Evaluation of cardiovascular effects of intravenous robenacoxib in dogs.

The objective of the study was to assess the cardiovascular effects of intravenous (IV) dosing with robenacoxib (Onsior® ) in conscious adult healthy beagle dogs. The study employed a randomized, open, placebo-controlled, four-phase Latin square design. A total of eight dogs received a single dose of 2 mg/kg and 4 mg/kg IV robenacoxib (test groups), 2 mg/kg subcutaneous (SC) robenacoxib (reference dose and route), and IV isotonic saline (control). There were no significant differences between groups for clinical observations, buccal mucosal bleeding time or blood hematology, coagulation, and clinical chemistry variables in all eight dogs. In a subset of four dogs, no significant differences between groups were detected using telemetric assessment for arterial blood pressure, heart rate, electrocardiogram, or body temperature over 8 hr postdose. In conclusion, no significant cardiovascular effects were detected after a single IV dose of 2 or 4 mg/kg robenacoxib in conscious healthy dogs.

The high frequency relationship: implications for torsadogenic hERG blockers.

BACKGROUND AND PURPOSE: Ventricular arrhythmias induced by human ether-a-go-go related gene (hERG; Kv 11.1 channel) blockers are a consequence of alterations in ventricular repolarisation in association with high-frequency (HF) oscillations, which act as a primary trigger; the autonomic nervous system plays a modulatory role. In the present study, we investigated the role of ß1 -adrenoceptors in the HF relationship between magnitude of heart rate and QT interval changes within discrete 10 s intervals (sorted into 5 bpm heart rate increments) and its implications for torsadogenic hERG blockers. EXPERIMENTAL APPROACH: The HF relationship was studied under conditions of autonomic blockade with atenolol (ß1 -adrenoceptor blocker) in the absence or presence of five hERG blockers in beagle dogs. In total, the effects of 14 hERG blockers on the HF relationship were investigated. KEY RESULTS: All the torsadogenic hERG blockers tested caused a vertical shift in the HF relationship, while hERG blockers associated with a low risk of Torsades de Pointes did not cause any vertical shift. Atenolol completely prevented the effects four torsadogenic agents (quinidine, thioridazine, risperidone and terfenadine) on the HF relationship, but only partially reduced those of dofetilide, leading to the characterization of two types of torsadogenic agent. CONCLUSIONS AND IMPLICATIONS: Analysis of the vertical shift in the HF relationship demonstrated that signs of transient sympathetic activation during HF oscillations in the presence of torsadogenic hERG blockers are mediated by ß1 -adrenoceptors. We suggest the HF relationship as a new biomarker for assessing Torsades de pointes liability, with potential implications in both preclinical studies and the clinic.

Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations.

BACKGROUND AND PURPOSE: The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K(+) channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency. EXPERIMENTAL APPROACH: The short-term variability of beat-to-beat QT interval (STVQT ), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium. KEY RESULTS: Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans. CONCLUSIONS AND IMPLICATIONS: These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals.

Cardioprotection by omega-3 fatty acids: involvement of PKCs?

It has been known since the 1970s that an increased consumption of n-3 long chain polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid has cardioprotective effects. Epidemiological studies have reported that this effect is due to the prevention of the arrhythmias responsible for sudden cardiac death. Mechanistically, different hypotheses have been put forward to give an explanation. Among them, there are a direct effect of the polyunsaturated fatty acids on ion channels and/or a modification of the regulation of ion channels by protein kinase C's.

Peroxidation of docosahexaenoic acid is responsible for its effects on I TO and I SS in rat ventricular myocytes.

1 Exposure to docosahexaenoïc acid (DHA), a long-chain polyunsaturated fatty acid, is known to block several ionic currents such as the transient outward current I(TO). It has also been reported to activate certain potassium channels. It has been suggested that these effects, observed in single-cell experiments, participate in the antiarrhythmic properties of these compounds in vivo. 2 DHA is highly prone to peroxidation. To investigate the influence peroxidation may have on the effects of DHA on ion channels, we studied I(TO) and the steady-state outward current I(SS) in isolated rat ventricular myocytes under ruptured whole-cell patch-clamp conditions. 3 A measure of 10 micro M DHA alone reduced I(TO), evoked by a pulse to +70 mV, by 74.8+/-10.8% (n=7) and activated a delayed outward current with kinetic properties different from I(SS). 4 When an antioxidant, alpha-tocopherol (1 micro M), was added together with DHA, the blockade of I(TO) was reduced to 38.5+/-7.7% (n=8) and the delayed outward current was not activated. alpha-Tocopherol alone had no effect on these currents. 5 When an oxidant, hydrogen peroxide (1 micro M), was applied together with DHA, the blockade of I(TO) was almost complete (98.4+/-1.0%, n=7) and a large delayed outward current was activated. A measure of 1 micro M hydrogen peroxide alone had no effect on these currents. 6 Measurements of nonperoxidized DHA in experimental solutions confirmed the negative relation between DHA concentration and the effects on the currents. 7 We conclude that rather than DHA itself, it is the peroxidation products of DHA that block I(TO) and activate a delayed outward current in in vitro single-cell experiments. These findings have important implications for the extrapolation of in vitro experimental findings to the antiarrhythmic effects of DHA in vivo because, in vivo, peroxidation of DHA is unlikely to occur.

Comparative antihypertensive and renoprotective effects of telmisartan and lisinopril after long-term treatment in hypertensive diabetic rats.

This study compared the cardiovascular and renal effects of long-term telmisartan (3 and 10 mg/kg/day)and lisinopril (10 mg/kg/day) in an animal model combining hypertension and diabetes mellitus. It was a parallel-group study of diabetic, spontaneously hypertensive rats (SHR), treated with control or active treatment for eight months. A non-diabetic SHR control group was run in parallel. Diabetes was induced by streptozotocin (45 mg/kg i.v.) in SHRs aged 9-10 weeks. Animals were treated with telmisartan (3 or 10mg/kg/day), lisinopril (10 mg/kg/day) or vehicle. Plasma glucose levels, blood pressure (BP), and urinary protein and albumin excretion were measured monthly. Telmisartan treatment significantly reduced BP of diabetic SHRs in a dose-dependent manner (p<0.05, low-dose, n= 18; p<0.01, high-dose, n=15). The BP reduction in the lisinopril group was similar to that in the telmisartan 10 mg/kg/day group. Compared with non-diabetic SHRs, untreated diabetic SHRs developed severe proteinuria and albuminuria over the experimental period (p<0.01). In diabetic SHRs, proteinuria and albuminuria were dose-dependently and significantly attenuated by treatment with telmisartan (p<0.01 with the higher dose) and lisinopril (p<0.01). Compared with the untreated diabetic SHRs, cardiac hypertrophy was significantly reduced after treatment with both doses of telmisartan and with lisinopril. Telmisartan, 10 mg/kg/day, but not lisinopril, significantly attenuated the diabetes-induced increase in glomerular volume. In conclusion, telmisartan, 10 mg/kg/day, is at least as beneficial as lisinopril, 10 mg/kg/day, in lowering BP, reducing cardiac hypertrophy and attenuating renal excretion of protein and albumin in this model.

Hemodynamic effects of MF 10058, a new cardioselective muscarinic M(2) receptor antagonist, in conscious dogs.

The 5-¿4-[4-(diethylamino)butyl]-1-piperidinyl¿acetyl-5H-dibenz[b, f]-azepine (MF 10058) is a new potent and selective muscarinic M(2) receptor antagonist. The hemodynamic effects of MF 10058 were investigated in conscious freely moving dogs. Placebo and three doses of MF 10058 (2, 4 and 8 mg/kg) were orally administered according to a randomised four-way crossover design. Heart rate, cardiac conduction times, systolic and diastolic blood pressure were telemetrically recorded for 12-24 h after dosing. After placebo administration, a consistent reduction over time in heart rate was observed during the night-time period (-15%, P=0.019). MF 10058 administration antagonised the nocturnal bradycardia and shortened QT interval. The effect of the drug reached statistically significance, compared to placebo, with the highest dose of 8 mg/kg (+19% on heart rate, P=0.013; -4% on QT interval, P=0.049). The effect on heart rate lasted for the entire 24-h observation period (+16%, P=0.030). Nocturnal systolic and diastolic blood pressure were not significantly affected by MF 10058. No other signs of peripheral or central cholinergic block were observed at any dose. The results of this study demonstrated that oral administration of MF 10058 produces long-lasting hemodynamic effects in the conscious dog. The drug has a therapeutic potential for the treatment of bradycardic disorders.

Effects of clomipramine hydrochloride on heart rate and rhythm in healthy dogs.

OBJECTIVE: To determine the effects of clomipramine hydrochloride on heart rate and rhythm in dogs. ANIMALS: 17 healthy Beagles. PROCEDURES: In experiment 1, 8 dogs received placebo or clomipramine (20 mg/kg of body weight, q 24 h, PO) for 7 days in a 2-way crossover design. In experiment 2, 9 dogs were evaluated for 48 hours before and 24 hours after oral administration of clomipramine (4 or 12 mg/kg) in a 2-way crossover design. Electrocardiogram and heart rate were monitored continuously by use of telemetry. RESULTS: A significant diurnal rhythm in heart rate was detected; minimum values were recorded at night. Administration of 20 mg of clomipramine/kg induced a significant reduction in heart rate, with peak effect achieved approximately 12 hours after dosing. Administration of 4 or 12 mg of clomipramine/kg did not result in significant changes in heart rate. Sinoatrial and second-degree atrioventricular block and ventricular escape beats were observed during periods of slow heart rate in more dogs that received clomipramine (3 to 4 of 8 dogs), compared with dogs that received placebo (1 to 2 of 8 dogs), but this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE: Short-term administration of clomipramine induced benign cardiovascular effects in dogs rather than the potentially dangerous arrhythmias or tachycardia reported following administration of tricyclic antidepressants to humans. Precautions regarding cardiovascular effects may not be needed for the use of clomipramine in healthy dogs.

The preclinical assessment of the risk for QT interval prolongation.

Some drugs have been reported to induce severe ventricular arrhythmias, including torsades de pointes, and have been responsible in some cases for sudden death of patients. Although the mechanisms of these arrhythmias are not well understood, they are often, but not always, associated with QT interval prolongation. Regulatory authorities (CPMP in Europe) have recently pointed out the necessity to assess most carefully the potential, especially of non-cardiovascular drugs, for QT interval prolongation. Different methodological approaches are presented in this paper and experimental protocols are suggested; limitations and advantages of the presently available in vitro and in vivo models are discussed. It appears that both in vitro and in vivo approaches are complementary. In particular it is pointed out that only the in vitro models using isolated cardiac tissues (Purkinje fibres or papillary muscles) enable assessment of the drug properties under low cardiac rhythm conditions. This model allows us to mimic pathological situations of long QT interval (such as acquired or congenital long QT syndrome) in which most of the major clinical problems are encountered. Finally, a strategy for the preclinical assessment of the potential of a molecule for QT interval prolongation is presented.

Pharmacokinetics of ketoprofen in rabbit after a single topical application.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used by topical application in management of joint pain and inflammation. Little is known, however, about their pharmacokinetics, especially in the synovial compartment versus the plasma compartment, following topical administration. Ketoprofen, a NSAID, was delivered by a single topical application (KETUM 2.5% gel) on the rabbit knee-joint region of one hind limb. Concentrations of ketoprofen were measured in plasma, synovial fluid, joint capsule and synovial fat tissue at 2, 4, 6 and 12 hours after application. Whatever the time period after application, ketoprofen concentrations in synovial fluid were much higher than in plasma. The time-course of the decrease in ketoprofen plasma concentrations was more rapid than that in synovial fluid. Similarly, concentrations in joint capsule were higher than those found in synovial fat tissue. Finally, while ketoprofen concentrations decreased rapidly in plasma and in synovial fat tissue, concentrations in joint capsule and particularly in synovial fluid were more sustained. The increase in residence time of ketoprofen in synovial fluid could be in favour of its efficiency in the management of joint pain and inflammation.

Pharmacological properties of trimebutine and N-monodesmethyltrimebutine.

Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxybenzoate hydrogen maleate (TMB)] has been demonstrated to be active for relieving abdominal pain in humans. To better understand its mechanism of action, we have tested TMB; nor-TMB, its main metabolite in humans; and their respective stereoisomers for their affinity toward sodium channels labeled by [3H]batrachotoxin, their effect on sodium, potassium, and calcium currents in rat dorsal root ganglia neurons, and their effect on veratridine-induced glutamate release from rat spinal cord slices. TMB has also been tested in an animal model of local anesthesia. TMB (Ki = 2.66 +/- 0.15 microM) and nor-TMB (Ki = 0.73 +/- 0.02 microM) displaced [3H]batrachotoxin from its binding site with affinities similar to that of bupivacaine (Ki = 7.1 +/- 0.9 microM). nor-TMB was found to block veratridine-induced glutamate release with an IC50 value of 8.5 microM, which is very similar to that of bupivacaine (IC50 = 8.2 microM); the effect of TMB was limited to 50% inhibition at 100 microM. TMB and nor-TMB blocked sodium currents in sensory neurons from rat dorsal root ganglia (IC50 = 0.83 +/- 0.09 and 1.23 +/- 0.19 microM, respectively), whereas no effect was observed on calcium currents at the same concentrations. A limited effect was observed on potassium currents (IC50 = 23 +/- 6 at 10 microM) for TMB. In vivo, when tested in the rabbit corneal reflex, TMB displayed a local anesthetic activity 17-fold more potent than that of lidocaine.

Interference of myrtol standardized with inflammatory and allergic mediators.

Myrtol standardized (Gelomyrtol/Gelomyrtol forte) inhibits the activity of 5-lipoxygenase of human basophil and eosinophil leukocytes and the formation of leukotriene C4 as well as 1.8-cineole (eucalyptol). An increase of prostaglandins (PGE2) in mucous membranes of teat cisterns after topical administration of TPA (tetradecanoylphorbol-13-acetate) was inhibited. In vitro and in vivo studies revealed spasmolytic and broncholytic effects of Myrtol stand. After topical administration into the teat cisterns of the isolated bovine udder Myrtol stand. increased the surface temperature, comparable to effects of menthol.

Mechanisms of the cardiovascular deconditioning induced by tail suspension in the rat.

The aim of the present work was to obtain insights into the pathophysiology of cardiovascular deconditioning (CVD) induced by tail suspension (TS) in the rat: during TS, when central venous pressure (CVP) has been normalized (E. Martel, P. Champéroux, P. Lacolley, S. Richard, M. Safar, and J. L. Cuche. J. Appl. Physiol. 80: 1390-1396, 1996), and during simulated orthostatism (SO), when transient episodes of hypotension and bradycardia are disclosed, bradycardia with SO represents a response that seems peculiar to the rat compared with humans. According to basic physiology, a reduced activity of the sympathetic system induced by increased CVP was suspected but was not supported by data obtained through spectral analysis of blood pressure (BP) and heart rate (HR) variability or measurements of plasma catecholamine concentration during TS. Nonetheless, indirect evidence was obtained. During SO, plasma catecholamine concentration was lower in TS rats than in controls, suggesting a reduced synthesis of catecholamines, itself secondary to reduced activity of the sympathetic system. Furthermore, after 48 h of TS, the number of binding sites and affinity of alpha-receptors in rat aorta were increased, compatible with a reduced level of neurotransmitter in the synaptic cleft. A second series of experiments was carried out to study hypotension and bradycardia in TS rats during SO. Hypersensitivity of serotonergic mechanisms was suspected. Two 5-HT3 receptor antagonists (ondansetron and MDL-72222) blocked hypotension and restored tachycardia, basic features of orthostatic adaptation of the circulatory system. Response to the 5-HT3 receptor agonist was measured through dose-response curves of BP and HR after injection of 2-methylserotonin. After low doses, hypotension (10 micrograms/kg) and bradycardia (3 and 10 micrograms/kg) were significantly greater in 48-h TS rats than in controls. Thus CVD in the rat induced by TS appears to implicate at least two mechanisms: reduced activity of the sympathetic system and hypersensitivity of serotonergic mechanisms.

Role of endothelium in the endothelin-1-mediated potentiation of the norepinephrine response in the aorta of hypertensive rats.

OBJECTIVE: To investigate the role of the endothelium in the functional interaction between endothelin-1 and norepinephrine in the contractile response of aortas from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Thoracic aorta rings with and without endothelium from SHR and from WKY rats were suspended in an organ bath to record the isometric tension. After an equilibration period of 120 min, the preparations with and without endothelin-1 were subjected to single and cumulative additions of norepinephrine in different experiments. To characterize the mechanisms involved in the interaction between endothelin-1 and norepinephrine, the aortic rings were pretreated with a cyclooxygenase pathway inhibitor (piroxicam, SO29548), an inhibitor of NO synthase [NG-nitro-L-arginine (NLA)], or selective endothelin receptor blockers (BQ-123 or BQ-788). In some experiments we examined the contractile responses to norepinephrine in aortas pretreated either with angiotensin II (AII) or with U46619, an agonist of prostaglandin H2-thromboxane A2 receptors. Finally, we examined the effect of the combination of calcium-entry blockade by administration of nifedipine and treatment with either endothelin-1 or U46619 on the norepinephrine reactivity. RESULTS: Administration of 3 x 10(-10) mol/l endothelin-1 potentiated the contractile response to norepinephrine in SHR aortas with endothelium, irrespective of whether they had been treated with NLA. No endothelin-1-mediated enhancement of the response to norepinephrine was observed in SHR denuded rings and in untreated and NLA-treated WKY rat aortas. All did not affect the response to norepinephrine in SHR rings with endothelium. The amplification by endothelin-1 of the response to (1-100) x 10(-9) mol/l norepinephrine was abolished by blockade of the cyclooxygenase pathway with piroxicam or SO29548. In WKY rat and SHR denuded aortas, 10(-8) mol/l U46619 potentiated the contractile responses to norepinephrine. Administration of 3 x 10(-6) mol/l BQ-123 abolished the increase in reactivity to norepinephrine evoked by endothelin-1 in intact SHR aorta, whereas 3 x 10(-6) mol/l BQ-788 failed to modify this potentiating effect. Administration of 10(-8) mol/l nifedipine inhibited the potentiation of the norepinephrine-induced contractions evoked both by endothelin-1 in SHR aortic rings with endothelium and by U46619 in SHR denuded rings. CONCLUSION: Our results show that a low concentration of endothelin-1 induced potentiation of the contractile response to norepinephrine in SHR aortas but not in WKY rat aortas. This response was endothelium-dependent. Furthermore, our study affords functional arguments that both endothelial and smooth muscle pathways are involved in the potentiating interaction. We propose that endothelin-1 stimulates the production of endothelium- and cyclooxygenase-generated vasoconstrictor factors, which in turn may serve directly as priming stimuli at the vascular smooth muscle level, to activate the Ca(2+)-signal pathway and consequently to increase locally the vascular sensitivity to norepinephrine.

Ambroxol improves the broncho-spasmolytic activity of clenbuterol in the guinea-pig.

The effects of ambroxol on the spasmolytic action of clenbuterol were investigated on acetylcholine-induced bronchospasm in guinea-pigs. Ambroxol (50 mg kg-1 day-1) or vehicle was administered orally for 14 days. Approximately 45 min after the final dose on day 14, the animals were anaesthetized and the spasmolytic effects of clenbuterol (3, 6 or 12 micrograms kg-1 injected intravenously) were determined by use of acetylcholine (40 micrograms kg-1, i.v.)-induced bronchoconstriction. For both vehicle- and ambroxol-treated animals, a positive linear relationship was observed between the log-dose of clenbuterol and the percent inhibition of bronchospasm. The calculated ED25 of clenbuterol (i.e., the dose producing 25% inhibition of the acetylcholine-induced bronchospasm) was 3.98 micrograms kg-1 (3.29 to 4.82 micrograms kg-1, 95% confidence interval) in the presence of ambroxol and 5.81 micrograms kg-1 (4.98 to 6.79 micrograms kg-1) in the absence of ambroxol. The linear regressions with or without ambroxol differed from each other (P < 0.001) but ran parallel (covariance analysis), enabling us to calculate a relative potency, the value of which was 1.46 (1.16 to 1.84). These results demonstrate that the spasmolytic activity of clenbuterol is significantly improved in animals pretreated with ambroxol.

Central hypervolemia in the conscious rat: a model of cardiovascular deconditioning.

The aim of the present study as to investigate whether increased central hypervolemia induced by tail suspension (TS) in the rat is an appropriate model of cardiovascular deconditioning (CVD). First, the physiological relationship between central venous pressure (CVP) and extracellular fluid volume (ECFV) was studied. TS (20 degrees) increased CVP (5.8 +/- 0.7 vs. 2.8 +/- 0.8 mmHg; P < 0.01). After 24 h of TS, CVP had returned to control range while ECFV was reduced by 19%. CVP kinetics during 24 h of TS was not affected by either reduction (-20%) or augmentation (/35%) of the ECFV. The normalization of CVP is likely to be a consequence of ECFV reduction, which itself is reduced by increased urinary excretion of water and sodium. Second, recovery from TS was studied. Resumption of the horizontal position was shown to be associated with a significant increase of heart rate (HR) and a slight reduction of blood pressure (BP); there was an apparent delay between increased HR and reduced BP. This imbalance between HR and BP is compatible with CVD. A model of simulated orthostatism (SO) was developed to further investigate the responses of HR and BP. Interestingly, SO (90 degrees rotation) in the normal rat was associated with significant tachycardia and a slight increase of BP. This pattern remained stable for at least 3 h. In rats that were tail suspended for 48 h, episodes of hypotension and bradycardia (5 +/- 1 in 3 h) suggested a defect in adaptation to increased hydrostatic pressure. In conclusion, TS appears to be an appropriate model of CVD. Reduction process. Return to horizontal position in TS rats induced a tachycardia with minimal effects on BP; this pattern is close to that observed in humans assuming upright posture. SO in previously TS rats disclosed episodes of hypotension and bradycardia that deserve further investigation.

Early disturbance of baroreflex control of heart rate after tail suspension in conscious rats.

Experiments were performed on conscious chronically instrumented rats maintained on tail suspension to determine the time course of changes in baroreceptor control of heart rate produced by this procedure. Pressor responses were elicited by bolus injections of graded doses of phenylephrine and sodium nitroprusside, permitting evaluation of the totality of the sigmoidal curve relating mean arterial pressure to heart rate. Compared with control rats maintained at 0 degrees, rats maintained at 20 degrees using tail suspension for 24 h showed a significant reduction in reflex gain (-3.9 +/- 0.1 vs. -5.8 +/- 0.3 beats/min; P < 0.001) together with a reduction in the upper (472 +/- 11 vs. 512 +/- 5 beats/min; P < 0.01) and lower (270 +/- 3 vs. 284 +/- 2 beats/min; P < 0.01) plateaus of the sigmoidal curve. In three groups of rats, the sigmoidal curve was studied successively after returning for 1, 24, and 48 h at 0 degrees. The observed change in the gain of the reflex returned toward control values after 48 h, whereas the other parameters characterizing the sigmoidal curve did not change significantly. Transient but significant modifications of heart rate (tachycardic response) after the immediate return to the horizontal position were observed. The study provides evidence that 1) a significant change of the totality of the sigmoidal curve characterizing baroreceptor control of heart rate occurs very early after tail suspension in rats and 2) the gain of the reflex is restored during the 48 h after release of tail suspension, whereas the other parameters characterizing the curve, particularly the plateaus, remain altered.

Twenty four hours head-down tilt decreases arterial baroreflex function in conscious rat.

In human zero gravity induces a cardiovascular deconditioning. The transfer of blood from the periphery to the thoracic compartment, occuring immediately at the beginning of the exposure to microgravity seems to be involved in this phenomenon. We have previously shown that LBNP (-40 mm Hg) produced an exaggerated heart rate response at the end of 24 hours of bed rest without modification of the cardiopulmonary receptors in human. Some other studies have shown that microgravity induces an impairment of the baroreflex sensitivity in human, but its involvement in the cardiovascular deconditioning is not completely understood. The aim of this study was to determine the modification of the arterial baroreflex using a model of simulated weightlessness in conscious rats during the exposure to microgravity.

Central hypotensive effects of nicardipine in conscious freely moving spontaneously hypertensive rat.

The central cardiovascular effects of the calcium channel blocker nicardipine was studied in conscious freely moving normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Nicardipine was administered in a 1.5 microliters volume into the lateral ventricle of the brain (i.c.v.) or intravenously (i.v.). The injection of vehicle alone did not significantly change mean arterial pressure (MAP) or heart rate (HR). Nicardipine (10, 30, 100 and 300 micrograms/kg) intravenously administered, dose-dependently decreased MAP and increased HR in WKY and SHR. However, when administered i.c.v., nicardipine (10 micrograms/kg) increased MAP and HR in WKY and decreased MAP without any significant change in HR in SHR. These results are consistent with previous work reporting an exaggerated hypotensive response to i.c.v. administration of dihydropyridine calcium channel blockers in anesthetized SHR as compared to WKY. They suggest that a 1,4-dihydropyridine-sensitive pressor system is present in the SHR but not in the WKY.

Pressor responses to endothelin-1 in normotensive and spontaneously hypertensive rats.

In freely moving rats, endothelin-1 (0.0135-4.5 nmol/kg) administered as an intravenous bolus injection, produced an immediate, short-lasting, dose-related fall in blood pressure followed by a long-lasting, dose-related increase in blood pressure. There was a higher sensitivity in the pressor responses to endothelin-1, in spontaneously hypertensive (SH) rats (ED(50) = 0.11 +/- 0.02 and 0.28 +/- 0.02 nmol/kg, in SH and normotensive rats, respectively), but no change in the maximal pressor effect of endothelin-1 in SH rats. In rat isolated aorta, endothelin-1 induced a greater vasocontractile effect in SH rats than in normotensive rats. In both rat strains, removal of the endothelium did not change the concentration-effect curves obtained in endothelium-intact preparations. These data add further support to the hypothesis that endothelin-1 could play a role in genetic hypertension, at least in the maintenance of high blood pressure.