Cardiovascular effects of long-term central and peripheral administration of urocortin, corticotropin-releasing factor, and adrenocorticotropin in sheep

The neuroendocrine hormones ACTH and corticotropin- releasing factor (CRF), which are involved in the stress response, have acute effects on arterial pressure. New evidence indicates that urocortin (UCN), the putative agonist for the CRF type 2 receptor, has selective cardiovascular actions. The responses to long-term infusions of these hormones, both peripherally and centrally, in conscious animals have not been studied. Knowledge of the long-term effects is important because they may differ considerably from their acute actions, and stress is frequently a chronic stimulus. The present experiments investigated the cardiovascular effects of CRF, UCN, and ACTH in conscious sheep. Infusions were made either into the lateral cerebral ventricles (i.c.v.) or i.v. over 4 d at 5 microg/h. UCN infused i.c.v. or i.v. caused a prolonged increase in heart rate (HR) (P < 0.01) and a small increase in mean arterial pressure (MAP) (P < 0.05). CRF infused i.c.v. or i.v. progressively increased MAP (P < 0.05) but had no effect on HR. Central administration of ACTH had no effect, whereas systemic infusion increased MAP and HR (P < 0.001). In conclusion, long-term administration of these three peptides associated with the stress response had prolonged, selective cardiovascular actions. The striking finding was the large and sustained increase in HR with i.c.v. and i.v. infusions of UCN. These responses are probably mediated by CRF type 2 receptors because they were not reproduced by infusions of CRF.     

Azelnidipine attenuates cardiovascular and sympathetic responses to air-jet stress in genetically hypertensive rats.

Azelnidipine is a new dihydropyridine calcium channel blocker that causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. In the present study, we examined the effects of oral or intravenous administration of azelnidipine on cardiovascular and renal sympathetic nerve activity (RSNA) responses to air-jet stress in conscious, unrestrained stroke-prone spontaneously hypertensive rats. Oral administration of high-dose azelnidipine (10 mg/kg per day) or nicardipine (150 mg/kg per day) for 10 days caused a significant and comparable decrease in blood pressure, but low-dose azelnidipine (3 mg/kg per day) did not. Air-jet stress increased mean arterial pressure (MAP), heart rate (HR) and RSNA. High-dose azelnidipine significantly attenuated the increases in MAP, HR and RSNA in response to air-jet stress while nicardipine did not. Low-dose azelnidipine significantly attenuated the pressor response with a trend of decrease in RSNA. Intravenous injection of azelnidipine induced a slowly developing depressor effect. To obtain a similar time course of decrease in MAP by azelnidipine, nicardipine was continuously infused at adjusted doses. Both drugs increased HR and RSNA significantly, while the change in RSNA was smaller in the azelnidipine group. In addition, intravenous administration of azelnidipine attenuated the responses of MAP, HR, and RSNA to air-jet stress; by comparison, the inhibitory actions of nicardipine were weak. In conclusion, oral or intravenous administration of azelnidipine inhibited cardiovascular and sympathetic responses to air-jet stress. This action of azelnidipine may be mediated at least in part by the inhibition of the sympathetic nervous system.     

Non-symmetrical double-logistic analysis of 24-h blood pressure recordings in normotensive and hypertensive rats

OBJECTIVE: To determine the suitability of a new logistic curve fitting procedure to measure the diurnal rates of transition from the active to the asleep periods separately. METHOD: We applied this method to 24-h telemetry recordings of systolic, mean, diastolic arterial pressure (SAP, MAP, DAP, respectively), heart rate (HR) and locomotor activity of normotensive Sprague-Dawley rats (SDR) and spontaneously hypertensive rats (SHR). RESULTS: There was a similar pattern of higher awake and lower sleep values (16 +/- 1 mmHg SAP, 77 +/- 2 bpm HR and 40 +/- 2 units activity) in SHR. In SDR, awake-asleep differences were less for SAP (9 +/- 1 mmHg) but similar for HR (83 +/- 2 bpm). In SHR, while the blood pressure patterns were symmetrical, the rate of rise in activity and HR during arousal was more rapid than the rate of decline during the dark to light transition. By contrast in SDR, the arousal rate of increase in blood pressure and HR was much less than the rate of decline. Thus SHR have an exaggerated arousal surge in DAP compared with SDR. Double logistic provides a better fit than Cosinor or square wave and better estimates of day-night differences than partial Fourier. CONCLUSIONS: Analysis of 24-h recordings by a new logistic curve method reveals distinct asymmetric circadian patterns of cardiovascular and activity changes in rats. The greater surge in arousal blood pressure in SHR is not associated with differences in HR or activity changes and may be inherent to the underlying mechanisms contributing to the hypertension in SHR.     

Corticotropin-releasing factor induces differential behavioral and cardiovascular effects after intracerebroventricular and lateral hypothalamic/perifornical injections in rats.

The contribution of the lateral hypothalamic/perifornical (LH/PFx) area in mediating central effects of corticotropin-releasing factor (CRF) on cardiovascular and behavioral activity was assessed by monitoring blood pressure, heart rate and behavioral responses for a 45-min period after injections of various doses of CRF into the LH/PFx region or the lateral cerebral ventricle (intracerebroventricular, i.c.v.) in conscious, unrestrained rats in a familiar environment. After LH/PFx injection, CRF (3 and 30 ng) dose-dependently induced behavioral activation, predominantly consisting of grooming, eating and locomotor activity. Concomitantly, dose-related increases in mean arterial pressure (delta MAP) and heart rate (delta HR) were observed. Increases in MAP and HR following injection of 3 ng CRF were associated with the paroxysmal occurrence of behavioral activation and as such superimposed on CRF-induced elevation of baseline MAP and HR. Thirty nanograms CRF given i.c.v. produced grooming behavior similar to that observed after the same dose injected into the LH/PFx region, but failed to induce significant changes in cardiovascular concomitants. Rats receiving 100 ng CRF i.c.v., showed a significant increase in behavioral activity, respective to rats treated with 30 ng CRF in the LH/PFx, the tachycardiac responses, however, being similar in these groups. Both doses of CRF i.c.v. failed to induce significant delta MAP. The effects of CRF on cardiovascular and behavioral activity were more marked when the peptide was injected into the caudal part of the LH than those measured after administration into the rostral LH. Similarly, injections of CRF around or dorsal to the fornix (PFx) were more effective than those located ventrally to it. This site specificity of CRF-evoked responses was reflected in differential time response relations of the various effects. In summary, when i.c.v. is the route of administration, a higher dose of CRF is required to induce autonomic and behavioral responses similar to those elicited by CRF injected into the LH/PFx. The cardiovascular and behavioral effects of LH/PFx-CRF indicate that this region may be an important site for central CRF to produce stress-related autonomic and behavioral responses. In addition, the CRF-induced effects, both in magnitude and onset, show site specificity, the caudal LH and perifornical area being more responsive to the peptide than the rostral LH and the area ventral to the Fx. As CRF-evoked behavioral activation does not necessarily coincide with changes in MAP and HR, our data suggest a dissociation of the peptide's central actions to influence behavioral and autonomic responses.     

Circadian differences in stress-induced pressor reactivity in mice

The objective of this study was to determine the effect of chronic stress exposure on the circadian pattern of cardiovascular responses in mice. Using male C57BL6 mice with carotid arterial catheters, we tested the effect of 7 days of intermittent shaker stress on body weight, food intake, drinking activity, plasma corticosterone, mean arterial pressure (MAP), and heart rate. The stress was delivered automatically for 2-minute periods (150 cycles/min), 45 times/d for 7 days. Plasma corticosterone was significantly increased in acutely and chronically stressed mice, with a partial attenuation in the chronic condition. Stress increased water intake, produced no change in food intake, and significantly decreased body weight (5% change). MAP and heart rate were measured continuously on stress days 1, 3, and 7 and during the basal and recovery periods. Chronic stress did not produce a sustained increase in MAP; however, there was an increase in MAP during the first stress day and a decrease during the recovery period. There was a circadian pattern in the pressor responses, with greater increases seen during the light period (nonactive phase) than in the dark period (+24% versus +11% on stress day 3, light versus dark). The results suggest that a stress delivered during the nonactive phase represents a higher cardiovascular risk.     

Sinoaortic denervation does not increase cardiovascular/endocrine responses to stress.

Sinoaortic baroreceptor denervation is reported to produce exaggerated centrally derived cardiovascular and endocrine responses. We examined the effect of sinoaortic denervation (SAD) on the cardiovascular and endocrine responses to two acute stressors, footshock and immobilization, in male Sprague-Dawley rats. Parameters measured were mean arterial pressure (MAP), heart rate (HR) and plasma levels of oxytocin (OT) and vasopressin (VP). Baseline MAP was elevated in the SAD group (approximately 25 mm Hg) and footshock stress increased arterial pressure equivalently in both groups. This stress caused tachycardia and increased plasma OT, with a tendency for the SAD group to show blunted responses. Immobilization increased HR but caused no change in MAP and no significant difference between the groups. This form of stress also increased plasma OT, and again the SAD group showed a diminished response. Plasma VP was not significantly altered by either stressor. The results of these studies indicate that SAD does not uniformly increase the cardiovascular and endocrine responses to all stressors or centrally derived stimuli. These results also suggest that the lack of an increase in plasma VP is not related to baroreceptor-mediated inhibition of secretion under stressful conditions.     

Differential hypothalamic-pituitary-adrenal axis reactivity to psychological and physical stress.

Healthy men exhibit a differential hypothalamic-pituitary-adrenal axis (HPA) response to exercise stress and fall into two groups: high responders (HR) and low responders (LR). The present study examined whether HR to physical stress also exhibit higher HPA reactivity to psychological stress than LR. We examined 14 HR and 13 LR classified based on their ACTH responses to high intensity exercise after pretreatment with dexamethasone. Both groups were of similar age, height, weight, and fitness level. Trait anxiety scores on the Spielberger Trait Anxiety Scale were not different. Subjects underwent a psychological stress test consisting of an interview and mental arithmetic. This test raised heart rate, blood pressure, and plasma ACTH and cortisol levels in both HR and LR. HR tended to have higher heart rates and blood pressures in anticipation of the psychological stress test than LR. ACTH responses of HR were higher, although not significantly, throughout the psychological stress test than LR. HR had a significantly (P < 0.05) greater net integrated cortisol response to the psychological stress than LR. This suggests that the adrenal cortexes of the HR are hypertropic and/or hypersensitive to ACTH. We conclude that men who are highly responsive to exercise stress are also highly responsive to psychological stress.     

The effect of the removal of the area postrema on insulin and IGF-1-induced cardiovascular and sympathetic nervous responses

Previous studies have demonstrated that insulin and IGF-1 both increase lumbar sympathetic nerve activity (LSNA) and decrease mean arterial pressure (MAP). We hypothesized that the peripheral responses to insulin and IGF-1 are mediated, at least in part, via the central nervous system. In this study we determined the effects of the peripheral administration of both insulin and IGF-1 on cardiovascular dynamics and LSNA following removal of the area postrema (APX), a major site of blood-brain communication. Insulin infusion in normal rats decreased MAP but increased HR and LSNA. When insulin was infused in APX rats it also decreased the MAP but the MAP recovered rapidly and plateaued at a level equivalent to normals after 40 min. Insulin significantly increased the HR and LSNA in the APX rats compared to normals. However, when hypoglycemia was prevented by glucose infusion, the HR and LSNA responses to insulin in the APX rats were similar to normals. IGF-1 also decreased MAP and to a greater extent in the APX rats compared to normals but the increased LSNA in APX rats was equivalent to normals. The APX rats when compared to normals had a greater sensitivity to insulin-induced hypoglycemia while IGF-1 decreased the plasma glucose to a lesser degree in APX rats. We conclude that insulin and IGF-1 entry into the CNS at least via the area postrema does not contribute significantly to the hypotensive response and that the greater depressor response to IGF-1 is likely due to enhanced vascular sensitivity in APX rats. The increased HR and LSNA following insulin were likely mediated by an increased reflexive response to hypoglycemia.     

Dopaminergic modulation of pressor and hormonal responses in essential hypertension

Hormonal and mean arterial pressure (MAP) responses to posture, isometric handgrip, angiotensin II (AII), adrenocorticotrophic hormone (ACTH), and metoclopramide (MCP), a dopamine (DA) antagonist, were examined in nine men with essential hypertension and nine age- and weight-matched normotensive men on a constant 100 mEq sodium and 80 mEq potassium intake before and after 4 days of administration of the DA agonist, bromocriptine (BEC; 2.5 mg three times a day). BEC depressed supine basal MAP in the hypertensives, and decreased MAP response to posture and isometric exercise in both groups. Hypertensives displayed greater (p less than 0.01) NE responses to posture and exercise than the normotensives. BEC decreased the NE response to 10 minutes of upright posture and exercise more in hypertensives (p less than 0.01) than in normotensives, but following BEC, the responses were similar. BEC did not affect basal PRA or PRA responses to posture and exercise in the two groups. PA responses to ACTH and MCP were similar in both groups, but the hypertensives displayed greater (p less than 0.01) PA responses to AII. BEC suppressed PA responses to AII (p less than 0.01) and to high dose ACTH (p less than 0.05) to a similar extent in both groups. The prolactin as well as the PA response to DA antagonism with MCP was similar in the two groups. These results suggest that dopaminergic control of NE secretion may be altered in essential hypertension. Blood pressure lowering effects of BEC in patients with essential hypertension may be related, in part, to depression of sympathetic nervous system activity.     

Cardiovascular stress associated with concentric and eccentric isokinetic exercise in young and older adults

Heart rate (HR), mean arterial blood pressure (MAP), and rate-pressure product (RPP) responses to submaximal isokinetic concentric (CON) and eccentric (ECC) knee extension exercise were compared at the same absolute torque output in 20 young (mean+/-SD=23.2+/-1.7 years) and 20 older (mean+/-SD=75.2+/-4.6 years) adults. After determination of peak CON and ECC torques, subjects performed separate, randomly ordered, 2-minute bouts of isokinetic CON and ECC exercise (90 degrees/s, exercise intensity: 50% of CON peak torque). CON exercise elicited greater changes in HR, MAP, and RPP than ECC exercise (p<.001) for both age groups. There were no age-related differences in HR, MAP, or RPP responses for either CON or ECC exercise. At the same absolute torque output, isokinetic CON knee extension exercise elicited significantly greater increases in cardiovascular stress than ECC exercise in both young and older adults. This result has implications for determining appropriate fitness and rehabilitation programs.     

Effects of continuous infusions (10 days) and cessation of infusions of clonidine and rilmenidine (S 3341) on cardiovascular and behavioral parameters of spontaneously hypertensive rats

Clonidine is a centrally acting antihypertensive drug that acts in vivo at both alpha 1- and alpha 2-adrenoceptor sites, whereas rilmenidine (S 3341) is more selective for alpha 2 adrenoceptors. The present study compared the effects of continuous 10-day infusions of clonidine (5 micrograms/kg/hour) with those of rilmenidine (100 micrograms/kg/hour) on various cardiovascular and behavioral parameters in the spontaneously hypertensive rat. The changes in these parameters after cessation of the infusions were also compared. At these rates of infusion, clonidine and rilmenidine produced quantitatively similar reductions in mean arterial pressure (MAP), lability of MAP and cardiovascular responsiveness during normal behaviors such as eating and grooming. Neither drug infusion affected heart rate. The cessation of the clonidine infusion resulted in a "withdrawal" syndrome characterized by prominent rapid eye movement-sleep rebound, and cardiovascular and behavioral disturbances including an increased lability of MAP, exaggerated cardiovascular responses during normal behaviors, tachycardia, and an "opiate abstinence-like" syndrome including head and body shakes. Cessation of rilmenidine infusion resulted in somewhat similar cardiovascular and behavioral disturbances, but unlike clonidine there was a return to normal rapid eye movement sleep without rebound.     

Stress-induced inhibition of the plasma corticosterone response to a subsequent stress in rats: a nonadrenocorticotropin-mediated mechanism

The present study was designed to define further the relationships between ACTH and corticosterone secretion after repeated administration of a discrete restraint stress in rats. The possibility that plasma ACTH and corticosterone responses to stress may be modified by prior exposure to stress was examined in male rats using a 2-min restraint stress. The peak plasma ACTH response to a single restraint stress occurred at 2.5-5 min after the onset of the stress, and plasma ACTH returned to the basal concentration by 30 min. The plasma corticosterone concentration after this stress peaked at 15-30 min and returned to the control range by 60-90 min. The time courses of the plasma ACTH and corticosterone responses to restraint stress after administration of three prior stresses at 90-min intervals were similar to those after a single stress. Stress-induced increments in plasma concentrations of ACTH and corticosterone were similar in rats that received either a single restraint stress or as many as seven stresses repeated at 90-min intervals. Next, we examined the plasma ACTH and corticosterone responses to repeated stress applied at intervals of less than 90 min (30 or 60 min), that is, at times at which the plasma corticosterone concentration had not yet returned to basal levels. The plasma ACTH responses to the second stress were similar in magnitude and duration to the response after a single stress, whether the second stress was applied 30, 60, or 90 min after the first stress. The plasma corticosterone response to a second stress applied at 90 min was identical to the response after the initial stress. In contrast, the plasma corticosterone responses to a second stress applied 30 or 60 min after the initial stress were markedly reduced. The decrease in plasma corticosterone response to the second stress did not result from a decrease in secretion of bioactive ACTH; no difference was found between the magnitude of the plasma ACTH response to the initial stress and a subsequent stress applied 30 min later using either bioassay or immunoassay measurements. Also, the rate of corticosterone catabolism was not increased by prior stress; the rate of disappearance of corticosterone from plasma was identical after an initial or a subsequent stress applied at 30 min. We were unable to demonstrate decreased adrenocortical responsiveness to ACTH after an initial stress in dexamethasone-suppressed rats; in these rats the plasma corticosterone response to exogenous ACTH was not decreased by prior restraint stress. These data clearly define a period of decreased adrenocortical response to subsequent stress after stress-induced activation of adrenocortical secretion. Furthermore, this altered adrenocortical response appears to be mediated by a nonadrenocorticotropin mechanism.     

Stress activation of cellular markers of inflammation in rheumatoid arthritis: protective effects of tumor necrosis factor alpha antagonists

OBJECTIVE: Psychological stress is thought to aggravate disease activity in rheumatoid arthritis (RA), although the physiologic mechanisms are unclear. Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine involved in the exacerbation of RA, and TNFalpha antagonists have emerged as efficacious treatments. The purpose of this study was to determine whether RA patients show increased monocyte production of TNFalpha following acute psychological stress and whether such responses are abrogated in RA patients taking TNFalpha antagonists. METHODS: A standardized stress task was administered to 3 groups of subjects: RA patients taking TNFalpha antagonists, RA patients not taking such medications, and healthy controls. Lipopolysaccharide-stimulated monocyte production of inflammatory cytokines was repeatedly measured using intracellular staining and flow cytometry. Subjective stress, cardiovascular responses, adrenocorticotropic hormone (ACTH) levels, and cortisol levels were also measured. RESULTS: The stress task induced increases in subjective stress, cardiovascular activity, and levels of ACTH and cortisol, with similar responses in the 3 groups. In addition, the stress task induced a significant increase (P < 0.001) in monocyte production of TNFalpha among RA patients who were not taking TNFalpha antagonists. However, monocyte production of TNFalpha did not change following psychological stress in RA patients taking TNFalpha antagonists or in healthy controls. CONCLUSION: Brief psychological stress can trigger increased stimulated monocyte production of TNFalpha in RA patients. The use of TNFalpha antagonists protects against stress activation of cellular markers of inflammation in RA patients.     

Combined effects of heart rate and pulse pressure on cardiovascular mortality according to age

OBJECTIVES: The aim of the study was to assess the combined effects of pulse pressure (PP) and heart rate (HR) on cardiovascular mortality in a large French population. DESIGN: The study population was composed of 125,513 men and 96,301 women aged 16-95 years who had a health check-up at the IPC Center between January 1978 and December 1988. Subjects taking antihypertensive treatment were excluded. Mortality was assessed for an 8-year period. HR and PP were classified into three groups. HR groups were: < 60, 60-79 and > or = 80 beats per minute (bpm). PP groups were: < 50, 50-64 and > or = 65 mmHg. RESULTS: In men, PP and HR were both positively associated with cardiovascular mortality risk. In women, mean arterial pressure (MAP) but not PP or HR was associated with cardiovascular mortality. In men, a combined elevation of PP and HR was associated with an important increase of cardiovascular mortality risk. The group with the highest PP and the highest HR had a 4.8-fold increase in cardiovascular mortality risk as compared to the reference group (PP < 50 mmHg and HR < 60 bpm). This effect was more pronounced in younger men (5.4-fold increase) than in older men (3.7-fold increase), as compared to the reference groups of the same age. In women, the combined effects of PP and HR on cardiovascular mortality were not significant. CONCLUSION: A combined elevation of the two components of pulsatile arterial stress is associated with an important increase in cardiovascular mortality in men, especially in younger men. In women, steady-state stress (evaluated primarily by MAP), but not pulsatile stress, is an important determinant of cardiovascular mortality.     

Neuroendocrine responses to hypertonic saline/dextran resuscitation following hemorrhage.

The neuroendocrine responses to resuscitation with 7.5% hypertonic saline/6% Dextran-70 (HSD) following hemorrhagic hypotension were evaluated in conscious swine. Following hemorrhage (37.5 ml/kg/60 min) animals received 4 ml/kg of HSD (n = 6) or 0.9% saline (n = 8). Administration of normal saline did not alter cardiovascular function nor attenuate an increase in hormones. HSD rapidly improved cardiovascular function and acutely decreased ACTH, plasma renin activity (PRA), cortisol, norepinephrine (NE), epinephrine (E), aldosterone, and lysine vasopressin levels (LVP). The initial decreased in ACTH, cortisol, and aldosterone levels was due primarily to hemodilution associated with the expansion of plasma volume. The reductions in NE, E, LVP, and PRA were greater than those attributed to hemodilution alone. Values for LVP, NE, and E remained at values below those at the end of hemorrhage, but greater than basal levels, while PRA returned to values similar to these at the end of hemorrhage. The decrease in LVP, NE, and E following HSD resuscitation for the treatment of hemorrhagic hypotension may result from and contribute to the rectification of cardiovascular and metabolic function.     

Catecholamines in individual hypothalamic nuclei of acutely and repeatedly stressed rats.

Norepinephrine (NE) and dopamine (DA) concentrations in 17 individual hypothalamic nuclei and 3 other brain regions were measured in rats, acutely or repeatedly stressed by immobilization, using a microdissection technique and a radioisotopic-enzymatic assay. Following the first 20 min immobilization (IMO) a significant NE decrease in the ventromedial (NVM) and supraoptic (NSO) nuclei and a DA decrease in the arcuate nucleus (NA) as well as NE and DA increase in the dorsomedial nucleus (NDM) were seen. Repeated IMO (40 times) produced a NE increase in the NVM, NDM, NSO paraventricular nucleus (NPV) and median eminence (ME), and a DA increase in the NDM and NPV. Changes of NE and DA concentration found in some individual hypothalamic nuclei under the influence of stress indicate that catecholamines (CAs), particularly in the medial basal hypothalamus, could be involved in the regulation of some neuroendocrine processes which are being activated during stress, especially ACTH release.     

Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat

Adult rats handled (H) daily for the first 3 weeks of life show a dramatically altered adrenocortical response to stress. We found that H animals secreted less ACTH and corticosterone (B) during and following the termination of stress than did nonhandled (NH) controls. In contrast, H and NH animals did not differ in basal B secretion at any point in the diurnal cycle, nor in adrenocortical responses to exogenously administered oCRF or ACTH. Moreover, the clearance rate for B was similar in H and NH animals. H animals were more sensitive than NH animals to the inhibitory effects of either B or dexamethasone on stress-induced adrenocortical activity. In a dose-response study, both glucocorticoids administered 3 h prior to testing suppressed the adrenocortical response to a 20-min restraint stress to a greater extent in the H animals. Handling increased type II, glucocorticoid receptor binding capacity in the hippocampus of adult animals (approximately 50% increase in capacity, with no change in affinity). There were no handling-induced changes in type II receptor binding capacity in the hypothalamus or pituitary, nor in type I receptor binding capacity in the hippocampus. Following chronic (5 mg/kg/day) treatment with B, hippocampal type II receptor binding capacity was significantly reduced in the B-treated H animals, compared with saline-treated H animals, and indistinguishable from saline-treated NH animals. Down-regulated H animals, like NH animals, hypersecreted B following the termination of stress in comparison to the saline-treated H animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of 2-Hydroxypropyl-Beta-Cyclodextrin on Cardiovascular Signs of Amitriptyline Poisoning in a Rat Model

The aim of this study was to investigate the efficacy of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) as an antidotal treatment for the in vivo cardiovascular effects of amitriptyline poisoning. Experiments were carried out on 33 Wistar rats. To evaluate cardiovascular effects of HPBCD, rats were infused with dextrose or HPBCD. In the poisoning model, amitriptyline (0.94 mg/kg/min) was infused until the mean arterial blood pressure (MAP) dropped to 50 % of the baseline. Following amitriptyline infusion, dextrose, low-dose HPBCD (4.19 mg/kg/min), or high-dose HPBCD (16.76 mg/kg/min) was infused, and MAP, heart rate (HR), and electrocardiogram were recorded for 60 min. Hearts were examined for tissue damage and apoptosis. HPBCD infusion alone did not yield significant difference for MAP, HR, QRS duration, QT interval, and cardiac tissue damage when compared to dextrose (p > 0.05). In the poisoning model, MAP and HR decreased, while QRS duration and QT interval prolonged significantly following amitriptyline infusion (p < 0.0167). Dextrose, low-dose HPBCD, and high-dose HPBCD infusion similarly corrected MAP, HR, QRS duration, and QT interval values at the end-experiment time point (p > 0.05). Histological scores for tissue damage and apoptosis showed no significant difference between the groups (p > 0.05). Based on our results, HPBCD did not show cardiovascular toxicity, while it was not more effective than dextrose for the treatment of amitriptyline poisoning. Further antidotal studies of cyclodextrins with higher doses and/or binding affinities are needed for poisonings.     

Cardiovascular effects of thyrotropin-releasing hormone in normotensive and hypotensive rats: role of rostral ventrolateral medulla.

To ascertain the central mechanism of the effects of thyrotropin-releasing hormone (TRH) on the cardiovascular system, we evaluated the effects of this neuropeptide on unit fires in the rostral ventro-lateral medulla (RVL), mean arterial pressure (MAP), and heart rate (HR) in normotensive and hypotensive rats. Intracerebroventricular injection (i.c.v.) of 10 micrograms TRH significantly increased MAP and HR in both normotensive and hypotensive rats. No similar effects were observed after saline injection. If electrolytic lesions of bilateral RVL were made, the cardiovascular effects of TRH i.c.v. failed to occur. TRH i.c.v. markedly increased the firing frequency of most units in the RVL. In particular, TRH i.c.v. increased the firing frequency of most units excitatory to a fall in MAP and decreased the firing frequency of most units inhibitory to a fall in MAP in normotensive rats. Moreover, a drop of MAP as low as 40 mmHg for 10 min resulted in an increase of the firing frequency of most units. The effect of TRH i.c.v. on the RVL units in the hypotensive rats was similar to that in the normotensive rats. Our findings suggest that TRH is able to intensify the cardiovascular activities and the RVL plays a key role in the effects of TRH on the cardiovascular system in both normotensive and hypotensive rats.