Dominique Laude

Spectral analysis of blood pressure and heart rate in conscious rats: effects of autonomic blockers

We investigated the fluctuations which underly the spontaneous variability of blood pressure and heart rate in conscious rats. Intrafemoral blood pressure was computed to generate evenly spaced signals (systolic, diastolic, mean blood pressure, heart rate) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic blood pressure and heart rate exhibited low-frequency oscillations (Mayer waves, 20-605 mHz) and a high- frequency oscillation related to respiration (1855 mHz). The respiratory fluctuations in heart rate were almost abolished by vagal blockade (atropine). Heart rate fluctuations in the low-frequency regime were diminished by vagal blockade or cardiac sympathetic blockade (atenolol). The respiratory frequency fluctuations in systolic blood pressure were markedly increased by alpha-sympathetic blockade (prazosin). In contrast, the low-frequency oscillations in systolic blood pressure were reduced by alpha-sympathetic blockade. These data indicate that in conscious rats: (1) the heart rate oscillation with respiration is vagally mediated; (2) the heart rate fluctuation in the low-frequency range is jointly mediated by beta-sympathetic and parasympathetic activities; (3) the respiratory oscillation in systolic blood pressure depends on fluctuations in cardiac output and is normally counteracted by the sympathetic tone; (4) the low-frequency oscillations in systolic blood pressure reflect the sympathetic activity to the resistance vessels.

Effects of the 5-HT1c/5-HT2 receptor agonists DOI and α-methyl-5-HT on plasma glucose and insulin levels in the rat

Abstract Administration of the 5-HT 1C /5-HT 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 0.125–2.0 mg/kg i.v.) triggered dose-dependent increases in plasma insulin levels remained unchanged. Pretreatment with the 5-HT 1C /5-HT 2 receptor antagonists LY 53857, risanserin, or the mixed 5-HT 2 / α 1 -adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT 1C receptor agonists/5-HT 2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-(trifluoromethyl) phenyl)piperazine (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The α 2 -adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, whilst the α 1 -adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT 1C /5-HT 2 receptor agonist α-methyl-5-HT (0.5–1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished α-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT 2 receptors, but not 5-HT 1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT 2 receptors may affect glycemia.

Ganglionic transmission is a prerequisite for the adrenaline-releasing and hyperglycemic effects of 8-OH-DPAT

The present study concerned the influence of ganglionic nicotinic blockade (by hexamethonium, 5 mg/kg and 10 mg/kg) of the 8-OH-DPAT-induced elevations in plasma adrenaline, corticosterone and glucose levels in conscious rats. Prior treatment with hexamethonium dose dependently decreased the basal glucose levels and increased the basal corticosterone levels but did not significantly affect the basal adrenaline levels. Hexamethonium decreased in a dose-dependent manner the elevations in plasma adrenaline, corticosterone and glucose levels that were elicited by the 5-HT1A receptor agonist, 8-OH-DPAT (0.25 mg/kg). These results indicate that acetylcholine release is a prerequisite for both the adrenaline-releasing and hyperglycemic effects of 8-OH-DPAT. The data also point to the possibility that adrenaline release participates in the elevation in plasma corticosterone levels that is elicited by 5-HT1A receptor activation.

Early detection of cardiovascular autonomic neuropathy in diabetic pigs using blood pressure and heart rate variability

Cardiac autonomic neuropathy is a common complication in insulin dependent diabetes mellitus. Nevertheless, little is known about when this impairment occurs during the time course of the disease. Analysis of blood pressure (BP) and heart rate (HR) variability could be used to detect early signs of autonomic alteration. To test this proposal, twelve sexually mature male Yucatan miniature pigs were equipped with an arterial catheter for telemetric BP analysis, and with a venous access. BP and HR were recorded together with respiratory movements while the animals were resting in a sling. After the first recording session performed when the pigs were 5 months old, streptozotocin (STZ) was used to induce diabetes in seven pigs, while the five others were controls. BP and HR were measured 3 and 6 months after the onset of diabetes and at a similar age in the controls. BP and HR oscillated at the respiratory range (0.19 Hz). Spectral analysis showed this respiratory component was the main determinant of the short-term variability of BP and HR. Atropine increased HR and BP and markedly diminished the respiratory sinus arrhythmia. Propranolol diminished HR and the respiratory peak of HR. A reduced respiratory oscillation of BP paralleled the diminution of the respiratory peak of HR. Baroreceptor-HR reflex was estimated using injections of phenylephrine and nitroprusside, and by cross-spectral analysis between BP and HR. Atropine shifted the curve to higher HR values, while propranolol reduced the level of the upper plateau. Atropine decreased both the coherence and gain of the cross-spectral analysis. STZ injection resulted in a type 1 diabetes. At 3 months, diabetic pigs exhibited low levels of BP and a reduced overall variability of HR and BP. Spectral analysis indicated the respiratory sinus arrhythmia was markedly reduced. In addition, the sensitivity of the baroreceptor-HR reflex was reduced. At a latter stage of diabetes these alterations were marked and the level of the resting HR was increased. These data demonstrate the dual (vagal and sympathetic) control of HR in pigs and the dominant role of respiration in the genesis of HR and BP fluctuations. The spectral and cross-spectral analysis of BP and HR were altered after 3 months of diabetes and could be proposed as early detectors of cardiac autonomic neuropathy.

Influence of the novel antidepressant tianeptine on neurochemical, neuroendocrinological, and behavioral effects of stress in rats

Tianeptine is a novel tricyclic agent that activates the neuronal uptake of serotonin (5-hydroxytryptamine, 5-HT). Taking into account the antidepressant effect of tianeptine in animals and humans, we have measured the influence of a pretreatment with tianeptine (10 mg/kg IP 1 hr beforehand) on some consequences of a single 2-hr restraint stress session in male rats. Thus, we have analyzed (1) 5-HT metabolism in various brain regions and plasma glucose (an index of sympathoadrenal activity) and corticosterone levels at the end of stress, and (2) open field scores 18-19 hr after immobilization in saline- or tianeptine-pretreated rats. Tianeptine was found to leave unaltered stress-induced increases in cortical, hippocampal, hypothalamic, midbrain, and striatal serotonergic metabolism. Similarly, stress-elicited elevations in plasma glucose and corticosterone levels were not affected by tianeptine pretreatment. On the other hand, tianeptine pretreatment reversed stress-induced deficit in exploratory activity. To test whether the latter positive effect of tianeptine was associated with changes in plasma glucose and corticosterone levels during the early phase of stress, we have measured plasma glucose and corticosterone levels (at 0, 5, 15, 30, and 60 min) in resting and stressed (catheterized) rats. The results indicated that tianeptine pretreatment did not alter plasma glucose and corticosterone early responses to stress. Although this study confirmed the antidepressant effect of tianeptine, the neurochemical and neuroendocrinological mechanisms underlying this positive effect remain to be determined.

Contribution of the autonomic nervous system to blood pressure and heart rate variability changes in early experimental hyperthyroidism

A great deal of uncertainty persists regarding the exact nature of the interaction between autonomic nervous system activity and thyroid hormones in the control of heart rate and blood pressure. We now report on thyrotoxicosis produced by daily intraperitoneal (i.p.) injection of L-thyroxine (0.5 mg/kg body wt. in 1 ml of 5 mM NaOH for 5 days). Control rats received i.p. daily injections of the thyroxine solvent. In order to estimate the degree of autonomic activation in hyperthyroidism, specific blockers were administered intravenously: atropine (0.5 mg/kg), prazosin (1 mg/kg), atenolol (1 mg/kg) or the combination of atenolol and atropine. A jet of air was administered in other animals to induce sympathoactivation. Eight animals were studied in each group. The dose and duration of L-thyroxine treatment was sufficient to induce a significant degree of hyperthyroidism with accompanying tachycardia, systolic blood pressure elevation, increased pulse pressure, cardiac hypertrophy, weight loss, tachypnea and hyperthermia. In addition, the intrinsic heart period observed after double blockade (atenolol + atropine) was markedly decreased after treatment with L-thyroxine (121.5+/-3.6 ms vs. 141.2+/-3.7 ms, P < 0.01). Of the autonomic indices, vagal tone (difference between heart period obtained after atenolol and intrinsic heart period) was negatively linearly related to intrinsic heart period (r = 0.71, P < 0.05). Atenolol modified neither the heart period nor blood pressure variability in rats with hyperthyroidism and in these rats the jet of air did not significantly affect the heart period level. The thyrotoxicosis was associated with a reduction of the 0.4 Hz component of blood pressure variability (analyses on 102.4 s segments, modulus 1.10+/-0.07 vs. 1.41+/-0.06 mm Hg, P < 0.01) and prazosin was without effect on this 0.4 Hz component in these animals. These data show a functional diminution of the vascular and cardiac sympathetic tone in early experimental hyperthyroidism. The marked rise in the intrinsic heart rate could be the main determinant of tachycardia. The blood pressure elevation may reflexly induce vagal activation and sympathetic (vascular and cardiac) inhibition.

Effects of the 5-HT1 receptor agonists DP-5-CT, CGS 12066B, and RU 24969 on plasma adrenaline and glucose levels in the rat

SummaryRecent results have indicated that the 5-HT1A receptor subtype mediates the adrenaline-releasing and hyperglycemic effects of 8-hydroxy-2-(di-n-propylamino)tetralin in the rat. The aim of this study was to analyse, by means of the peripherally acting 5-HT1A receptor agonist, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT), whether these 5-HT1A receptors are peripherally or centrally localised. In view of the appreciable affinity of DP-5-CT for the 5-HT1D receptor subtype, the effects of the mixed 5-HT1B/5-HT1D receptor agonist 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo(1,2-a)quinoxaline (CGS 1206613), and the mixed 5-HT1A5-HT1B/5-HT1D receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)1H-indole (RU 24969) were also investigated.Administration of DP-5-CT (0.3 and 1 mg/kg i. v.) increased plasma glucose levels dose-dependently, whereas only the 1 mg/kg dose of DP-5-CT elicited a rise in plasma adrenaline levels. In contrast, CGS 1206613(1.5 and 4.5 mg/kg 1. v.) did not affect either plasma adrenaline or plasma glucose levels. Administration of RU 24969 (0.5–4.5 mg/kg i. v.) increased dose-dependently both plasma adrenaline and glucose levels. The data suggest that central 5-HT1A receptors, but neither 5-HT1B nor 5-HT1D receptors, regulate plasma adrenaline and glucose levels.

Pentobarbital anaesthesia prevents the adrenaline-releasing effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin

Administration of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.v.), to conscious rats increased plasma adrenaline and glucose levels for 30 and 60 min, respectively. Both 8-OH-DPAT-induced changes in plasma adrenaline and glucose levels were totally abolished in pentobarbital-anaesthetized rats. The present data indicate that pentobarbital anaesthesia, a procedure that is commonly used in pharmacological studies, prevents the release of adrenaline evoked by 5-HT1A receptor activation.

Are 5-HT1A autoreceptors involved in the inhibitory effect of ipsapirone on cold-elicited thyrotropin secretion ?

Administration of the serotonin (5-HT)1A receptor agonist ipsapirone has been shown to decrease cold-elicited thyrotropin (TSH) secretion. We have analyzed (1) the influence of 5-HT1A receptors and ipsapirone metabolism into 1-(2-pyrimidinyl)-piperazine (1-PP, an alpha 2-adrenoceptor antagonist) on the effect of ipsapirone on TSH release, and (2) the interaction between the corticosterone-releasing effect of ipsapirone and its inhibitory influence on TSH release. Pretreatment with proadifen (50 mg/kg, 5 h before ipsapirone), i.e. an inhibitor of ipsapirone metabolism into 1-PP, did not affect ipsapirone-induced inhibition of cold-elicited TSH secretion. Pretreatment (15 min before ipsapirone) with the 5-HT1/5-HT2 receptor antagonist metergoline 2 mg/kg) or with the 5-HT1A receptor blocker (-)-pindolol (5 mg/kg) increased baseline and cold-elicited TSH release but the inhibitory influence of ipsapirone on cold-elicited TSH release was alleviated by (-)-pindolol pretreatment only. Cold exposure increased corticosterone release, an effect which was insensitive to (-)-pindolol pretreatment. Lastly, pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine prevented the immediate inhibitory effect of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) upon cold-induced TSH release, but it amplified the late release of TSH in cold-exposed 8-OH-DPAT-injected rats. These results suggest that presynaptic 5-HT1A receptors mediate ipsapirone-induced inhibition of cold-elicited TSH release, an effect which may be partially opposed by postsynaptic 5-HT1A receptor stimulation.

Cardiovascular and adrenaline-releasing effects of the 5-HT1A receptor agonist 8-hydroxy-2-(DI-N-propylamino) tetralin in streptozotocin diabetic rats

The 5-hydroxytryptamine1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) has been reported to trigger sympathoinhibition, as evidenced by its cardiovascular effects, and adrenal catecholamine secretion. The purpose of this study was to analyze the cardiovascular and adrenaline-releasing effects of 8-OH-DPAT in 1 week streptozotocin diabetic rats. 8-OH-DPAT-induced changes in mean arterial pressure (MAP) and heart rate (HR) were determined directly in anesthetized rats, whilst changes in plasma adrenaline (and plasma corticosterone and glucose) levels were analyzed in conscious rats. Resting blood pressure and heart rate were diminished in diabetics, when compared with controls. These changes were associated with a decrease in body weight and a marked increase in resting plasma glucose levels. Diabetes did not affect MAP response to 8-OH-DPAT, except for a decrease in the amplitude of MAP maximal fall, which was associated with a diminished bradycardic response to 8-OH-DPAT. Blood pressure response to prazosin (0.5 mg/kg) in 8-OH-DPAT-pretreated rats was also diminished in diabetics. Lastly, diabetes prevented the adrenaline-releasing and hyperglycemic effects of 8-OH-DPAT (250 ug/kg).