118 of islet neogenesis-associated protein (INGAP(104-118)) to euglycaemic Syrian hamsters, as well as to euglycaemic CD-1 mice. The incidence of islet neogenesis, average beta cell size, and beta cell replication and apoptotic rates were determined. RESULTS: Partial duct obstruction led to a approximately 2.5-fold increase in endocrine tissue at day 56 (p<0.05). From day 0 to day 7 the average rate of change of islet area was 12.7% per day, and this rate decreased to 5.3% per day from day 7 to day 42, and to 2.8% per day from day 42 to day 56. Administration of INGAP(104-118) to adult hamsters led to a 31% increase in total beta cell mass at day 30 (p=0.031). From day 0 to day 10 the average rate of beta cell mass expansion was 148 mug/day, whereas from day 10 to day 30 it decreased to 45 mug/day. INGAP(104-118) administration to adult CD-1 mice resulted in an approximately twofold increase in beta cell mass after 31 days (p=0.021). However, at day 90, there was no significant difference vs age-matched control mice (p=0.30), even though the neogenic beta cell mass was approximately fourfold greater (p=0.026). Beta cell replication was decreased by 56% (p<0.048), whereas beta cell apoptosis was fourfold greater (p<0.003) in 90-day INGAP(104-118)-treated mice compared with age-matched control mice. CONCLUSIONS/INTERPRETATION: These data indicate that in the presence of ongoing islet neogenesis, homeostatic regulatory mechanisms intervene to regulate beta cell mass according to the prevailing metabolic requirements.

Animals↗
PubMed2001

Norepinephrine-induced aortic hyperplasia and extracellular matrix deposition are endothelin-dependent.

BACKGROUND: Sympathetic hyperactivity is observed in several disease states and may contribute to cardiovascular hypertrophic remodeling. Endothelin has been suggested to be a mediator of hypertrophy. OBJECTIVE: To examine the involvement of endothelin in maintaining the growth response induced by exogenous norepinephrine. DESIGN AND METHODS: Rats were treated with norepinephrine (2.5 microg/Kg per min subcutaneously) for 2 and 4 weeks, alone or in association with the selective endothelin-A (ETA) receptor antagonist, darusentan (LU135252, 30 mg/Kg per day orally) for weeks 3 and 4. RESULTS: Increases in medial cell number and accumulation of collagen and elastin characterized norepinephrine-induced aortic remodeling. These effects occurred without marked changes of mean arterial pressure, but may be related to enhanced pressure variability in addition to direct effects of norepinephrine. Inhibition of ETA receptors by darusentan reversed aortic alterations produced by infusion of norepinephrine. Evaluation of medial apoptosis did not reveal any significant change in any group at 4 weeks. CONCLUSIONS: Antagonism of ETA receptors effectively and rapidly reversed norepinephrine-induced aortic structural and compositional changes, suggesting a central role of endothelin in mediating this response. Thus, ETA receptor antagonists may help to regress large artery remodeling in conditions of increased circulating catecholamine concentrations.

Animals↗
PubMed2000

Angiotensin I-converting enzyme activity and vascular sensitivity to angiotensin I in rat injured carotid artery.

We used a vasoreactivity assay to examine the functional significance of angiotensin I-converting enzyme overexpression in smooth muscle cells after vascular injury. Rat carotid arteries isolated at days 2 to 14 after in vivo endothelial denudation were compared with the contralateral freshly denuded (control) vessels. Arterial rings were constricted ex vivo with angiotensin I in the absence or presence of the angiotensin I-converting enzyme inhibitors captopril (300 nM and 3 microM) or perindoprilate (1 nM). Angiotensin I-converting enzyme activity was determined by cleavage of the chromogenic substrate Hip-His-Leu. Angiotensin I-converting enzyme activity in injured arteries was increased (2-fold) at day 7 only after vascular injury. Contractions to angiotensin I were unaffected after injury. Inhibition by captopril and perindoprilate of angiotensin I-induced contractions was significantly less potent in injured arteries at day 7 as compared to control vessels. Mechanical removal of neointimal smooth muscle cells normalized the inhibition by captopril in injured arteries at day 7. Captopril did not affect angiotensin II-induced contractions. Thus, upregulation of angiotensin I-converting enzyme after arterial injury confers resistance to angiotensin I-converting enzyme inhibitors.

Angioplasty, Balloon↗
PubMed2000

Evidence that nitric oxide regulates AT1-receptor agonist and antagonist efficacy in rat injured carotid artery.

Vascular injury stimulates AT1-receptor expression and nitric oxide (NO) production in smooth muscle cells (SMCs). We examined the ability of AT1 agonists and antagonists to regulate vascular tone ex vivo in injured arteries and the possible modulation by SMC-derived NO. Rings of rat carotid arteries were isolated at day 7 after endothelial denudation and stimulated with angiotensin (Ang) II in the absence or presence of the AT1 antagonists losartan, L-158,809, or EXP-3174. Freshly denuded contralateral arteries were used as controls. AngII-induced contractions were similar in control and injured arteries. Losartan caused an insurmountable inhibition of AngII-induced contractions in injured but not control arteries. Enhanced inhibition of AngII in injured arteries also was observed in the presence of L-158,809 and EXP-3174. In the presence of the NO synthesis inhibitor nitromonomethyl-L-arginine (L-NMMA), maximal contractions to AngII were greater in injured than in control vessels, and AT1-receptor blockade with losartan was surmountable in all vessels. Mechanical removal of superficial neointimal SMCs attenuated NO production and normalized the efficacy of losartan in injured arteries. These results suggest a role for NO in reducing the biologic effects of AT1-receptor agonists and potentiating the efficacy of AT1 antagonists in vessels undergoing remodeling after injury.

Angiotensin Receptor Antagonists↗
PubMed2000

Losartan-induced apoptosis as a novel mechanism for the prevention of vascular lesion formation after injury.

Smooth muscle cell (SMC) apoptosis is transiently increased at the onset of the regression of aortic hypertrophy in spontaneously hypertensive rats (SHR) treated with the angiotensin II AT(1) antagonist losartan. We postulated that losartan induction of SMC apoptosis contributes to suppression of neointimal hyperplasia after vascular injury. Losartan or placebo treatment was initiated two days before balloon injury in the SHR aorta. Compared with time-matched placebo, losartan decreased neointimal cross-sectional area at Days 5 and 10 after injury by 50% and 64% respectively, without affecting medial mass. At Day 10, losartan significantly decreased SMC number (by 56%) in the neointima, but not in the media. DNA synthesis was significantly inhibited at Day 5 but not at Day 10. Losartan significantly increased aortic DNA fragmentation by 2.6- and 4.1-fold, at Days 5 and 10, respectively. In situ labeling of SMC with terminal deoxynucleotidyltransferase revealed significant 61% and 68% increases in apoptotic SMC at Days 5 and 10 with losartan treatment, predominantly in the neointima. Thus, losartan suppressed neointima formation in part by the induction of SMC apoptosis, which may be dissociated from the inhibition of DNA synthesis. Therefore, losartan-induced SMC apoptosis may be a potential therapeutic approach to control occlusive vascular disorders.

Animals↗
PubMed1997

Oral calcium transiently increases calbindin9k gene expression in adult rat duodena.

In rat intestine, the 9 kilodalton calbindin (CaBP9K) is significantly increased in vivo by 1,25-dihydroxyvitamin D3 (1, 25(OH)2D3) through a vitamin D (D) response element located in the 5'-flanking region of the gene. However, in vitro calcium has also been reported to increase CaBP9K gene expression in fetal duodenal culture preparations. The aim of the studies was to investigate whether calcium feeding alone can influence CaBP9K gene expression in vivo in adult rat duodena by evaluating the pattern of expression of its mRNA following short- or long-term exposure to oral calcium, comparing the data to exposure to the known inducer of the gene, 1, 25(OH)2D3. Hypocalcemic D-depleted rats were acutely or chronically supplemented with calcium per os, or with 1,25(OH)2D3 in the presence or absence of oral calcium. Short-term calcium feeding was shown to significantly increase the expression of the CaBP9K gene to a level similar to that observed in 1,25(OH)2D3-treated rats but no additive effect between oral calcium and 1,25(OH)2D3 on the level of its mRNA was observed. Moreover, the calcium effect on CaBP9K gene expression was shown to be independent of the circulating ionized calcium concentration and, contrary to the effect of 1,25(OH)2D3, not sustained following long-term exposure. Our data clearly indicate that oral calcium alone has a significant but only transient effect of the expression of the adult rat intestinal CaBP9K gene in vivo and that maintenance of its expression requires normalization of the D endocrine system.

Administration, Oral↗
PubMed1997

Comparative in vivo expression of the calcitriol-24-hydroxylase gene in kidney and intestine.

Although the kidney and intestine are among the major organs involved in both the biotransformation and action of vitamin D3, they exhibit very distinct roles in calcium and D3 homeostasis. The aim of the present studies was to investigate the relative in vivo responsiveness of renal and intestinal 1,25(OH)2D3-24-hydroxylase (24-hydroxylase) mRNA levels to calcitriol (1,25(OH)2D3) following acute or chronic 1,25(OH)2D3 exposure using hypocalcemic vitamin D-depleted rats as an experimental model. Intestinal 24-hydroxylase mRNA levels were very responsive to a single i.v. injection of 2.4, 12 or 120 nmol 1,25(OH)2D3/kg but in kidney the mRNA levels only increased following exposure to the highest 1,25(OH)2D3 concentration, and exhibited a maximum response only 30% of that in the intestine despite similar tissue uptake of the hormone. To evaluate whether the kidney might preferentially respond to endogenously produced 1,25(OH)2D3, animals received increasing doses of 25(OH)D3. Although the intestinal 24-hydroxylase transcript was highly induced, the renal transcript was unresponsive to 25(OH)D3 treatment despite circulating 1,25(OH)2D3 concentrations of 24 nmol/l. By contrast, intestinal 24-hydroxylase mRNA levels were largely unresponsive to longterm calcitriol administration while the renal transcript, although insensitive to a physiological dose, responded to pharmacological 1,25(OH)2D3 doses. However, when challenged acutely with 1,25(OH)2D3 following chronic exposure, the kidney 24-hydroxylase mRNA levels remained largely unresponsive in contrast to the intestinal transcript which was markedly induced. These data indicate that significant differences exist in the in vivo tissue responsiveness of the 24-hydroxylase mRNA. Indeed, the gene exhibited high intestinal responsiveness to acutely, but not chronically, administered 1,25(OH)2D3, while in the kidney it only responded to high exogenous 1,25(OH)2D3 delivered either acutely or chronically. In addition, these site-specific regulatory mechanisms governing the expression of the 24-hydroxylase gene are independent of the endocrine calcium status and render the kidney relatively resistant to endogenously produced 1,25(OH)2D3.

Animals↗
PubMed1995

Expression of the 1,25-dihydroxyvitamin D3-24-hydroxylase gene in rat intestine: response to calcium, vitamin D3 and calcitriol administration in vivo.

The 25(OH)D3/1,25(OH)2D3 24-hydroxylase (24-hydroxylase) displays an induction profile responsive to vitamin D (D) abundance and is hence only observed in normal extracellular Ca2+ concentrations. However, the participation of Ca2+ in the expression of the 24-hydroxylase gene in vivo is not known. The present studies investigate the role played by the circulating Ca2+ and the D3 and/or 1,25(OH)2D3 status on the 1,25(OH)2D3-mediated inducibility of the 24-hydroxylase gene in rat duodenum. Hypocalcemic D-depleted rats were supplemented with calcium alone to normalize serum Ca2+ without normalizing the D3 status or were acutely or chronically supplemented with D3 or 1,25(OH)2D3. Messenger RNA for the 24-hydroxylase was undetectable in the intestine of hypocalcemic D-depleted rats, and short- or long-term calcium supplementation was completely unsuccessful in inducing its expression. By contrast, acute 1,25(OH)2D3 administration led to significant increases in the levels of expression of the gene which was independent of the calcium intake, the prevailing circulating Ca2+, and the D3 or 1,25(OH)2D3 status. Moreover, 24-hydroxylase gene expression was only found to respond to acutely administered 1,25(OH)2D3, the mRNA levels being unaltered following continuous exposure to physiological or pharmacological doses of the hormone for 7 days. Time-course studies revealed, however, that induction of the gene was clearly apparent early in the 1,25(OH)2D3 supplementation course but gradually faded by 3 days to return to basal uninduced levels by 7 days, suggesting the presence of intestinal adaptation mechanism(s) which down-regulated the responsiveness in the continuous presence of 1,25(OH)2D3. Our data show the lack of effect of calcium alone or in combination with 1,25(OH)2D3 on the in vivo induction of the 24-hydroxylase gene expression in rat intestine. By rapidly reacting to surges in 1,25(OH)2D3 concentrations, the 24-hydroxylase efficiently controls the amount of 1,25(OH)2D3 in intestine as the first step in the biotransformation pathway aimed at the irreversible clearance of the secosteroid hormone.

Analysis of Variance↗
PubMed1992

Responsiveness of the intestinal 1,25-dihydroxyvitamin D3 receptor to magnesium depletion in the rat.

In contrast to man, the rat exhibits hypercalcemia during the course of magnesium depletion. To investigate the role of the vitamin D (D) endocrine system in the induction of hypercalcemia, circulating D metabolites, the binding properties of the duodenal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), and 45Ca transport studies were undertaken in magnesium-replete rats or after 10 days of magnesium depletion in animals presenting the following D status: D depletion and hypo- or normocalcemia (achieved by oral calcium supplementation), D3 or 1,25-(OH)2D3 repletion. Magnesium depletion did not influence serum calcium in hypo- or normocalcemic D depleted rats, but increased serum calcium in animals receiving D3 (P less than 0.002) or 1,25-(OH)2D3 (P less than 0.0001), suggesting that the D3 endocrine system is necessary to mediate the rise in extracellular calcium and that dietary calcium alone is not sufficient to significantly increase extracellular calcium in the hypomagnesemic rat. The data also show that 25-hydroxyvitamin D formation was not perturbed, but circulating 1,25-(OH)2D3 concentrations were reduced by 10 days of magnesium depletion (P less than 0.0001) even in animals infused with 1,25-(OH)2D3, suggesting increased clearance of the hormone. The kinetic data of the duodenal VDR revealed maximum binding sites ranging from 1018-1500 fmol/mg DNA and Kd ranging from 0.17-0.38 nM, with no significant between-group difference in magnesium-sufficient animals. Ten days of magnesium depletion did not significantly influence VDR affinity in any of the groups, but significantly increased receptor number in hypocalcemic D-depleted rats from 1190 +/- 154 to 2748 +/- 430 fmol/mg DNA (P less than 0.004). Calcium transport studies in D-replete animals indicate that intestinal calcium transport is influenced by the progressive depletion in magnesium, with time-related increases coinciding with the in vivo increase in circulating ionized calcium (day 6 of magnesium depletion). However, despite persistent elevated serum ionized calcium, calcium transport declined only to predepletion levels on days 8 and 10 of magnesium depletion. To investigate the influence of the D3 endocrine system on 45Ca absorption, D-depleted rats sufficient or depleted in magnesium were injected with 1,25-(OH)2D3, either acutely (to reveal its membrane effects) or 16 and 5 h before death (to reveal its genomic effect). The data reveal a reduced response in magnesium-depleted rats to acute 1,25-(OH)2D3 injection (P less than 0.0002), but similar responses when the hormone was injected 16 and 5 h before the experiment.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗
PubMed1991

Hepatic drug metabolism during development in food-restricted female Sprague-Dawley rats.

Hepatic drug metabolism was investigated in female Sprague-Dawley rats fed ad libitum (A) or a restricted diet (R) (implemented from age 1 month), at 1.5, 4.5 and 12 months to determine the short- and long-term effects of caloric restriction. Microsomal cytochrome P-450 content and NADPH cytochrome c reductase activity were not modified by age. While dietary restriction did not affect cytochrome P-450, it significantly increased NADPH cytochrome c reductase activity at all time periods when compared to corresponding A-fed groups. Aniline hydroxylase and aminopyrine N-demethylase activity tended to decrease with age in the A-fed groups but the differences did not prove to be statistically significant. A significant decrease of aminopyrine N-demethylase was observed with age in R rats. A significant reduction of aniline hydroxylase activity was noted in the R groups compared to age-matched A-fed controls. In contrast, aminopyrine N-demethylase activity increased significantly, but only at 1.5 months of age. Glutathione S-transferase activity was augmented between 1.5 and 4.5 months of age, and this was followed by a significant decrease at age 12 months in both A and R groups. Dietary restriction had no effect on this enzymatic activity. The microsomal cholesterol and phospholipid content as well as the cholesterol/phospholipid molar ratio changed significantly between 1.5 and 4.5 months of age but not between 4.5 and 12 months of age. These parameters were unaltered by dietary restriction. In conclusion, in the female Sprague-Dawley rat there are no statistically significant changes in hepatic microsomal components and drug metabolizing capacity between 1.5 and 12 months of age. Dietary restriction resulted in significant changes in enzymes related to drug metabolism which varied with the enzyme examined. In general, these changes were similar after short- or long-term dietary intervention.

Aging↗
PubMed1988

Binding of the non-selective opioid [3H]etorphine in the human fetal central nervous system.

The existence of specific, high-affinity opioid binding sites was demonstrated in 21-week-old human fetuses with the use of tritiated etorphine, a non-selective opioid ligand. Binding capacities measured in the brain, the cerebellum and the spinal cord give values of 2.83, 3.71 and 5.42 pmol/g of tissue. Kd values do not vary from one region to the other and are respectively 0.29, 0.35 and 0.33 nM. These results are compared with the characteristics of opioid binding sites found in adults.

Binding Sites↗
PubMedDate not supplied

Specific binding of [3H]-substance P to various regions of the human foetal brain.

The existence of specific binding sites for the tachykinin Substance P was investigated in various regions of the central nervous system of a 28-week-old human foetus. Tritiated Substance P binds with high affinity to various amounts of binding sites in the limbic area of the brain, in the frontal, parietal and occipital cortices as well as in the cerebellum. The presence of these specific sites in the foetus is discussed in relation with the proposed neurotrophic role of Substance P.

Brain↗
PubMedDate not supplied

Development of a flow simulator to study haemodynamic behaviour of natural and artificial blood vessels under physiologic flow conditions.

A new computer-controlled flow simulator has been designed to study the haemodynamic behaviour of natural and artificial blood vessels under physiologic flow conditions. The simulator can generate well characterized and fully developed laminar flow properties. It includes a unique perfusion case that imposes an axial tension on the vessel segment, and a commercial programmable pump to reproduce pulsatile flow rates. Response to high frequency commands was greatly attenuated and displayed a frequency dependent phase angle. Thus, for complex pulsating flow rates containing different frequency components, the system response was significantly distinct from the command. To reproduce physiologic waveforms, the transfer function of the whole system was determined for different amplitudes and frequencies of flow rate excitations. Each input command was compared to the measured flow rate, and the values of the gain and phase angle were evaluated. If the desired flow rate was composed of a sum of n sine wave components, each has a frequency fj and an amplitude Aj, a corrected command signal was then reconstructed by amplifying the attenuated components and advancing those lagged in time. The corrected signal was finally applied as the new command to the pump. The results showed an excellent agreement with physiologic waveforms. Examples of different pulsatile flow experiments to investigate the effects of frequency, pressure, and wall elasticity are presented.

Blood Flow Velocity↗
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

Development of a parallel plate flow chamber for studying cell behavior under pulsatile flow.

The design of a new parallel plate perfusion chamber for cell behavior studies involving pulsatile flowrates is presented. It was based on fluid mechanical considerations to ensure a region of regular and uniform shear stress at the wall. A numeric solution of the flow was performed to study the effect of pulsating flow on the entrance length. Dye injection investigations in the chamber showed laminar and uniform flow in the culture region under steady state conditions.

Cell Adhesion↗