Biomedical subjects

J Sassard

Publications and source records attributed to J Sassard.

At least 55 records · Page 3Linked to original sources

PubMed1994

Cardiovascular effects of basic fibroblast growth factor in rats.

We determined the effects of human basic fibroblast growth factor (bFGF) on blood pressure (BP) and heart rate (HR) in pentobarbital-anesthetized rats and examined the possible involvement of nitric oxide (NO) and prostanoids in these effects. Intravenous (i.v.) injections of bFGF (1, 7.5, and 15 micrograms/kg) induced dose-dependent short-lasting decreases in BP followed by a striking increase in BP and HR variability. The BP and HR increases in variability were closely related (r = 0.95; n = 20; p < 0.001). Pretreatment with a single intravenous (i.v.) dose of N omega-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg) almost suppressed (-90%) the cardiovascular effects of bFGF, an effect that was restored by a single dose of L-arginine (100 mg/kg i.v.). Similar suppression was observed with use of indomethacin (10 mg/kg i.v.). Indomethacin given 50-60 min after bFGF abolished the increased variability of BP and HR. We conclude that the BP decrease and the increase in BP and HR variability induced by bFGF involve release of both NO and vasoactive prostanoids.

Animals↗

PubMed1994

Influence of hepatic impairment on the pharmacokinetics of nefazodone and two of its metabolites after single and multiple oral doses.

The pharmacokinetics of nefazodone, a new antidepressant, and two of its active metabolites, hydroxy-nefazodone and m-chlorophenylpiperazine, were determined after single and repeated oral escalating doses of 50, 100 and 200 mg, in healthy volunteers (n = 13) and patients with mild (n = 13) or severe (n = 6) hepatic impairment. All subjects were classified according to their dextromethorphan oxidation capacity. In healthy volunteers, nefazodone was rapidly absorbed after which the plasma concentrations declined with an apparent elimination half-life ranging from 2.7 +/- 1.7 h to 10.2 +/- 4.4 h according to the dosage. Hydroxy-nefazodone appeared rapidly in plasma and its time-course (half-life ranging 1.4 +/- 0.9 h to 6.5 +/- 1.6 h) paralleled that of nefazodone, while mCPP showed low and variable concentrations. The disproportionately longer half-life and more markedly increased Cmax and AUC0-48 which was observed with dosage and treatment duration, and moreover AUC0-12 at steady state significantly higher (P < 0.05) than AUC0-infinity after single dose demonstrated the non-linearity of the pharmacokinetics of nefazodone and hydroxy-nefazodone. The constant molar AUC0-48 hydroxy-nefazodone/nefazodone ratio (0.32 +/- 0.04) and the close correlation (r2 = 0.95) between kinetic parameters of nefazodone and hydroxy-nefazodone suggest that nefazodone hydroxylation is not a saturable process. The kinetics of nefazodone and metabolites were significantly affected by severe but not by mild liver insufficiency. As a consequence, on a pharmacokinetic basis nefazodone should be used with caution in severely hepatic impaired patients.

Adolescent↗

PubMed1994

Cardiovascular effects of human recombinant interleukin-1 beta in conscious rats.

Cardiovascular effects of human recombinant interleukin-1 beta (hrIL-1 beta) were investigated in normotensive rats using a computerized analysis of arterial blood pressure in conscious, unrestrained animals. Intravenous injection of hrIL-1 beta induced a rapid and short-lasting rise in blood pressure associated with a first slight tachycardia followed by a second sustained and pronounced increase in heart rate. These effects occurred in a dose-related manner. Pretreatment with a converting-enzyme inhibitor (perindopril) did not modify the hrIL-1 beta-induced increase in blood pressure. Blockade of beta 1-adrenoceptors (atenolol) prevented the tachycardia, but did not significantly affect the pressor response to hrIL-1 beta. On the contrary, the hrIL-1 beta-induced increase in blood pressure was inhibited by an alpha 1-adrenoceptor antagonist (prazosin), whereas the tachycardia was untouched. Finally, pretreatment with a cyclooxygenase inhibitor (indomethacin) completely abolished the cardiovascular response to hrIL-1 beta. These results suggest that the hrIL-1 beta-induced pressor response and associated tachycardia require the synthesis of prostaglandins and involve a sympathetic nervous system activation but do not depend on the renin-angiotensin system.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Prostaglandin H2-thromboxane A2 and renal functions in the Lyon hypertensive rat.

The influence of renal perfusion pressure (RPP) on renal functions was studied in anesthetized 8-wk-old Lyon hypertensive (LH) and normotensive (LN) rats before and after a specific blockade of prostaglandin (PG) H2-thromboxane (Tx) A2 receptors using GR-32191B. The nervous and hormonal influences on the kidneys were controlled by renal denervation, adrenalectomy, and an infusion of norepinephrine, aldosterone, hydrocortisone, and vasopressin. With the use of inflatable cuffs, RPP was varied from 100 to 125 and then to 150 mmHg. In control conditions, the renal blood flow (RBF) and glomerular filtration rate (GFR) were independent of RPP in both strains. LH kidneys differed from LN controls by an increased preglomerular vasoconstriction as indicated by a similar decrease in RBF and GFR. Moreover, the pressure-natriuresis curve was blunted in LH compared with LN kidneys. GR-32191B did not affect the renal function of LN rats. In LH kidneys, it normalized RBF and renal vascular resistance and improved GFR, whereas it had no effect on the pressure-natriuretic relationship. It is concluded that the elevated preglomerular vascular resistance that characterizes LH rats is dependent on an overstimulation of PGH2-TxA2 receptors whereas these latter are not involved in the control of pressure-natriuresis.

Analysis of Variance↗

PubMed1994

Thromboxane A2-prostaglandin H2 and renovascular hypertension in rats.

To evaluate the contribution of thromboxane (Tx) A2-prostaglandin (PG) H2 in two-kidney, one-clip Goldblatt hypertension (GH), 26 GH rats were chronically treated (GHT) with a specific TxA2-PGH2 receptor antagonist, CGS-22652 (30 mg.kg-1.24 h-1 sc); 28 others as well as 17 sham-clipped (SC) rats received vehicle. Twelve GH and 3 GHT rats developed malignant hypertension and died. After 6 wk of treatment, GH rats exhibited higher mean blood pressure (BP; 189 +/- 3 vs. 118 +/- 2 mmHg) and an increased vascular reactivity to the main pressor agents compared with SC rats. Chronic TxA2-PGH2 receptor blockade lowered mean BP in 13 GHT rats (125 +/- 3 mmHg) and decreased their vascular reactivity compared with GH rats. However, 10 GHT rats remained hypertensive (190 +/- 9 mmHg) and differed from the former by an increased vascular reactivity to vasopressin. It is concluded that renal artery clipping induces either benign or malignant hypertension. In benign forms, TxA2-PGH2 blockade normalizes BP through decreasing the vascular responsiveness to the main pressor agents. In malignant forms, it limits the elevation of BP and markedly reduces mortality.

Aging↗

PubMed1994

Pressure control of renal renin release in Lyon hypertensive rats.

OBJECTIVE: To assess whether the pressure-independence of renin release by isolated kidneys of Lyon hypertensive (LH) rats could result from long-term exposure to high blood pressure, sodium retention or an altered regulation of intracellular calcium through L-type voltage operated channels. DESIGN: Renin release was studied in kidneys from LH rats, either controls or chronically (aged 3-7 weeks) treated with hydralazine or deprived of sodium. The influence of L-type calcium channels was studied acutely using a specific activator (BAY K8644) or modulator (verapamil). Lyon low blood pressure (LL) rats served as controls. METHODS: Kidneys were isolated from LH or LL rats aged 7 weeks and single-pass perfused at three pressure levels: 70, 85 and 160 mmHg. RESULTS: LH rat kidneys differed from LL rat kidneys in having elevated vascular resistances, decreased glomerular filtration rate, pressure natriuresis and pressure-dependent renin release. Hydralazine treatment and sodium deprivation did not significantly modify the pressure-independence of renin release by LH rat kidneys. BAY K8644 (1 x 10(-8) and 5 x 10(-8) mol/l) induced significantly greater vasoconstrictor effects in LH than in LL rat kidneys but did not affect the renin release already stimulated by low perfusion pressure. Verapamil (5 x 10(-6) mol/l) dilated LH more than LL rat kidneys. It did not change the renin release observed at low, but enhanced it at high, perfusion pressure. This effect was more marked in LL than in LH rat kidneys. CONCLUSIONS: The poor stimulation of renin release by low perfusion pressure in LH rat kidneys does not appear to be a consequence of high blood pressure level, sodium retention and alteration in L-type calcium channels. However, results demonstrate that these channels participate in the increased vascular resistances exhibited by LH rat kidneys.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1994

Decreased cardiac baroreflex sensitivity is not due to cardiac hypertrophy in NG-nitro-L-arginine methyl ester-induced hypertension.

OBJECTIVE: To investigate the link between cardiac hypertrophy, elevated blood pressure level and baroreflex impairment, we assessed cardiac baroreflex function in a hypertensive model almost devoid of cardiac hypertrophy, obtained by nitric oxide synthesis inhibition. METHODS: Thirteen adult male Wistar rats were treated orally with NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg per 24 h) for 4 weeks. Fifteen control rats received tap water. At the end of the treatment aortic blood pressure was recorded continuously and the baroreceptor-heart rate curve was assessed by bolus injections of phenylephrine and sodium nitroprusside (10 different doses of each). RESULTS: Mean blood pressure was higher in L-NAME rats than in control rats, whereas body weight was similar. Total heart weight and left ventricular weight did not differ between the groups. Cardiac baroreflex was reset in hypertensive rats, as indicated by a rightwards shift of the mean blood pressure-heart rate curve. Its gain was decreased significantly in L-NAME rats, whereas the heart rate range was not different between the two groups. CONCLUSION: L-NAME hypertensive rats exhibit an original impairment of cardiac baroreflex, characterized by a range-independent decreased gain which is not due to cardiac hypertrophy.

Animals↗

PubMed1993

Atrial natriuretic factor: plasma concentration and specific binding to renal glomeruli during the development of genetic hypertension in rats of the Lyon strain.

1. The pathophysiologic role of atrial natriuretic factor (ANF) in genetic hypertension was investigated in 5- and 21-week-old genetically hypertensive (LH), normotensive (LN) and low blood pressure (LL) rats of the Lyon strain. 2. Plasma ANF was significantly higher in 5-week-old LH than in age-matched LN and LL animals. It tended to be lower in 21-week-old LH than in LN rats. 3. Left and right atrial ANF content was also significantly lower at 21 weeks in the LH group. 4. Glomerular ANF receptors showed a significant decrease in LH in comparison to LL and LN animals.

Animals↗

PubMed1993

Genetic determinants of diastolic and pulse pressure map to different loci in Lyon hypertensive rats.

Several genetic loci involved in blood pressure regulation have recently been localized in experimental models of hypertension, but the manner in which they influence blood pressure remains unknown. Here, we report a study of the Lyon hypertensive rat strain showing that different loci are involved in the regulation of steady-state (diastolic pressure) and pulsatile (systolic-diastolic, or pulse pressure) components of blood pressure. Significant linkage was established between diastolic blood pressure and a microsatellite marker of the renin gene (REN) on rat chromosome 13, and between pulse pressure and the carboxypeptidase B gene (CPB) on chromosome 2. These findings show that two independent loci influence different haemodynamic components of blood pressure, and that pulse pressure has a specific genetic determination.

Analysis of Variance↗

PubMed1993

Do thymic-neuroendocrine interactions play a role in the antihypertensive effect of neonatal thymectomy in Lyon hypertensive rats?

Previous studies showed that neonatal thymectomy prevented the spontaneous increase in blood pressure in genetically hypertensive rats (LH) of the Lyon strain, leaving untouched that of their normotensive controls (LN). As the thymus is connected to the neuroendocrine system through secretion of hormonal factors, we investigated the possible role played by these factors in hypertension of LH rats. To that end we studied, in sham-operated and neonatally thymectomized LH rats, the blood pressure effects of thymostimulin, a partially purified thymus extract and examined whether changes in major neuroendocrine factors of blood pressure regulation occurred in thymectomized LH rats. Thymostimulin (1 or 10 mg/kg/48 h) did not modify blood pressure in sham-operated LH rats and failed to consistently increase it in neonatally thymectomized animals. Urinary mineralocorticoids, catecholamines and their metabolites, and plasma renin levels were not altered by neonatal thymectomy. Plasma testosterone was decreased to a similar degree by neonatal thymectomy in LH and normotensive controls. These results do not favor a pressor role of thymic hormonal factors in LH rats and show that the antihypertensive effect of neonatal thymectomy is not secondary to a decreased secretion of catecholamines, renin, mineralocorticoids, and testosterone. They therefore suggest that the role of the thymus in genetically hypertensive LH rats is more likely mediated by cellular immune mechanisms than by hormonal processes.

Animals↗

PubMed1993

Failure of the heat-shock protein 70 locus to cosegregate with blood pressure in spontaneously hypertensive rat x Wistar-Kyoto rat cross.

OBJECTIVE: To investigate the involvement of the heat-shock protein 70 (hsp70) locus, located in the rat major histocompatibility complex (RT1), in hypertension of the spontaneously hypertensive rat (SHR). Previous studies have shown abnormal expression of hsp70 in the SHR and an association of the SHR hsp70 allele with increased blood pressure in recombinant inbred strains derived from a cross of SHR with Brown-Norway rats. DESIGN: SHR were crossed with normotensive Wistar-Kyoto (WKY) rats to produce a large cohort of F2 rats segregating for blood pressure and hsp70 alleles. Two hundred and thirty-three rats were maintained on a normal-salt diet and 167 were put on a high-salt diet (1% sodium chloride in drinking water) from 16 to 26 weeks of age. METHODS: Blood pressure was measured indirectly at 12, 16 and 20 weeks of age in rats on the normal-salt diet and at 16 (pre-salt), 18 and 20 weeks in rats on the high-salt diet. Both groups had direct conscious blood pressure measurements at 25-26 weeks of age. Genotyping was carried out for a BamH1 polymorphism in the hsp70 gene by Southern blotting. RESULTS: The hsp70 genotype had no effect on any of the blood pressure measurements in rats on either diet. CONCLUSIONS: We find no evidence of linkage between the hsp70 gene locus, and by implication other genes located within the rat RT1 complex, and blood pressure in our cross of SHR and WKY rats.

Animals↗

PubMed1993

Effects of naftidrofuryl on isolated perfused kidneys of spontaneously hypertensive rats.

1. Experiments were designed to determine the effects of low concentrations (5-500 nmol/L) of naftidrofuryl, a 5-hydroxytryptamine (5-HT) antagonist, on renal functions and prostanoid synthesis responses to noradrenaline (NA) and 5-HT. Isolated kidneys of 8 week old male spontaneously hypertensive rats were perfused at a constant flow rate in a single-pass system. 2. In baseline conditions, naftidrofuryl did not modify the renal vascular resistance and the glomerular filtration rate (GFR), although it elicited a significant but not dose-dependent increase in the venous excretion of 6-keto-prostaglandin (PG) F1 alpha and thromboxane (Tx)B2, the stable end-products of PGI2 and TxA2, respectively. 3. NA increased renal vascular resistance and GFR in a dose-dependent manner and enhanced the venous excretion of 6-keto-PGF1 alpha and TxB2. Naftidrofuryl significantly attenuated the effects of NA on renal vascular resistance, abolished those on GFR and enhanced, at the highest concentration (500 nmol/L) only, those on 6-keto-PGF1 alpha excretion. 4. 5-HT increased renal vascular resistance but not GFR. It did not change the sodium excretion and the release of 6-keto-PGF1 alpha and TxB2. Naftidrofuryl blunted the RVR response to 5-HT without change in the prostanoid release. The inhibitory action of naftidrofuryl was not modified by indomethacin which, by itself, prevented the vasoconstrictor response to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1993

Blood pressure effects of thromboxane A2 blockade in spontaneously hypertensive rats.

1. The effects of CGS 22652, a thromboxane (Tx) A2 synthase inhibitor and TxA2/prostaglandin (PG) H2 receptor antagonist, on blood pressure (BP) were studied in conscious freely moving spontaneously hypertensive rats (SHR). 2. Three groups of 13 male SHR were subcutaneously infused from 5 to 11 weeks of age via osmotic minipumps with CGS 22652 at doses of 5 (SHRa) or 10 (SHRb) mg/kg per 24 h or with the vehicle only (SHRc). A fourth group (SHRd, n = 13) was orally treated from 3 to 11 weeks of age with CGS 22652 (30 mg/kg) given by gavage once a day. 3. CGS 22652 dose-dependently reduced the age-related increase in systolic BP. The pressor response to noradrenaline (200 ng/kg, i.v.) but not to angiotensin I or II was slightly (P < 0.05) diminished in 11 week old SHRb and SHRd compared to SHRc. Acute ganglionic blockade by trimethaphan (10 mg/kg, i.v.), as well as angiotensin converting enzyme inhibition by perindopril (2 mg/kg, i.v.) decreased BP to a similar extent in the four groups. After combined blockade of vasopressin receptors and of the autonomic nervous system and the administration of a direct vasodilator (hydralazine, 3 mg/kg, i.v.), the residual mean BP was identical in the four groups of rats. 4. Chronic treatment with CGS 22652 dose-dependent antagonized the TxA2/PGH2 receptors but did not modify the TxA2 synthesis. The urinary sodium excretion did not differ between groups. 5. In conclusion, at the doses used, CGS 22652 given either orally or subcutaneously exhibited only TxA2/PGH2 receptor blocking properties in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1993

Eicosanoid-dependence of responses of pre- but not postglomerular vessels to noradrenaline in rat isolated kidneys.

1. We investigated the role of nitric oxide (NO) and of vasoactive eicosanoids in the control of renal vascular resistance (RVR) and glomerular filtration rate (GFR) and of their responses to noradrenaline (NA). This study was conducted in single-pass perfused, isolated kidney preparations of the rat. 2. NA (63, 110 and 160 nM) dose-dependently increased RVR and to a lesser degree GFR. 3. In baseline conditions, N omega-nitro-L-arginine methylester (L-NAME, 100 microM) increased GFR more than RVR, thus demonstrating a basal release of NO which predominates in postglomerular vessels. 4. In kidneys stimulated with NA, L-NAME potentiated the increases in RVR but not in GFR. Indomethacin (1.5, 150 nM and 15 microM) did not alter GFR but markedly and dose-dependently reduced the NA-induced increase in RVR. Similar results were obtained with GR 32191B (10 and 100 microM), a prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor antagonist. 5. Indomethacin (15 microM) suppressed the enhancing effects of L-NAME on RVR responses to NA but did not affect those on GFR. 6. It is concluded that the mechanisms of the response to NA differ among pre- and postglomerular vessels. In preglomerular vessels the vasoconstrictor action and the NO release depend upon the activation of PGH2/TxA2 receptors, while both are eicosanoid-independent in the postglomerular vessels.

Animals↗

PubMed1993

Alteration of cardiac energy state during development of hypertension in rats of the Lyon strain: a 31P-NMR study on the isolated rat heart.

The effect of different chronic blood pressure levels on cardiac energy metabolism was studied by 31P-NMR spectroscopy in perfused hearts from the Lyon strains of hypertensive (LH), normotensive (LN) and hypotensive (LL) rats at the ages of 12 and 21 weeks. The in vivo assessment of haemodynamic parameters measured at 21 weeks in anaesthetized rats with an ultraminiature catheter pressure transducer confirmed that left ventricular systolic pressure and mean aortic pressure were significantly greater (+25%) in LH rats than in LN and LL rats. In the LL animals, left ventricular systolic pressure was slightly reduced (-10%) and cardiac contractility (estimated by LV dP/dtmax) showed a 24% decreased compared to normotensive animals. The energy state of the cardiomyocytes was characterized at different work levels of isolated rat hearts, by determining the concentration of the free phosphorylated compounds at each work level. Changes in workload were induced by varying the calcium concentration in the perfusion fluid. Increasing extracellular calcium concentration resulted in a similar increase in left ventricular developed pressure (LVDP) in all groups studied. Intracellular pH was not influenced by either the age of the animals or the level of cardiac work, in the three groups of animals. ATP content of the LN and LL rats remained constant during the whole perfusion period while the 12 week-old LH rats showed a decreased ATP content with increasing cardiac work. In the older LH rats, ATP content was decreased at the highest work level (corresponding to 2 mM calcium). In response to the increase in work, phosphocreatine (PCr) content diminished and inorganic phosphate (Pi) content increased in both LN, LH and LL animals. PCr degradation and Pi accumulation were higher in the LH rats and less in LL rats compared to the LN. These changes were more important in the younger than in the older hypertensive animals. The relationship between LVDP and [Pi]/[PCr] indicates that oxidative metabolism is maximally activated in the young hypertensive rats and suggests that this maximal activation represents an adaptive phase to the increase in blood pressure. Since the difference between the metabolic pattern of the 21 week-old LH rats and age-matched LN rats was less pronounced, it is likely that a compensatory stage has been reached at that age.

Animals↗

PubMed1993

High blood pressure maintenance in transgenic mRen-2 vs. Lyon genetically hypertensive rats.

The present work was aimed to assess the factors involved in the maintenance of hypertension in adult transgenic mRen-2 (TG) rats. Special attention was paid to the renal handling of sodium, the sympathetic, and the renin-angiotensin system (RAS) activity. TG rats were compared with age-matched Lyon genetically hypertensive rats (LH), as both are of Sprague-Dawley origin. Blood pressure (BP), heart rate, and renal sympathetic nerve activity (RSNA) were recorded in conscious freely moving animals. Kidneys were isolated and single-pass perfused at different pressure levels. It was observed that the peripheral sympathetic drive was identical in TG and LH rats as indicated by their similar 24-h urinary excretion of catecholamines and methoxylated metabolites, baseline RSNA and its control by the baroreflex, and hypotensive response to ganglion-blockade. On the contrary, TG rats differed from LH rats by a more rapid excretion of an oral isotonic sodium load, a greater hypotensive and natriuretic response to furosemide, and a more marked BP response to acute RAS blockade. The TG kidney responses to stepwise changes in renal perfusion pressure (RPP) differed from those of LH rats by significantly higher perfusate flow and glomerular filtration rate. However, the pressure natriuresis curve of TG kidneys did not differ from that of LH rats because of an elevated tubular sodium reabsorption rate. These results suggest that adult TG rats, compared with LH rats, exhibit a tendency toward sodium and water retention, which may explain that despite low renal and circulating renin levels, the RAS remains involved in the maintenance of high BP in that model.

Animals↗

PubMed1993

A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure.

The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that a recently identified gene of yet unknown function, termed SA, which is differentially expressed in the kidney of the spontaneously hypertensive rat, cosegregates with an increase in blood pressure in F2 rats derived from a cross of the spontaneously hypertensive rat with normotensive Wistar-Kyoto rats, accounting for 28 and 21% of the genetic variability in systolic and diastolic blood pressures, respectively. Further, the genotype at this locus appears to determine the level of expression of the gene in the kidney. The findings provide strong evidence for a primary genetic involvement of the kidney in hypertension.

Aging↗

PubMed1993

[Genetic hypertension in the rat is partially dependent of parathyroid glands. Results of a crossed transplantation trial].

The parathyroid hypertensive factor (PHF) is present in the plasma of SHR rats. The authors of this study set out to determine whether this factor was also present in the Lyon (LH male and female) and Milan (MHS male) hypertensive rats. Five week old normotensive rats (LN and MNS) were transplanted with the parathyroid glands of LH and MHS rats immediately after parathyroidectomy (PTX). Plasma calcium fell rapidly after PTX but returned to physiological levels, confirming the functional activity of the graft. Systolic blood pressures of transplanted rats were significantly higher than normotensive LN and MNS controls. These results confirm the role of the parathyroid glands in the genesis of hypertension in Lyon and Milan male and female rats. They suggest that PHF may be implicated in the hypertensive mechanisms of these two models of genetic hypertension.

Animals↗