Nitric oxide and eicosanoid interactions in kidneys of Lyon hypertensive rats.
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Animals↗
Biomedical subjects
J Sassard
Publications and source records attributed to J Sassard.
Round table 1. Do transgenic techniques help us to understand hypertension?
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Animals↗
Arterial baroreflex control of heart period is not related to blood pressure variability in conscious hypertensive and normotensive rats.
1. The short-term (within 30 min periods) and the long-term (among 30 min periods) variabilities, expressed as variation coefficients, of blood pressure (BP) and heart period (HP) were studied using a computer analysis of BP recordings in freely moving genetically hypertensive (LH), normotensive (LN) and low BP (LL) rats of Lyon strains at ages 5, 9, 21 and 40 weeks. The baroreflex control of HP was estimated with the slope of the linear relationship between systolic BP (SBP) and HP (SBP-HP slope) computed after phenylephrine and nitroglycerin injections. 2. Short-term variability of BP increased between 5 and 9 weeks of age and then remained stable. Hypertension was accompanied by an increase in both short- and long-term variabilities of diastolic BP in adult rats. 3. A sharp increase in SBP-HP slope was observed between 5 and 9 weeks of age in LN rats. SBP-HP slope of LH rats increased slightly up to 21 weeks but remained lower than that of normotensive controls. 4. The weak inverse correlation existing between SBP-HP slope and BP variability appeared to be mediated by the BP level. In addition, atropine which is known to abolish almost completely the SBP-HP slope, did not increase BP variability. It is concluded that SBP-HP slope is not linearly associated with BP variability in conscious rats.
Aging↗
Renal thromboxane A2 synthesis in the Lyon hypertensive rat.
The aim of the present study was to assess the mechanisms by which norepinephrine (NE) increased the synthesis of prostanoids and revealed a hyperactivity of the Thromboxane (Tx) A2 synthase in the Lyon genetically hypertensive (LH) rat kidney. To this purpose, the effects of NE (1.2 x 10(-8) to 9.6 x 10(-7) M) on renal function and prostanoid synthesis were assessed in isolated perfused kidneys following beta-adrenoceptor blockade by sotalol (10(-5)M) and compared to those of equipressor concentration of an alpha 2-adrenoceptor agonist, BHT 933 (3.5 x 10(-4) M) and angiotensin II (AII) (7.7 x 10(-9) M). Kidneys were isolated from eight week-old male LH rats and from their normotensive (LN) and low blood pressure (LL) controls and perfused in a single pass system. In baseline conditions, sotalol did not modify renal function or urinary prostanoids in any of the three strains. Following NE stimulation, it potentiated the increase in renal vascular resistance of LL and LN controls but not that of LH rats. The pressure-natriuresis and the urinary prostanoids remained unchanged. BHT 933 elicited a weak stimulation of prostanoid release while AII markedly increased it and revealed, as did NE, the hyperactivity of the TxA2 synthase. It is concluded that the NE-induced stimulation of prostanoid synthesis does not involve beta-adrenoceptors and is unrelated to the associated hemodynamic changes. These results also demonstrate that the increased renal synthesis of TxA2 observed in LH rat kidney is not a specific response to alpha-adrenoceptor stimulation and is likely to involve activation of the phosphoinositide pathway.
Adrenergic beta-Antagonists↗
Sympathoinhibitory effects of rilmenidine may be mediated by sites located below the brainstem.
1. To determine the site of action of rilmenidine, we examined its effets on arterial blood pressure (BP), heart rate (HR) and postganglionic renal sympathetic nerve activity (RSNA) after intracerebroventricular (i.c.v.) administration (300 micrograms kg-1), in groups (all n = 6) of conscious and freely moving, pentobarbitone-anaesthetized and pentobarbitone-anaesthetized and spinally transected, fifteen week-old male spontaneously hypertensive rats (SHRs). 2. In conscious SHRs, which exhibited a low sympathetic nerve activity (RSNA: 3.4 +/- 0.9 muV), rilmenidine was inactive on systolic BP (SBP), diastolic BP (DBP), HR and RSNA. 3. In intact pentobarbitone-anaesthetized SHRs, which exhibited an elevated sympathetic nerve activity (RSNA: 10.6 +/- 0.9 muV), rilmenidine exerted potent antihypertensive (delta SBP: -37 +/- 4%; delta DBP: -43 +/- 6%), bradycardic (delta HR: -32 +/- 3%) and sympathoinhibitory (delta RSNA: -68 +/- 9%) activities. 4. In pentobarbitone-anaesthetized SHRs with cervical spinal cord transection, BP was markedly decreased and sympathetic nerve activity (RSNA: 10.3 +/- 3.1 muV) returned to the level observed in conscious SHRs (RSNA: 3.6 +/- 0.5 muV). In these conditions, rilmenidine remained sympathoinhibitory (delta RSNA: -74 +/- 5%). 5. In conclusion, we have shown that pentobarbitone-anaesthesia enhances the peripheral sympathetic tone by a central action, as the spinal cord transection allows RSNA to return to normal levels and that, spinal or ganglionic structures could be a major site of the sympathoinhibitory action of rilmenidine.
Adrenergic alpha-Agonists↗
Influence of anaesthesia on the cardiovascular effects of rilmenidine and clonidine in spontaneously hypertensive rats.
1. The acute cardiovascular effects of two alpha 2-adrenoceptor agonists, rilmenidine and clonidine, were studied in 15-week-old male spontaneously hypertensive rats (SHRs). The effects of these drugs were compared with intravenous (i.v.) and intracerebroventricular (i.c.v.) administration in conscious and pentobarbitone-anaesthetized SHRs, in which aortic blood pressure (BP) was continuously recorded. 2. In conscious SHRs, i.v. doses of either rilmenidine (30, 100, 300 micrograms kg-1) or clonidine (3, 10, 30 micrograms kg-1) induced dose-dependent short-lasting increases in BP followed by moderate decreases associated with bradycardia, while the same three doses of both drugs given i.c.v. were devoid of BP and heart rate (HR) effects. 3. Pentobarbitone-anaesthesia increased the sympathetic control of BP and suppressed the cardiac baroreflex sensitivity. 4. In anaesthetized SHRs, i.v. injections of the same 3 doses of rilmenidine and clonidine induced a slight increase in BP, rapidly followed by profound and long-lasting BP and HR decreases. Surprisingly, when given i.c.v., these 3 doses lowered BP and HR to the same extent but in a more progressive manner. 5. The lack of efficacy of both drugs in conscious SHRs after the i.c.v. administration of i.v. active doses and the lack of more marked and rapid effects in anaesthetized SHRs, after i.c.v. than after i.v. injections, question the involvement of a major central site of action for these antihypertensive alpha 2-adrenoceptor agonists. Moreover, these results show that the cardiovascular effects of these drugs are profoundly influenced by baseline sympathetic nervous system activity which is enhanced by pentobarbitone-anaesthesia.
Adrenergic alpha-Agonists↗
Pressure independence of renin release by isolated kidneys of Lyon hypertensive rats.
In the present work the influence of perfusion pressure on renal functions and renin release was studied before and after the blockade of thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors using isolated kidneys from 7-week-old genetically hypertensive (LH), normotensive (LN), and low blood pressure (LL) rats of the Lyon strain. Kidneys were single pass perfused with Krebs-Henseleit solution with a gelatine derivative (Polygeline) added as an oncotic agent. A servocontrolled system stabilized the renal perfusion pressure (RPP) at any chosen (+/- 1 mm Hg) level. In baseline conditions (RPP, 90 mm Hg), LH (n = 7) kidneys differed from LN (n = 6) and LL (n = 8) controls by increased vascular resistance, decreased glomerular filtration rate, and natriuresis. The LH kidney responses to stepwise changes in RPP (between 60 and 170 mm Hg) differed from those of LN and LL rats by a significantly lower perfusion flow, glomerular filtration rate, and natriuresis. Above all, the reduction in RPP, which induced a marked and highly reproducible renin release in LN and LL kidneys, was devoid of effects in LH kidneys. The blockade of TXA2/PGH2 receptors by AH23848 (4 x 10(-6) M) did not change the baseline (RPP, 90 mm Hg) functions of kidneys of the three strains. During changes in RPP, the responses of LN and LL kidneys were not modified, whereas LH kidneys exhibited significant increases in both glomerular filtration rate and natriuresis. Finally, AH23848 significantly decreased the renin release by kidneys of the three strains.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Arterial pressure control in the sympathectomized rat.
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Animals↗
Increased serotonin platelet uptake after tianeptine administration in depressed patients.
Tianeptine is a new antidepressant drug reported to enhance serotonin (5-hydroxytryptamine [5-HT]) uptake in rat brain. The effect of tianeptine on 5-HT platelet uptake was studied in 10 depressed patients treated for 28 days. Tianeptine increases Vmax of 5-HT platelet uptake during treatment without inducing any change in Km. As early as 2 hr after the first administration, Vmax increased significantly (+23%, alpha = 0.01). Although of a lesser magnitude, 5-HT platelet uptake remains increased after chronic administration (+14% on day 10 and +13% on day 28). This suggests that tianeptine affects 5-HT platelet uptake sites, either directly or via an action on modulators of 5-HT uptake. These results, in contrast with the action of other tricyclic antidepressants, confirm the original action of tianeptine on 5-HT platelet metabolism.
Adolescent↗
Pharmacokinetics of chlormezanone in elderly patients.
The pharmacokinetics of Chlormezanone (CM) has been determined after a single oral dose of 400 mg CM in 5 young volunteers (28 y) and in 8 elderly patients (79 y). In the young subjects, CM was rapidly absorbed and distributed, and was slowly eliminated with a half-life of 38 h major metabolites were not detected in plasma or urine. Only 3% of CM was excreted unchanged in urine. In elderly patients absorption was delayed but not reduced; the Cmax and AUC did not differ from those in younger subjects, the elimination rate was reduced compared to the younger subjects (mean 54 h). The increase was in part related to the reduction in renal function and metabolism observed in aging. However, the change in pharmacokinetics was moderate and no adjustment in dosage seems necessary for treatments of limited duration in elderly patients.
Administration, Oral↗
Fetal liver cell transplantation fails to transfer hypertension from genetically hypertensive rats to normotensive rats of the Lyon strain.
The involvement of an auto-immune mechanism has been suggested in the development and/or the maintenance of hypertension in male, genetically hypertensive rats of the Lyon strain (LH). The aim of this study was to determine whether hypertension may be transferred, by lymphoid cells, from hypertensive donors to male, normotensive rats of the Lyon strain (LN). Experiments designed to induce a resistance to hypertension in LH rats by transfer of lymphoid cells from LN animals were also performed. Since LH and LN are mismatched at the major histocompatibility complex, transfers of fetal liver cells (FLC) from fetuses of 13-14 days gestation were performed. These experiments demonstrate the ability of FLC to allow a prolonged survival (over 17 weeks) without graft versus host disease in the rat. As regards the blood pressure level, no LN recipient having received FLC from LH donor became hypertensive, thus showing that hypertension cannot be transferred by lymphoid cells in normotensive animals. Resistance to hypertension was so weakly transferred to hypertensive rats (results being significantly different only at 10 weeks post-grafting) that it may be considered doubtful.
Animals↗
The effect of infinitesimal drug dilutions on the pharmacokinetics of nalidixic acid and atenolol.
1. Ten healthy subjects received two treatments: a single 1 g oral dose of nalidixic acid (NA) followed 1 h later by either an infinitesimal dilution of the drug (NA 7CH) or by succussed water which served as placebo. The study was repeated 18 months later in 10 different subjects. 2. A further 10 healthy subjects received three treatments: a single 100 mg oral dose of atenolol (AT) followed 3 h later by either placebo or a dilution of AT (AT 7CH) or of bisoprolol (BI 7CH). The homoeopathic preparations were administered by the sublingual route. 3. In the first NA experiment NA 7CH significantly shortened the elimination half-life of NA from 8.6 +/- 2.2 (placebo) to 6.4 +/- 1.6 h (NA 7CH). In the second NA experiment none of the pharmacokinetic parameters was modified significantly by the administration of NA 7CH. Neither AT 7CH nor BI 7CH modified the pharmacokinetics of AT.
Administration, Oral↗
Urinary excretion of prostanoids during sleep in obstructive sleep apnoea patients.
1. Given the unexplained frequent association between systemic hypertension and obstructive sleep apnoea (OSA), the secretion of prostanoids during sleep was investigated (more specifically, the ratio of prostacyclin (PGI2) to thromboxane A2 (TxA2), since they have marked opposite effects on vascular tone). Prostacyclin has vasodilating effects, whereas thromboxane results in vasoconstriction. 2. In 11 OSA drug-free male patients (age 53 +/- 2 years, mean +/- s.e.m.; apnoea index 55 +/- 15 apnoeas/hour of sleep; body mass index 31 +/- 2 kg/m2), we measured the urinary excretion during sleep of 6-keto-PGF1-alpha and of thromboxane TxB2 (the stable metabolites of prostacyclin PGI2 and of thromboxane A2 respectively). This was done on two consecutive nights; one untreated, the other with nasal continuous positive airway pressure (CPAP) treatment. The results were compared with those of nine normal unobese male subjects. 3. The urinary ratio of 6-keto-PGF1-alpha to TxB2 was significantly (P less than 0.001) lower in the untreated OSA patients (1.7 +/- 0.2) than in the controls (3.1 +/- 0.3). It significantly increased with CPAP treatment to 2.3 +/- 0.2, P less than 0.02, which was no longer different from the controls. 4. These results suggest that OSA is associated with an abnormal release of prostanoids during sleep resulting in a decrease of the prostacyclin to thromboxane ratio which potentially has a vasoconstricting effect. The relationship between these changes and the systemic hypertension often observed in OSA patients remains to be established.
6-Ketoprostaglandin F1 alpha↗
Autonomic nervous system and cardiovascular variability in rats: a spectral analysis approach.
Mechanisms underlying systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) beat-to-beat variability were investigated using spectral analysis in conscious genetically normotensive (LN) and hypertensive (LH) adult rats from the Lyon strains. In LN rats, basal SBP, DBP, and HR spectra exhibited peaks in low (LF: 0.38-0.45 Hz) and high (HF: 1.04-1.13 Hz) frequencies. The LF peak of SBP, and even more of DBP, could be attributed to the influence of the sympathetic nervous system as it disappeared after destruction of the sympathetic nerves or a combined alpha- and beta-adrenoceptor blockade, whereas it was higher after blockade of the parasympathetic system. The HF peak of HR, linked to the respiratory rate, was abolished by the parasympathetic system blockade, whereas those of SBP and DBP were enhanced. In LH rats, which exhibit a lower sympathetic activity, the LF peaks of SBP and DBP were less distinct compared with LN controls. We conclude that the LF peak of DBP and the HF peak of HR are likely to represent useful estimates of the sympathetic vascular control and of the parasympathetic cardiac control, respectively.
Angiotensin Receptor Antagonists↗
Renal denervation does not prevent hypertension in Lyon hypertensive rats.
The effects on blood pressure (BP) of a single and repeated renal denervations (RD) were compared in genetically hypertensive (LH) and normotensive (LN) rats of the Lyon strain. Indirect BP was measured by the tail-cuff method, and direct BP was measured through an aortic catheter in conscious quiet rats receiving a normal-sodium diet. Single RD (10 wk of age) did not reduce BP in both LN and LH rats. Repeated RD (4, 7, and 10 wk of age) partly prevented the age-related increase in tail-cuff BP but did not affect the directly recorded BP in 11-wk-old LH rats. Single and repeated RD reduced the renal norepinephrine content by greater than 90%. Both procedures did not alter the BP lowering effects of angiotensin-converting enzyme inhibition and of ganglionic blockade. It is concluded that renal nerves are not necessary for the development and the maintenance of hypertension in LH rats.
Animals↗
Blood pressure maintenance in hypertensive sympathectomized rats. I. Adrenal medullary catecholamines.
To assess the role of the sympathetic nervous system in the development of genetic hypertension, blood pressure (BP) was recorded in conscious adult Lyon hypertensive (LH) and normotensive (LN) rats that had received daily injections of saline or guanethidine at 1-13 wk of age. Guanethidine abolished the pressor response to tyramine, decreased plasma norepinephrine by greater than 70% and plasma 3,4-dihydroxyphenylglycol by approximately 90%, and did not change plasma epinephrine. Bilateral adrenalectomy further reduced plasma norepinephrine to 8 and 5% of control levels in LH and LN rats, respectively. BP was lowered (-7%) in sympathectomized rats, but the mean absolute BP difference between LH and LN rats was unaltered. Despite marked supersensitivity to alpha-adrenoreceptor stimulation, phentolamine induced only a small transient depressor response, which was abolished by adrenalectomy in sympathectomized rats. It is concluded that the sympathetic nervous system is not necessary for the development of hypertension in LH rats. After sympathectomy, circulating catecholamines, which mostly derive from the adrenal medulla, play only a minor role in BP maintenance.
Adrenal Medulla↗
Blood pressure maintenance in hypertensive sympathectomized rats. II. Renin-angiotensin system and vasopressin.
This study examined the contribution of the main pressor systems to the residual hypertension exhibited by genetically hypertensive (LH) rats of the Lyon strain after early chronic sympathectomy with guanethidine. Blood pressure (BP) was recorded in conscious LH and normotensive control (LN) rats, either intact or sympathectomized, during sequential blockade of the renin-angiotensin system, vasopressin receptors, the autonomic nervous system, and finally after maximal vasodilation with hydralazine. In sympathectomized rats 1) renin-angiotensin system blockade equally reduced BP in both strains, whether it was realized before (-20%) or after (-30%) vasopressin antagonism; 2) isolated vasopressin antagonism decreased BP in LH (-8%) but not in LN rats; 3) autonomic blockade and hydralazine induced additional decreases in BP that were similar in both strains; and 4) intermediate and final levels of BP remained always higher in LH than in LN rats. It is concluded that, after sympathectomy, BP is maintained primarily by the renin-angiotensin system. In sympathectomized LH rats, the maintenance of hypertension does not depend on hyperactivity of the main pressor systems but rather on an increase in the intrinsic vascular resistance that develops in the absence of the sympathetic innervation of the vessels.
Angiotensin I↗
Calcium metabolism in the Lyon hypertensive rat.
In order to define relationships between hypertension and calcium metabolism, we have studied calcium metabolism in Lyon genetically hypertensive rats (LH) and their two normotensive controls (LN and LL). The total and ionized plasma calcium levels were slightly but significantly decreased in the LH compared to LN and LL from 4 to 23 weeks of age. During this period, dietary calcium intake was decreased in LH rats but urinary and fecal excretions did not differ. Intestinal utilization and balance were impaired during development of hypertension in LH rats. Thus minor alterations in calcium metabolism differentiate the LH rat from its normotensive controls.
Aging↗