Biomedical subjects

J Sassard

Publications and source records attributed to J Sassard.

At least 91 records · Page 5Linked to original sources

PubMed1991

Adrenergic stimulation of renal prostanoids in the Lyon hypertensive rat.

Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of norepinephrine and an elevated urinary excretion of thromboxane B2 when compared with normotensive (LN) and low blood pressure (LL) controls. Therefore, the effects of norepinephrine (1.2 x 10(-8) to 9.6 x 10(-7) M) and of phenylephrine (5 x 10(-8) to 1.9 x 10(-6) M) on renal function and the urinary excretion of prostanoids were assessed in isolated perfused kidneys of 8-week-old LH, LN, and LL rats. In addition, the effects of norepinephrine were assessed before and during thromboxane A2/prostaglandin H2 receptor blockade by AH23848 (4 x 10(-6) M). Before drug infusion, LH kidneys differed from those of LN and LL controls by having an elevated renal vascular resistance and a decreased natriuresis and glomerular filtration rate; the urinary output of prostaglandin E2 and F2 alpha, of 6-ketoprostaglandin F1 alpha, and of thromboxane B2 was similar in the three strains. The constrictor effects of norepinephrine and phenylephrine were significantly increased in LH rat kidneys compared with LL but not with LN controls, and their pressure-natriuresis was markedly reduced. Norepinephrine and phenylephrine induced a 10- to 20-fold dose-dependent increase in the synthesis of the four prostanoids, which was more pronounced in LH than in LN and LL rats for thromboxane B2 only. AH23848 infusion significantly reduced the vascular effects of norepinephrine and increased the natriuretic response of LH but not of LN and LL rat kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

[Origin and role of circulating catecholamines in the normotensive sympathectomized rat].

Early chronic treatment with guanethidine destroys peripheral sympathetic nerves while sparing the adrenal medulla, and does not lower blood pressure (BP) in conscious normotensive rats (Julien et al. Am J Physiol 1990; 259: H1337). Therefore, the origin and role of circulating catecholamines (CAs) in BP maintenance were examined in conscious normotensive control, sympathectomized (SNX)--daily s.c. injections of guanethidine from 1 to 13 weeks of age--and sympathectomized-adrenalectomized (SNX-A) rats by measuring i) their plasma CAs (norepinephrine, NE and epinephrine, E) and 3,4-dihydroxyphenylglycol (DHPG) by HPLC-FD, and ii) their mean BP (MBP) responses to phenylephrine and phentolamine (5 mg/kg i.v.). The doses of phenylephrine that produced similar MBP rises were 3 micrograms/kg in controls (44 +/- 4 mmHg) and 1.5 micrograms/kg in SNX (47 +/- 3 mmHg) and SNX-A (48 +/- 2 mmHg) rats. Results are as follows: [table: see text] In conclusion, in conscious normotensive SNX rats: (1) most of the circulating NE is of adrenomedullary origin and plasma DHPG derives from neuronal NE; (2) due to supersensitivity of the cardiovascular system, stimulation of alpha-adrenoreceptors by circulating CAs play a significant role in BP maintenance.

Adrenal Medulla↗

PubMed1991

[Role of sympathetic nervous system on blood pressure and heart rate variabilities in the rat: spectral analysis].

The role of the sympathetic nervous system (SNS) in the genesis of the beat-to-beat variability of blood pressure (BP) and heart rate (HR) was studied using spectral analysis. The SNS activity of genetically normotensive rats of the Lyon strain (LN) was abolished in 2 ways: 1) adrenergic blockade with administrations of phentolamine (PHE, 5 mg/kg i.v.) or propranolol (PRO, 5 mg/kg i.v.) or both drugs (PHEPRO) or 2) destruction of the sympathetic fibers with an early chronic treatment with guanethidine (LNSx). HR and systolic (SBP) and diastolic (DBP) BP spectra were computed using 50 to 100 stationary sequences from 1 h beat-to-beat recordings and covered the 0.015-3.85 Hz frequency band. In LN rats, spectra obtained in baseline conditions exhibited a high-frequency peak (HF, 1.04-1.13 Hz) related to the respiratory frequency and a mid-frequency peak (MF, 0.38-0.45 Hz). Concerning BP, the alterations of the SNS induced significant decreases of the total modulus (mmHg/Hz1/2) of the MF band (0.27-0.74 Hz): [formula: see text] In addition, the MF peak of SBP and DBP spectra was abolished in LNSx and PHEPRO rats. Concerning HR spectra, the moduli of all the frequency components were decreased in PHEPRO rats only. In conclusion, the similarity of the results observed in LNSx and PHEPRO rats shows that the MF oscillations of BP depend in a large extent (65%) on the action of the sympathetic fibers and involve the activation of both alpha- and beta-adrenoceptors. Concerning DBP, this effect is especially mediated by the activation of alpha-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Basal prostaglandin synthesis by the isolated perfused rat kidney.

In order to assess the main characteristics of the prostaglandin (PG) biosynthesis by the isolated perfused rat kidney, the urinary and venous outputs of PGE2, PGF2alpha, 6-keto-PGF1alpha and of thromboxane (Tx)B2 were followed during 120 min after an equilibration period of 30 min. Single pass kidneys were perfused with a Krebs-Henseleit solution added with Polygeline at a constant flow rate providing a perfusion pressure about 90 mm Hg. From the beginning of the study, major differences could be observed in the renal biosynthetic rate of the 4 PG studied which were mainly excreted into the venous effluent. During the perfusion, urinary and venous outputs of PGE2, PGF2alpha and of TxB2 remained stable whereas those of 6-keto-PGF1alpha sharply increased and were found inversely related to the glomerular filtration rate (r = -0.95; p n 0.001). Finally, the urinary and venous outputs of each of the four PGs studied were found positively related. It is concluded that the isolated perfused rat kidney is a valuable preparation for studying the biosynthesis of PGs and that, at least in thi model, the urinary excretion of PGs is a good index of their renal synthesis.

Animals↗

PubMed1990

Dietary calcium, vascular reactivity, and genetic hypertension in the Lyon rat strain.

In order to examine the relationship existing between dietary calcium and the development of hypertension, we developed a long-term study in the Lyon hypertensive rat strain (LH) and two control strains, the Lyon normotensive (LN) and low blood pressure rats (LL) given enriched (HCa, 2.5%), deprived (LCa, 0.03%) and normal (NCa, 0.6%) calcium diets. Evolution of body weight, systolic blood pressure (BP), plasma calcium and magnesium was monitored from 4 to 23 weeks of age. Total cardiovascular reactivity and contractile response of isolated aorta to norepinephrine were measured at 23 weeks of age. LH rats on HCa diet failed to develop hypertension (BP less than 150 mm Hg) whereas LH rats on LCa diet exhibited higher blood pressure levels than their controls fed the NCa diet. Moreover, in LN rats HCa diet slightly decreased BP whereas LCa had no effect. In the LL rats, on the contrary, only LCa diet slightly increased BP. In vivo responsiveness to NE was significantly higher in LH compared to LL and LN rats fed a NCa diet. HCa and LCa diets both induced a significant decrease in this response in LH rats. HCa diet increased the response in LN rats but decreased it in LL. In contrast, at the same age, the in vitro contractile response of isolated aorta to NE was significantly decreased in LH compared to LN and LL rats receiving NCa diet. Moreover in LH and LN rats on HCa diet the contractile response was markedly increased but no significant difference was observed with LCa diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Analysis of the renin gene intron A tandem repeat region of Milan and Lyon hypertensive rat strains.

The region of intron A of the rat renin gene containing a unique tandemly repeated sequence was analysed in the Milan and Lyon hypertensive rat strains and their controls, and in several Sprague-Dawley rats, using an oligonucleotide probe complementary to the tandemly repeated sequence and a renin complementary DNA probe. In the Milan rats, the size of the Bgl II DNA fragment encompassing the tandem repeat region was the same in the hypertensive (MHS) and normotensive (MNS) strains. In the Lyon model, a difference of 1.1 kilobase (equivalent to about 28 copies of the 38 basepair tandem repeat sequence) was observed in the size of the Bgl II fragment of the hypertensive (LH) and normotensive (LN) strains. However, the finding that the size of the fragment in the Lyon low-blood-pressure (LL) strain was the same as that in the LH strain rather than the LN strain suggests that the difference between the two latter strains is not by itself a major cause of the blood pressure difference between them in the intron A tandem region. An analysis of Sprague-Dawley rats, from which the Lyon strains are derived, showed that at least three different renin gene alleles, two with Bgl II fragments of the same size as those seen in the Lyon strains, are randomly segregating in this population.

Alleles↗

PubMed1990

Parathyroidectomy in the Lyon hypertensive rat: cardiovascular reactivity and aortic responsiveness.

We have studied the effect of parathyroidectomy on the systolic blood pressure, cardiovascular reactivity and the contractile response of isolated aorta to norepinephrine in the genetically hypertensive Lyon rat strain (LH), parathyroidectomized hypertensive Lyon rats (LH-PTX) and parathyroidectomized hypertensive Lyon rats given a Ca-enriched diet to re-establish normocalcemia (LH-PTX + Ca). Parathyroidectomy significantly lessened (-20%) the development of elevated blood pressure. In the LH-PTX + Ca, the blood pressure was lower than that of LH controls but was higher than that of LH-PTX. At 23 weeks, in vivo responsiveness to norepinephrine and angiotensin II was significantly lower in the LH-PTX and only slightly decreased in the LH-PTX + Ca. In contrast, at the same age, the in vitro contractile response of isolated aortas to norepinephrine was significantly higher in the LH-PTX compared with other groups. Interestingly, without endothelium, this difference disappeared. In conclusion, parathyroidectomy lessened the blood pressure elevation in the Lyon model of hypertensive rats via mechanisms that are partly independent of serum calcium levels.

Animals↗

PubMed1990

Predictive value of phase I studies: relevant criteria.

Phase I studies cannot predict the therapeutic efficacy of a new drug. However, they can lead to important information concerning: i), the undersirable effects and their mechanisms of occurrence; and ii), the pharmacokinetics and the metabolism of the drug as well as their possible alterations in renal or hepatic diseases. When considering the therapeutic effects, 3 cases have to be considered which are, in order of decreasing predictive value: i), when a direct relationship is expected between the drug concentration in the body and its therapeutic effects (eg, antibiotics); ii), when the drug has a known molecular or cellular target which is directly involved in the pathophysiology of the disease (eg, renin inhibitors); and iii), when the drug does not have a known target or is directed toward a precise target which is not directly involved in the disease. In all these cases, a phase I study in healthy volunteers should be able to describe, at least qualitatively, the pharmacodynamic effects of the drug which are relevant to its therapeutic goal.

Drug Evaluation↗

PubMed1990

Cardiovascular consequences of organophosphorus poisoning and of antidotes in conscious unrestrained rats.

The cardiovascular effects of two organophosphorus, paraoxon and soman, as well as of antidotes advocated in the treatment of these intoxications have been investigated using a computerized analysis of arterial blood pressure in conscious unrestrained rats. Intravenous administration of paraoxon as well as of soman produced a marked, sustained and dose-related increase in blood pressure associated with a bradycardia. Pyridostigmine, a quaternary carbamate, neither altered blood pressure nor heart rate. Benzodiaxepines, such as diazepam or loprazolam, and atropine induced a dose-dependent tachycardia while pralidoxime decreased heart rate. A complete therapeutic scheme including the intravenous administration of pyridostigmine 10 min. before a postpoisoning therapy made of pralidoxime, diazepam and atropine induced a transient tachycardia, which was followed, after a return to control values, by a second and more stable tachycardia concurrently to a slight hypertension. Postpoisoning therapy alone suppressed the pressor effect of soman within a few minutes after its administration. Afterwards, this therapy reduced the importance of the cardiovascular effects produced by soman. Pyridostigmine pretreatment decreased the protection afforded by postpoisoning therapy in soman-intoxicated rats. These results show that postpoisoning therapy with pralidoxime, diazepam and atropine has a noteworthy efficacy against cardiovascular manifestations of soman intoxications in the rat.

Animals↗

PubMed1990

Effects of sympathectomy on blood pressure and its variability in conscious rats.

To further assess the role of the sympathetic nervous system (SNS) in the control of blood pressure (BP), continuous recordings of BP were performed in conscious freely moving rats that had received daily injections of guanethidine or saline from 7 to 90 days of age. Guanethidine extensively destroyed the peripheral sympathetic fibers as indicated by marked decreases in the norepinephrine content of the heart and kidneys and the absence of pressor response to tyramine injection. Such a chronic sympathectomy did not alter the BP and heart rate (HR) levels but markedly enhanced the BP variability while the HR variability and the sensitivity of the cardiac baroreceptor reflex were not altered. Angiotensin-converting enzyme inhibition with perindopril induced a rapid fall in BP and normalized the BP variability in sympathectomized animals. It is concluded that in rats, the SNS is not necessary for the full development of the BP level but is essential to buffer the spontaneous variability of BP. After sympathectomy, BP is maintained at nearly normal levels mainly through activation of the renin angiotensin system.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

Antirenin immunization versus angiotensin converting enzyme inhibition in rats.

The effects of specific active immunization against renin were compared with those of chronic angiotensin converting enzyme (ACE) inhibition. Male spontaneously hypertensive rats (SHR) were immunized (SHR-I) (n = 10) against pure murine renin (four injections of 30 micrograms/kg s.c.) or received (SHR-P) (n = 11) a converting enzyme inhibitor (perindopril, 2 mg/kg/day per os for 4 weeks). Sham-immunized SHR (SHR-S) (n = 12) and normotensive Wistar-Kyoto (WKY-S) (n = 12) rats served as controls. At 15 weeks of age, 24-hour average blood pressure was obtained in freely moving rats using intra-aortic pressure recording with computer analysis. Antirenin immunization induced high circulating titers of antibodies, a fall in plasma renin activity (-95%), and urinary excretion of mineralocorticoids. Perindopril abolished the pressor response to angiotensin I, whereas plasma ACE was only partly (-56%) decreased. It also increased plasma renin activity and did not alter the urinary excretion of steroids. Both immunization and perindopril allowed the blood pressure of SHR to return to the level of WKY-S rats and reduced the left ventricular weight. These decreases were associated with an elevated sympathetic nervous system activity as indicated by increases in the urinary excretion of catecholamines and their metabolites. It is conclude that, apart from an unaltered steroid synthesis, most of the cardiovascular effects of chronic ACE inhibition are similar to those of antirenin immunization, thus indicating that blockade of the circulating and renal renin-angiotensin system accounts for most of the effects of ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

Thromboxane A2 and development of genetic hypertension in the Lyon rat strain.

To determine whether the increased renal biosynthesis of thromboxane A2 observed in young genetically hypertensive rats of the Lyon strain could be involved in the development of their hypertension, Lyon hypertensive female rats received either thromboxane synthetase inhibitors (Dazmegrel or OKY 046) or a thromboxane A2 receptor antagonist (AH 23848) during their prehypertensive stage. Treatment from 5 to 9 weeks of age with Dazmegrel failed to reduce systolic blood pressure. When given from 3 to 9 weeks of age, Dazmegrel and OKY 046 induced a similar progressive and specific reduction (60%) in the urinary excretion of thromboxane B2 that was associated with a transient decrease in blood pressure level with Dazmegrel and a longer lasting blood pressure-lowering effect with OKY 046. AH 23848, given according to the same schedule, normalized the blood pressure level. This effect persisted 1 week after the cessation of the treatment. Interestingly, active doses of thromboxane synthetase inhibitors or of thromboxane A2 receptor blocker required a 3-week delay to exhibit their antihypertensive properties. It is concluded that 1) the elevated production of thromboxane A2 observed in young Lyon hypertensive rats is likely to participate actively in their blood pressure regulation and 2) this effect may be independent of its direct vasoconstrictor properties.

Animals↗

PubMed1990

Cardiovascular reactivity to and renal impact of stress and exercise: effects of bisoprolol.

The orthosympathetic nervous system is involved in the pathogenesis of essential hypertension. In this study, we carried out tests of sympathetic stimulation using successfully an isometric exercise and a psychological stress. The efficacy of the two tests in 10 normotensive patients (NTs) was assessed by a significant increase in blood pressure and heart rate and a significant increase in metanephrine urinary excretion. These tests, repeated 2 months later, were perfectly reproducible in NTs. The cardiovascular response during exercise and stress was significantly higher in 10 hypertensive patients (HTs) than in NTs. At rest, urinary norepinephrine excretion was significantly higher in HTs. In contrast to NTs, stress in HTs significantly increased urinary excretion of epinephrine and norepinephrine, whereas exercise failed to increase urinary catecholamine excretion in both groups. In HTs, both tests induced an increase in microalbuminuria. Among functional renal parameters, only proximal sodium reabsorption (measured by lithium clearance) was significantly lower in HTs than in NTs, compensated by a higher distal reabsorption. In HTs, 2 months of treatment with bisoprolol reduced rest and peak heart rate and blood pressure, but failed to reduce blood pressure reactivity to the orthosympathetic stimulation. Proximal sodium reabsorption at rest was normalized by the treatment. Bisoprolol was also able to reduce microalbuminuria during the 24 h and in the rest period preceding the test, but the same percent increase was observed during tests.

Adrenergic beta-Antagonists↗

PubMed1990

[Adrenergic stimulation and renal synthesis of prostaglandins in genetically hypertensive rats of the Lyons strain].

An increased urinary excretion of thromboxane (Tx)B2 (Geoffroy & al., Hypertension 1986, 4 suppl 3: S37) and an elevated renal sympathetic activity (Sautel & al., Am J Physiol 1988, 255: H736) were simultaneously observed in the developing genetically hypertensive rat of the Lyon strain (LH). In the present work, the relationship between the adrenergic stimulation and prostaglandins (PGs) release was studied using isolated perfused kidney of 8 week-old LH rats and their normotensive controls (LN). Phenylephrine (PHE, 5 - 190 x 10(-8) M) and norepinephrine (NE, 1.2 - 96 x 10(-8) M) were administered in a single pass kidney perfused with a cell free solution and their effects were studied on the renal vascular resistances (RVR) and urinary excretion of TxB2 and 6-keto-PGF1 alpha (6KPGF) measured by specific radioimmunoassays after separation by HPLC. The results (mean +/- SE) obtained before (C) and after PHE and NE perfusions at concentrations: D1 = 31 and 10.5; D2 = 190 and 96 10(-8) M for PHE and NE respectively (* p less than 0.05 ** p less than 0.01 *** p less than 0.001 LH vs LN) were as follows: [table: see text] During the control period, kidneys of LH rats exhibited increased RVR when compared to LN controls but a similar PG excretion. The 2 concentrations of PHE and NE used which produced a similar increase in RVR strikingly stimulated the PG excretion. This effect which was more marked for NE than for PHE did not differ between the 2 strains for 6KPGF but was enhanced for TxB2 in kidney of LH rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

[Role of renin-angiotensin system and vasopressin in the control of blood pressure in genetically hypertensive rats after sympathectomy].

Early chronic sympathectomy does not normalize blood pressure (BP) in genetically hypertensive rats of the Lyon strain (LH). The purpose of this study was to examine the role of the renin angiotensin system (RAS) and vasopressin in the residual hypertension exhibited by LH sympathectomized rats. Chronic sympathectomy was achieved by treating male LH and control normotensive LN rats with guanethidine sulfate between 1 and 13 weeks of age (60 mg/kg daily from day 7 after birth to day 25, 30 mg/kg daily from day 26 to day 70 and 30 mg/kg every other day from day 71 to day 90). At 14 weeks of age, catheters were inserted into the lower abdominal aorta and inferior vena cava via the left femoral artery and vein. After 2 days of recovery, BP was continuously recorded in the conscious freely moving animals during 3 consecutive 1-hour periods: before and after administration of either an angiotensin converting enzyme inhibitor (perindopril 2 mg/kg i.v.) or a selective vascular vasopressin antagonist [beta-mercapto- beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2, Arg8-vasopressin, AVPX 10 micrograms/kg i.v.) and finally after conjoint administration of both drugs. At the end of each period, the efficacy of blockade was verified by the disappearance of pressor responses to respective agonists (angiotensin I 150 ng/kg i.v., Arg8-vasopressin 10 ng/kg i.v.). Chronic treatment with guanethidine resulted in the disappearance of pressor responses to tyramine (250 micrograms/kg i.v.) indicating complete functional denervation of the vessels. Under basal conditions, the 1-hour average value of mean BP (MBP) was higher in LH than in LN sympathectomized rats (134 +/- 3 vs 104 +/- 2 mmHg, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Antihypertensive effect of an immunosuppressive agent, cyclophosphamide, in genetically hypertensive rats of the Lyon strain.

The effect of a pharmacological immunosuppression on the development of hypertension and the part played by hormonal secretions of the thymus in this disease were investigated in genetically hypertensive rats (LH) of the Lyon strain. For this purpose, systolic blood pressure (SBP) was measured in cyclophosphamide-treated LH rats and in neonatally thymectomized LH rats receiving thymostimulin, a thymus extract. Cyclophosphamide treatment delayed the onset and attenuated the full development of hypertension in LH rats whereas it had no effect on SBP in normotensive rats (LN). Thymectomized LH rats also exhibited a significantly decreased SBP as compared to sham-operated controls. Thymostimulin treatment slightly increased the SBP of thymectomized LH rats but did not restore it to the level seen in sham-operated animals. These results showed that thymic hormonal secretions did not seem to be involved in the initiation of hypertension. By contrast, the fact that a reduction of hypertension could be obtained either by thymectomy or cyclophosphamide treatment suggested that immune disorders, mediated by thymus-dependent cellular reactions, could be of pathogenic importance in the development of hypertension in LH rats.

Aging↗

PubMed1989

Compared effects of isoxicam and indomethacin on the urinary excretion of prostaglandins in degenerative articular diseases.

The effects of a 7 day-treatment with isoxicam (200 mg/24 h) on the urinary excretion of prostaglandins (PG) were compared to those of indomethacin (150 mg/24 h) in a double-blind randomized study conducted in 18 patients with degenerative arthritic disease and normal renal function. Indomethacin decreased the urinary excretion of PGF2 alpha by about 70% and 6-keto-PGF1 alpha and thromboxane (Tx)B2, the stable break-down products of prostacyclin and TxA2 respectively, by about 40%. Isoxicam effects on urinary PG did not significantly differ from those of indomethacin. During both treatments, urinary gamma-glutamyl transferase and N- acetyl-glucosaminidase remained stable and none of the changes in the urinary excretion of PGs could be related to either plasma or urinary drug concentrations. In conclusion, chronic administration of isoxicam inhibited the renal PG biosynthesis to a similar extent than indomethacin which suggests that non steroidal anti-inflammatory drugs of the oxicam group ought also be used cautiously in patients with renal impairment.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

Antihypertensive effect of thromboxane A2 receptor blockade in genetically hypertensive rats of the Lyon strain.

In order to determine whether the increased renal biosynthesis of thromboxane A2, observed in young genetically hypertensive (LH) rats of the Lyon strain, could be involved in the development of their hypertension, 12 LH female rats were given a specific thromboxane A2 receptor antagonist, AH 23848 (Glaxo Group Research) orally (2 mg/kg twice a day) from 3 to 9 weeks of age. In addition, 12 LH and 12 normotensive (LN) rats were given vehicle only (sodium bicarbonate 8%). The thromboxane receptor antagonist AH 23848, which inhibited platelet aggregation by about 65%, did not modify the renal production of thromboxane A2, prostaglandin I2 (PGI2) or prostaglandin E2 (PGE2). It induced a progressive, potent and long lasting decrease in systolic blood pressure which was normalized in 6-, 7- and 8-week-old LH rats, thus demonstrating the involvement of thromboxane A2 in the onset of hypertension in this model. In contrast with thromboxane synthetase inhibitors, the AH 23848 antihypertensive effect persisted 1 week after the cessation of treatment, showing the superiority of thromboxane A2 receptor blockade over thromboxane synthetase inhibition.

Animals↗