A role for histamine in cardiovascular regulation in late stage embryos of the red-footed tortoise, Chelonoidis carbonaria Spix, 1824

A chorioallantoic membrane artery in embryos of the red-footed tortoise, Chelonoidis carbonaria was occlusively cannulated for measurement of blood pressure and injection of drugs. Two age groups of embryos in the final 10 % of incubation were categorized by the ratio of embryonic body to yolk mass. All embryos first received cholinergic and β-adrenergic blockade. This revealed that β-adrenergic control was established in both groups whereas cholinergic control was only established in the older group immediately prior to hatching. The study then progressed as two series. Series one was conducted in a subset of embryos treated with histamine before or after injection of ranitidine, the antagonist of H2 receptors. Injection of histamine caused an initial phasic hypertension which recovered, followed by a longer lasting hypertensive response accompanied by a tachycardia. Injection of the H2 receptor antagonist ranitidine itself caused a hypotensive tachycardia with subsequent recovery of heart rate. Ranitidine also abolished the cardiac effects of histamine injection while leaving the initial hypertensive response intact. In series, two embryos were injected with histamine after injection of diphenhydramine, the antagonist to H1 receptors. This abolished the whole of the pressor response to histamine injection but left the tachycardic response intact. These data indicate that histamine acts as a non-adrenergic, non-cholinergic factor, regulating the cardiovascular system of developing reptilian embryos and that its overall effects are mediated via both H1 and H2 receptor types. © 2013 Springer-Verlag Berlin Heidelberg.

Effects of ambient temperature on cardiovascular regulation during sleep in hypocretin-deficient narcoleptic mice

Hypocretin 1 and 2 (HCRT, also called Orexin A and B) are neuropeptides released by neurons in the lateral hypothalamus. HCRT neurons widely project to the entire neuroaxis. HCRT neurons have been reported to participate in various hypothalamic physiological processes including cardiovascular functions, wake-sleep cycle, and they may also influence metabolic rate and the regulation of body temperature. HCRT neurons are lost in narcolepsy, a rare neurological disorder, characterized by excessive daytime sleepiness, cataplexy, sleep fragmentation and occurrence of sleep-onset rapid-eye-movement episodes. We investigated whether HCRT neurons mediate the sleep-dependent cardiovascular adaptations to changes in ambient temperature (Ta). HCRT-ataxin3 transgenic mice with genetic ablation of HCRT neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure (BP) transducer (DSI, Inc.). Simultaneous sleep and BP recordings were performed on mice undisturbed and freely-behaving at 20 °C, 25 °C, and 30 °C for 48 hours at each Ta. Analysis of variance of BP indicated a significance of the main effects of wake-sleep state and Ta, their interaction effect, and the wake-sleep state x mouse strain interaction effect. BP increased with decreasing Ta. This effect of Ta on BP was significantly lower in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness regardless of the mouse strain. BP was higher in wakefulness than either in NREMS or REMS. This effect of sleep on BP was significantly reduced in mice lacking HCRT neurons at each Ta, particularly during REMS. These data suggest that HCRT neurons play a critical role in mediating the effects of sleep but not those of Ta on BP in mice. HCRT neurons may thus be part of the central neural pathways which mediate the phenomenon of blood pressure dipping on passing from wakefulness to sleep.

Autonomic cardiovascular regulation in obesity

Obese persons suffer from an increased mortality risk supposedly due to cardiovascular disorders related to either continuously lowered parasympathetic or altered sympathetic activation. Our cross-sectional correlation study establishes the relationship between obesity and autonomic regulation as well as salivary cortisol levels. Three patient cohorts were sampled, covering ranges of body mass index (BMI) of 27-32 (n=17), 33-39 (n=13) and above 40 kg/m(2)(n=12), and stratified for age, sex and menopausal status. Autonomic cardiovascular regulation was assessed by use of heart rate variability and continuous blood pressure recordings. Spectral analytical calculation (discrete Fourier transformation) yields indices of sympathetic and parasympathetic activation and baroreflex sensitivity. Morning salivary cortisol was concurrently collected. Contrary to expectation, BMI and waist/hip ratio (WHR) were inversely correlated with sympathetic activity. This was true for resting conditions (r=-0.48, P<0.001; r=-0.33, P<0.05 for BMI and WHR respectively) and for mental challenge (r=-0.42, P<0.01 for BMI). Resting baroreflex sensitivity was strongly related to the degree of obesity at rest (BMI: r=-0.35, P<0.05) and for mental challenge (r=-0.53, P<0.001). Salivary cortisol correlated significantly with waist circumference (r=-0.34, P=0.05). With increasing weight, no overstimulation was found but a depression in sympathetic and parasympathetic activity together with a significant reduction in baroreflex functioning and in salivary cortisol levels.

Cardiovascular regulation during administration of co-dergocrine to normal subjects

Whether and to what extent activation of peripheral presynaptic dopamine2-receptors may modulate the release of norepinephrine (NE) and so affect blood pressure (BP) in normal or hypertensive man is not clear. The hydrogenated ergotoxine derivative, co-dergocrine, given in effective antihypertensive rather than excessive experimental doses, has recently been shown to act predominantly as a peripheral dopamine2-receptor agonist in several species. Accordingly, BP regulation assessed has been in 8 normal men on placebo and after 3 weeks on codergocrine 4 mg/day. Co-dergocrine significantly reduced urinary NE excretion from 43 to 33 micrograms/24 h, supine and upright plasma NE 21 to 16 and 49 to 36 ng/dl, respectively, heart rate (-8 and -5%, respectively) and upright systolic BP, 115 to 102 mm Hg; upright diastolic BP also tended to be lower. A standard pressor dose of infused NE was lowered from 131 to 102 ng/kg/min, and the relationship between NE-induced changes in BP and concomitant NE infusion rate or plasma NE concentration was displaced to the left. Exchangeable sodium and plasma volume tended to be slightly decreased. Plasma and urinary electrolytes and epinephrine, plasma renin activity and aldosterone levels, pressor responsiveness to angiotensin II, the chronotropic responses to isoproterenol, and the NE-induced rise in BP, plasma clearance of NE, glomerular filtration rate and effective renal plasma flow were not consistently modified. The findings are consistent with effective peripheral dopamine2-receptor agonism by co-dergocrine in humans. Peripheral presynaptic dopaminergic activation may modulate sympathetic activity and BP in normal man.

Effects of chronic baroreceptor stimulation on the autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension

In patients with drug-resistant hypertension, chronic electric stimulation of the carotid baroreflex is an investigational therapy for blood pressure reduction. We hypothesized that changes in cardiac autonomic regulation can be demonstrated in response to chronic baroreceptor stimulation, and we analyzed the correlation with blood pressure changes. Twenty-one patients with drug-resistant hypertension were prospectively included in a substudy of the Device Based Therapy in Hypertension Trial. Heart rate variability and heart rate turbulence were analyzed using 24-hour ECG. Recordings were obtained 1 month after device implantation with the stimulator off and after 3 months of chronic electric stimulation (stimulator on). Chronic baroreceptor stimulation decreased office blood pressure from 185+/-31/109+/-24 mm Hg to 154+/-23/95+/-16 mm Hg (P<0.0001/P=0.002). Mean heart rate decreased from 81+/-11 to 76+/-10 beats per minute(-1) (P=0.001). Heart rate variability frequency-domain parameters assessed using fast Fourier transformation (FFT; ratio of low frequency:high frequency: 2.78 versus 2.24 for off versus on; P<0.001) were significantly changed during stimulation of the carotid baroreceptor, and heart rate turbulence onset was significantly decreased (turbulence onset: -0.002 versus -0.015 for off versus on; P=0.004). In conclusion, chronic baroreceptor stimulation causes sustained changes in heart rate variability and heart rate turbulence that are consistent with inhibition of sympathetic activity and increase of parasympathetic activity in patients with drug-resistant systemic hypertension; these changes correlate with blood pressure reduction. Whether the autonomic modulation has favorable cardiovascular effects beyond blood pressure control should be investigated in further studies.

The adrenergic regulation of the cardiovascular system in the South American rattlesnake, Crotalus durissus

The present study investigates adrenergic regulation of the systemic and pulmonary circulations of the anaesthetised South American rattlesnake, Crotalus durissus. Haemodynamic measurements were made following bolus injections of adrenaline and adrenergic antagonists administered through a systemic arterial catheter. Adrenaline caused a marked systemic vasoconstriction that was abolished by phentolamine, indicating this response was mediated through alpha-adrenergic receptors. Injection of phentolamine gave rise to a pronounced vasodilatation (systemic conductance (G(sys)) more than doubled), while injection of propranolol caused a systemic vasoconstriction, pointing to a potent alpha-adrenergic, and a weaker beta-adrenergic tone in the systemic vasculature of Crotalus. Overall, the pulmonary vasculature was far less responsive to adrenergic stimulation than the systemic circulation. Adrenaline caused a small but non-significant pulmonary vasodilatation and there was tendency of reducing this dilatation after either phentolamine or propranolol. Injection of phentolamine increased pulmonary conductance (G(pul)), while injection of propranolol produced a small pulmonary constriction, indicating that alpha-adrenergic and beta-adrenergic receptors contribute to a basal regulation of the pulmonary vasculature. Our results suggest adrenergic regulation of the systemic vasculature, rather than the pultrionary, may be an important factor in the development of intracardiac shunts. (c) 2007 Elsevier B.V. All rights reserved.

Regulation of wake-sleep states and state-dependent cardiovascular function in diet-induced obesity rats

Obesity often predisposes to coronary heart disease, heart failure, and sudden death. Also, several studies suggest a reciprocal enhancing interaction between obesity and sleep curtailment. Aim of the present study was to go deeper in the understanding of sleep and cardiovascular regulation in an animal model of diet-induced obesity (DIO). According to this, Wake-Sleep (W-S) regulation, and W-S dependent regulation of cardiovascular and metabolic/thermoregulatory function was studied in DIO rats, under normal laboratory conditions and during sleep deprivation and the following recovery period, enhancing either wake or sleep, respectively. After 8 weeks of the delivery of a hypercaloric (HC) diet, treated animals were heavier than those fed a normocaloric (NC) diet (NC: 441 ±17g; HC: 557±17g). HC rats slept more than NC ones during the activity period (Dark) of the normal 12h:12h light-dark (LD) cycle (Wake: 67.3±1.2% and 57.2 ±1.6%; NREM sleep (NREMS): 26.8±1.0% and 34.0±1.4%; REM sleep (REMS): 5.7±0. 6% and 8.6±0.7%; for NC and HC, respectively; p<0.05 for all). HC rats were hypertensive throughout the W-S states, as shown by the mean arterial blood pressure values across the 24-h period (Wake: 90.0±5.3 and 97.3±1.3; NREMS: 85.1±5.5 and 92.2±1.2; REMS: 87.2±4.5 and 96.5±1.1, mmHg for NC and HC, respectively; p<0.05 for all). Also, HC rats appeared to be slightly bradycardic compared to NC ones (Wake: 359.8±9.3 and 352.4±7.7; NREMS: 332.5±10.1 and 328.9±5.4; REMS: 338.5±9.3 and 334.4±5.8; bpm for NC and HC, respectively; p<0.05 for Wake). In HC animals, sleep regulation was not apparently altered during the sleep rebound observed in the recovery period following sleep deprivation, although REMS rebound appeared to be quicker in NC animals. In conclusion, these results indicate that in the rat obesity interfere with W-S and cardiovascular regulation and that DIO rats are suitable for further studies aimed at a better understanding of obesity comorbidities.

Sidestream cigarette smoke effects on cardiovascular responses in conscious rats: involvement of oxidative stress in the fourth cerebral ventricle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Commissural nucleus of the solitary tract is important for cardiovascular responses to caudal pressor area activation

The nucleus of the solitary tract (NTS) is the site of the first synapse of cardiovascular afferent fibers in the central nervous system. Important mechanisms for cardiovascular regulation are also present in the caudal pressor area (CPA) localized at the caudal end of the ventrolateral medulla. In the present study we sought to investigate the role of the commissural subnucleus of the NTS (commNTS) on pressor and tachycardic responses induced by L-glutamate injected into the CPA. Male Holtzman rats (n=8 rats/group) anesthetized with urethane (1.2 g/kg of body weight, iv) received injections of the GABAA receptor agonist muscimol into the commNTS. Unilateral injection of L-glutamate (10 nmol/ 100 nL) into the CPA increased mean arterial pressure (MAP, 31 4 mm Hg, vs. saline: 3 +/- 2 mm Hg) and heart rate (HR, 44 8 bpm, vs. saline: 10 7 bpm). inhibition of commNTS neurons with muscimol (120 pmol/60 nL) abolished the increase in MAP (9 4 mm Hg) and HR (17 7 bpm) produced by L-glutamate into the CPA. The present results suggest that the pressor and tachycardic responses to CPA activation are dependent on commNTS mechanisms.

Role of catecholaminergic neurones of the caudal ventrolateral medulla in cardiovascular responses induced by acute changes in circulating volume in rats

Several findings suggest that catecholaminergic neurones in the caudal ventrolateral medulla (CVLM) contribute to body fluid homeostasis and cardiovascular regulation. The present study sought to determine the effects of lesions of these neurones on the cardiovascular responses induced by changes in circulating volume. All experiments were performed in male Wistar rats (320-360 g). Medullary catecholaminergic neurones were lesioned by microinjection of anti-dopamine beta-hydroxylase-saporin (6.3 ng in 60 nl; SAP rats, n = 14) into the CVLM, whereas sham rats received microinjections of free saporin (1.3 ng in 60 nl, n = 15). Two weeks later, rats were anaesthetized (urethane, 1.2 g kg(-1), I.V..), instrumented for measurement of mean arterial pressure (MAP), renal blood flow (RBF) and renal vascular conductance (RVC), and infused with hypertonic saline (HS; 3 M NaCl, 0.18 ml (100 g body weight)(-1), I.V.) or an isotonic solution (volume expansion, VE; 4% Ficoll, 1% of body weight, I.V.). In sham rats, HS induced sustained increases in RBF and RVC (155 +/- 7 and 145 +/- 6% of baseline, at 20 min after HS). In SAP rats, RBF responses to HS were blunted (125 +/- 6%) and RVC increases were abolished (108 +/- 5%) 20 min after HS. Isotonic solution increased RBF and RVC in sham rats (149 +/- 10 and 145 +/- 12% of baseline, respectively, at 20 min). These responses were reduced in SAP rats (131 +/- 6 and 126 +/- 5%, respectively, at 20 min). Pressor responses to HS were larger in SAP rats than in sham rats (17 +/- 5 versus 9 +/- 2 mmHg, at 20 min), whereas during VE these responses were similar in both groups (6 +/- 3 versus 4 +/- 6 mmHg, at 20 min). Immunohistochemical analysis indicates that microinjections of anti-D beta H-saporin produced extensive destruction within the A1/C1 cell groups in the CVLM. These results suggest that catecholaminergic neurones mediate the cardiovascular responses to VE or increases in plasma sodium levels.

Ablation of NK1 receptor bearing neurons in the nucleus of the solitary tract blunts cardiovascular reflexes in awake rats

The nucleus of the solitary tract (NTS) receives primary afferents involved in cardiovascular regulation. We investigated the role of NK1-receptor bearing neurons in the NTS on cardiovascular reflexes in awake rats fitted with chronic venous and arterial cannulae. These neurons were lesioned selectively with saporin conjugated with substance P (SP-SAP, 2 mu M, bilateral injections of 20 nL in the subpostremal NTS, or 200 nL in both the subpostremal and the commissural NTS). Before, and 7 and 14 days after injection of SP-SAP, we measured changes in blood pressure and heart rate induced by i.v. injection of phenylephrine and nitroprusside (baroreceptor reflex), cyanide (arterial chemoreceptor reflex), and phenylbiguanide (Bezold-Jarisch reflex). The smaller injections with SP-SAP completely abolished NK1 receptor staining in the subpostremal NTS. The larger injections abolished NK1 receptor immunoreactivity in an area that extended from the commissural NTS to the rostral end of the subpostremal NTS. The lesions seemed to affect only a limited number of neurons, since neutral red stained sections did not show any obvious reduction in cell number. The smaller lesions reduced the gain of baroreflex bradycardia and the hypotension induced by phenylbiguanide. The larger lesions completely abolished the response to phenylbiguanide, blocked the baroreflex bradycardia induced by phenylephrine, severely blunted the baroreflex tachycardia, and blocked the bradycardia and reduced the hypertension induced by cyanide. Thus, these responses depend critically on NK1-receptor bearing neurons in the NTS. (c) 2006 Elsevier B.V. All rights reserved.

Cardiovascular responses to hydrogen peroxide into the nucleus tractus solitarius

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)