Beta-adrenergic mechanisms in arterial hemodynamics: A comparison between normotensive and hypertensive rats

The purpose of this study was to determine whether -adrenergically mediated cardiovascular functions such as arterial pressure (AP), heart rate (HR), stroke volume (SV), cardiac output (CO), peripheral resistance (R_p), arterial impedance (Z_c), mean arterial compliance (C_m) and pulse wave reflection (P_b) were altered in the spontaneously hypertensive rat (SHR) compared to the normotensive Wistar Kyoto rat (WKY). In pentobarbital-anesthetized and artificially ventilated rats, the aortic pressure wave was recorded with a high-fidelity Millar sensor, and aortic flow wave with an electromagnetic flow probe. The pressure and flow waves were subjected to Fourier transform so as to analyze impedance spectra. Acute -adrenergic blockade was produced by an intravenous injection of propranolol (nonselective) and atenolol (selective ₁-blocker) at doses of 2 and 5 mg/kg, respectively. Steady-state parameters were obtained 15–20 min after intravenous administration. The SHR had higher AP, HR, R_p and Z_c than the WKY. SV and CO remained unaltered while C_m was lower. In response to propranolol, the mean AP was increased by 7 mm Hg in the WKY, but did not change in the SHR. Moreover, significant decreases occurred in HR, CO and C_m in addition to increases in R_p, Z_c and P_b. These changes between the SHR and WKY were only slight. Atenolol caused decreases in AP, HR and CO in both SHR and WKY, but did not significantly alter the R_p, Z_c, C_m and P_b. Again, the atenolol-induced changes in AP, HR and CO did not appear to be significantly different between SHR and WKY. The results indicate that -adrenergic effects on the heart, Windkessel and resistance vessels are neither greatly enhanced nor impaired during the development of hypertension. In the hypertensive state, significant -adrenergic mechanisms still exert tonic vasodilatory effects on the large and small arterial system.     

Influences of exercise-stress and adrenaline upon intra- and extracellular acid-base status,electrolyte composition and respiratory properties of blood in tench (Tinca tinca) at different seasons

Summary Exercise-stress in tench resulted in severe acidoses in both the red cells and the extracellular fluid in vivo. These coincident pH decreases conformed to the in vitro pH_i-pH_e relationship for tench blood in the oxygenated state. The extracellular acidosis was primarily respiratory in winter and metabolic in spring and summer. This was due to more effective buffering of metabolic protons in winter by an elevation in [HCO ₃ ^– ] levels, rather than to differences in the lactic- and carbonic acid loads. A good correspondence was found between buffered metabolic protons and increases in [lactate].There was no evidence for -adrenergic red cell swelling and associated red cell pH changes in tench both after exercise and adrenaline infusion. Arterial O₂ transport was, however, improved in exercise by pronounced increases in .Large increases in plasma potassium concentration and small elevations of chloride and calcium levels occurred in exercise. Hematocrit and blood [Hb] also increased, probably due to an adrenergic release of erythrocytes from the spleen, but these increases were small and appeared unimportant for blood O₂ transport.Seasonal differences were found in exercise-induced changes in [lactate], in the magnitude of electrolyte and changes, as well as in resting values for pH_e, pH_i, [HCO ₃ ^– ], [Cl^–] and [Ca⁺⁺]. The origin and importance of these are discussed.     

Functional cardiovascular action of l-cysteine microinjected into pressor sites of the rostral ventrolateral medulla of the rat

The endogenous sulfur-containing amino acid l-cysteine injected into the cerebrospinal fluid space of the cisterna magna increases arterial blood pressure (ABP) and heart rate (HR) in the freely moving rat. The present study examined (1) cardiovascular responses to l-cysteine microinjected into the rostral ventrolateral medulla (RVLM), where a group of neurons regulate activities of cardiovascular sympathetic neurons and (2) involvement of ionotropic excitatory amino acid (iEAA) receptors in response. In the RVLM of urethane-anesthetized rats accessed ventrally and identified with pressor responses to l-glutamate (10 mM, 34 nl), microinjections of l-cysteine increased ABP and HR dose dependently (3–100 mM, 34 nl). The cardiovascular responses to l-cysteine (30 mM) were not attenuated by a prior injection of either antagonist alone, MK801 (20 mM, 68 nl) for the NMDA type of iEAA receptors, or CNQX (2 mM) for the non-NMDA type. However, inhibition of both NMDA and non-NMDA receptors with additional prior injection of either antagonist completely blocked those responses to l-cysteine. The results indicate that l-cysteine has functional cardiovascular action in the RVLM of the anesthetized rat, and the responses to l-cysteine involve both NMDA and non-NMDA receptors albeit in a mutually exclusive parallel fashion. The findings may suggest endogenous roles of l-cysteine indirectly via iEAA receptors in the neuronal network of the RVLM for cardiovascular regulation in physiological and pathological situations.     

Autonomic nervous control of blood pressure and heart rate during hypoxia in the cod,Gadus morhua

Summary The autonomic nervous and possible adrenergic humoral control of blood pressure and heart rate during hypoxia was investigated in Atlantic cod. The oxygen tension in the water was reduced to 4.0–5.3 kPa (i.e.. P_wO₂=30–40 mmHg), and the fish responded with an immediate increase in ventral and dorsal aortic blood pressure (P _va P _da), as well as a slowly developing bradycardia. The plasma concentrations of circulating catecholamines increased during hypoxia with a peak in the plasma level of noradrenaline occurring before the peak for adrenaline. Bretylium was used as a chemical tool to differentiate between neuronal and humoral adrenergic control of blood pressure and heart rate (f _H) during hypoxia. The increase in P _va and P _da in response to hypoxia was strongly reduced in bretylium-treated cod, which suggests that adrenergic nerves are responsible for hypoxic hypertension. In addition, a small contribution by circulating catecholamines to the adrenergic tonus affecting P _va during hypoxia was suggested by the decrease in P _va induced by injection of the -adrenoceptor antagonist phentolamine. The cholinergic and the adrenergic tonus affecting heart rate were estimated by injections of atropine and the -adrenoceptor antagonist sotalol. The experiments demonstrate an increased cholicholinergic as well as adrenergic tonus on the heart during hypoxia.     

Blood-gas,acid-base and catecholamine responses to lactic acid infusion in larval and adult Ambystoma tigrinum

Larval and adult Ambystoma tigrinum were subjected to acidosis by infusing lactic acid (2 M·g^-1) into the peritoneal cavity. Blood was sampled at intervals to establish the time-course of the ensuing acidosis. Both larvae and adults became significantly acidotic after 1 h. The larval acidosis was more pronounced (-4 pH units versus-2 pH units) than adults due to greater extracellular buffering capacity (higher [HCO₃ ^-]) in adults. Both forms recovered in about 8 h. Larvae showed a typical increase in circulating norepinephrine during the initial stages of the acidosis; adults did not, having significantly lower norepinephrine titer than larvae during the acidosis. Both larvae and adults showed transient increases in PO₂ during the acidosis. The ₁ and ₂ antagonists, timolol and butoxamine respectively, (0.2 g·g^-1) were administered to separate groups of larvae. Butoxamine (₂) delayed the recovery from the acidosis by prolonging the increase in arterial PCO₂ and reversing the recovery of [HCO₃ ^-]. Timolol (₁) did not delay recovery. We conclude that ₂ receptors are involved in the catecholamine responses to acidosis in larvae. Catecholamines appear not to play the same role in adult acid-base disturbances as they seem to in larvae.Abbreviations RBC red blood cell     

Effects of pretreatment with inducers of hepatic mixed function oxidases on DNA repair elicited by various compounds in hepatocytes from adult and neonatal rats

Studies were conducted to assess the effects of inducers of hepatic mixed function oxidases on DNA repair responses to 13 different genotoxic agents in hepatocytes from adult male mice. Phenobarbital pretreatment increased DNA repair elicited by diethylnitrosamine but had no effect on responses to the other compounds. Pretreatment with p,p-dichlorodiphenyltrichloroethane, 3-methylcholanthrene or -naphthoflavone induced the DNA repair responses to a variety of activation-dependent carcinogens. DNA repair responses to the direct-acting alkylating agents methyl methanesulfonate and N-methyl-N-nitro-N-nitrosoguanidine were not increased by any of the pretreatments, which indicated that the pretreatment-related enhancement of responses to the other compounds was due to induction of their metabolic activation. Taken together, the findings suggest that Aroclor, or other pretreatments, may increase the sensitivity of the hepatocyte DNA repair assay for detecting the genotoxicity of certain compounds; however, the potential benefit may be limited due to specific features of the assay. In contrast, Aroclor pretreatment did not produce any enhancement of in vivo DNA repair elicited by dimethylnitrosamine, diethylnitrosamine, o-aminoazotoluene, 2-acetylaminofluorene, 3-methylcholanthrene or aflatoxin B₁, and thus does not appear to be useful for improving the sensitivity of the in vivo/in vitro assay.Whereas the amount of DNA repair produced by dimethylnitrosamine was not increased by classical inducers of liver microsomal enzymes, pretreatment with pyrazole greatly augmented in vitro and in vivo DNA repair responses to dimethylnitrosamine; responses to diethylnitrosamine were increased to a lesser degree by pyrazole pretreatment. The effects of lactational exposure to enzyme inducing agents on DNA repair in neonatal hepatocytes was also investigated.Abbreviations 2-AAF 2-acetylaminofluorene - 4-AB 4-aminobiphenyl - 6-AC 6-aminochrysene - AFB aflatoxin B₁ - ARO Aroclor 1254 - o-AT o-aminoazotoluene - B(a)P benzo[a]pyrene - B-NF beta-naphthoflavone - BZ benzidine - DDT p,p-dichlorodiphenyltrichloroethane - DDE p,p-dichlorodiphenyldichloroethylene - DEN diethylnitrosamine - DMBA 7,12-dimethylbenzanthracene - DMN dimethylnitrosamine - 3-MC 3-methylcholanthrene - MMS methyl methanesulfonate - MNNG N-methyl-N-nitro-N-nitrosoguanidine - 2-NA 2-naphthylamine - NNG net nuclear grains - PB phenobarbital - PYR pyrazole     

Circulating Brain-Derived Neurotrophic Factor and Indices of Metabolic and Cardiovascular Health: Data from the Baltimore Longitudinal Study of Aging

Background

Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF) is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile.

Methodology/Principal Findings

To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age ∼70), in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3), and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin.

Conclusion/Significance

Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain) remains to be determined.     

Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome

Background

Metabolic syndrome is a cluster of common cardiovascular risk factors that includes hypertension and insulin resistance. Hypertension and diabetes mellitus are frequent comorbidities and, like metabolic syndrome, increase the risk of cardiovascular events. Telmisartan, an antihypertensive agent with evidence of partial peroxisome proliferator-activated receptor activity-gamma (PPARγ) activity, may improve insulin sensitivity and lipid profile in patients with metabolic syndrome.

Methods

In a double-blind, parallel-group, randomized study, patients with World Health Organization criteria for metabolic syndrome received once-daily doses of telmisartan (80 mg, n = 20) or losartan (50 mg, n = 20) for 3 months. At baseline and end of treatment, fasting and postprandial plasma glucose, insulin sensitivity, glycosylated haemoglobin (HBA_1c) and 24-hour mean systolic and diastolic blood pressures were determined.

Results

Telmisartan, but not losartan, significantly (p < 0.05) reduced free plasma glucose, free plasma insulin, homeostasis model assessment of insulin resistance and HbA_ic. Following treatment, plasma glucose and insulin were reduced during the oral glucose tolerance test by telmisartan, but not by losartan. Telmisartan also significantly reduced 24-hour mean systolic blood pressure (p < 0.05) and diastolic blood pressure (p < 0.05) compared with losartan.

Conclusion

As well as providing superior 24-hour blood pressure control, telmisartan, unlike losartan, displayed insulin-sensitizing activity, which may be explained by its partial PPARγ activity.     

Genetic characterization of a new splice variant of the β2 subunit of the voltage-dependent calcium channel

This study reports a novel splice variant form of the voltage-dependent calcium channel ₂ subunit (_2g). This variant is composed of the conserved amino-terminal sequences of the _2a subunit, but lacks the -subunit interaction domain (BID), which is thought essential for interactions with the ₁ subunit. Gene structure analysis revealed that this gene was composed of 13 translated exons spread over 107 kb of the genome. The gene structure of the ₂ subunit was similar in exon-intron organization to the murine ₃ and human ₄ subunits. Electrophysiological evaluation revealed that _2a and _2g affected channel properties in different ways. The _2a subunit increased the peak amplitude, but failed to increase channel inactivation, while _2g had no significant effects on either the peak current amplitude or channel inactivation. Other subunits, such as ₃ and ₄, significantly increased the peak current and accelerated current inactivation.     

Comparative metabolic and cardiovascular effects of carbuterol, isoproterenol, metaproterenol and salbutamol in the baboon

The metabolic and cardiovascular responses to two bronchiolar selective beta-adrenergic drugs, carbuterol (CAR) and salbutamol (SAL), were compared with isoproterenol (ISO) and metaproterenol (MET) in fasted, anesthetized baboons. ISO was more active than the selective beta-adrenergic drugs in elevating plasma levels of glucose, lactate, free fatty acids, insulin, and glucagon. Moreover, ISO was more active in increasing heart rate and respiratory rate and in depressing diastolic blood pressure. Although ISO was shown to have greater activity than CAR, MET, and SAL, the bronchiolar selective drugs (CAR and SAL) did produce significant changes in plasma levels of metabolic substrates and pancreatic hormones and in cardiovascular measurements at higher dose rates.     

Home-based exercise rehabilitation in addition to specialist heart failure nurse care: design, rationale and recruitment to the Birmingham Rehabilitation Uptake Maximisation study for patients with congestive heart failure (BRUM-CHF): a randomised controlled trial

Background

We aimed to assess whether we could identify a graded association between increasing number of components of the metabolic syndrome and cardiac structural and functional abnormalities independently of predicted risk of coronary heart disease by the Framingham risk score.

Methods

We conducted a cross-sectional study on a random sample of the urban population of Porto aged 45 years or over. Six hundred and eighty-four participants were included. Data were collected by a structured clinical interview with a physician, ECG and a transthoracic M-mode and 2D echocardiogram. The metabolic syndrome was defined according to ATPIII-NCEP. The association between the number of features of the metabolic syndrome and the cardiac structural and functional abnormalities was assessed by 3 multivariate regression models: adjusting for age and gender, adjusting for the 10-year predicted risk of coronary heart disease by Framingham risk score and adjusting for age, gender and systolic blood pressure.

Results

There was a positive association between the number of features of metabolic syndrome and parameters of cardiac structure and function, with a consistent and statistically significant trend for all cardiac variables considered when adjusting for age and gender. Parameters of left ventricular geometry patterns, left atrial diameter and diastolic dysfunction maintained this trend when taking into account the 10-year predicted risk of coronary heart disease by the Framingham score as an independent variable, while left ventricular systolic dysfunction did not. The prevalence of left ventricular diastolic dysfunction, and the mean left ventricular mass, left ventricular diameter and left atrial diameter increased significantly with the number of features of the metabolic syndrome when additionally adjusting for systolic blood pressure as a continuous variable.

Conclusion

Increasing severity of metabolic syndrome was associated with increasingly compromised structure and function of the heart. This association was independent of Framingham risk score for indirect indices of diastolic dysfunction but not systolic dysfunction, and was not explained by blood pressure level.     

Phase Synchronization of Hemodynamic Variables at Rest and after Deep Breathing Measured during the Course of Pregnancy

Background

The autonomic nervous system plays a central role in the functioning of systems critical for the homeostasis maintenance. However, its role in the cardiovascular adaptation to pregnancy-related demands is poorly understood. We explored the maternal cardiovascular systems throughout pregnancy to quantify pregnancy-related autonomic nervous system adaptations.

Methodology

Continuous monitoring of heart rate (R-R interval; derived from the 3-lead electrocardiography), blood pressure, and thoracic impedance was carried out in thirty-six women at six time-points throughout pregnancy. In order to quantify in addition to the longitudinal effects on baseline levels throughout gestation the immediate adaptive heart rate and blood pressure changes at each time point, a simple reflex test, deep breathing, was applied. Consequently, heart rate variability and blood pressure variability in the low (LF) and high (HF) frequency range, respiration and baroreceptor sensitivity were analyzed in resting conditions and after deep breathing. The adjustment of the rhythms of the R-R interval, blood pressure and respiration partitioned for the sympathetic and the parasympathetic branch of the autonomic nervous system were quantified by the phase synchronization index γ, which has been adopted from the analysis of weakly coupled chaotic oscillators.

Results

Heart rate and LF/HF ratio increased throughout pregnancy and these effects were accompanied by a continuous loss of baroreceptor sensitivity. The increases in heart rate and LF/HF ratio levels were associated with an increasing decline in the ability to flexibly respond to additional demands (i.e., diminished adaptive responses to deep breathing). The phase synchronization index γ showed that the observed effects could be explained by a decreased coupling of respiration and the cardiovascular system (HF components of heart rate and blood pressure).

Conclusions/Significance

The findings suggest that during the course of pregnancy the individual systems become increasingly independent to meet the increasing demands placed on the maternal cardiovascular and respiratory system.     

Respiratory adaptations to diving in the nile monitor lizard,Varanus niloticus

Summary The objectives of this study included directin vivo measurements of circulating blood gases, pH, heart rate, and blood pressure during voluntary dives of unrestrained Nile monitor lizards. A Radiometer flow-through cuvette was employed for continuous recording of arterial PO₂, PCO₂ and pH. Hematological properties revealed no particular adaptations for diving. Mean values were: hematocrit = 24%; hemoglobin concentration = 7.1 g %; oxygen capacity = 9.3 vol %; red cell dimensions = 22×12 ; red cell count = 0.67 million/l. The respiratory properties of the blood, studiedin vitro andin vivo, show distinct adaptations to habitual diving. Oxygen affinity of blood is low (P₅₀ = 42.4 mm Hg at pH 7.45, 25 °) and the dissociation curve is markedly sigmoid (n = 3.1). These features, coupled with a Bohr factor ( logP ₅₀/pH) of –0.48, ensure increased utilization of oxygen while maintaining relatively high tissue PO₂. Arterial pH decreases during diving from about 7.5 to 7.1 due to combined respiratory and metabolic acidosis. High plasma bicarbonate (30 mM/l at PCO₂ = 25 mm Hg) and a buffering capacity of H C₃ ^–O/ pH = 18.9 mM/l increase the tolerance to this acidosis and prolong diving time. Thein vivo oxygen dissociation curve shows a 90 % depletion of arterial oxygen content during typical dives. Diving elicited a rapidly developing bradycardia with maximum of 85 % reduction in heart rate. The temperature sensitivity of HbO₂ binding was very low (H = –3kcal). This would minimize the HbO₂ affinity increase accompanying the decrease in body temperature likely to occur in lizards going from sun basking to submergence in water.Supported by a grant from the Danish Natural Science Research Council.     

Daily Liquorice Consumption for Two Weeks Increases Augmentation Index and Central Systolic and Diastolic Blood Pressure

Background

Liquorice ingestion often elevates blood pressure, but the detailed haemodynamic alterations are unknown. We studied haemodynamic changes induced by liquorice consumption in 20 subjects versus 30 controls with average blood pressures of 120/68 and 116/64 mmHg, respectively.

Methods

Haemodynamic variables were measured in supine position before and after two weeks of liquorice consumption (daily glycyrrhizin dose 290–370 mg) with tonometric recording of radial blood pressure, pulse wave analysis, and whole-body impedance cardiography. Thirty age-matched healthy subjects maintaining their normal diet were studied as controls.

Results

Two weeks of liquorice ingestion elevated peripheral and central systolic and diastolic blood pressure (by 7/4 and 8/4 mmHg, 95% confidence intervals [CI] 2-11/1-8 and 3-13/1-8, respectively, P<0.05), and increased extracellular volume by 0.5 litres (P<0.05 versus controls). Also augmentation index adjusted to heart rate 75/min (from 7% to 11%, 95% CI for change 0.3-7.5, P<0.05) and aortic pulse pressure (by 4 mmHg, 95% CI 1-7, P<0.05) were elevated indicating increased wave reflection from the periphery. In contrast, peripheral (−3/−0.3 mmHg) and central blood pressure (−2/−0.5 mmHg), aortic pulse pressure (−1 mmHg), and augmentation index adjusted to heart rate 75/min (from 9% to 7%) decreased numerically but not statistically significantly without changes in extracellular volume in the control group. Heart rate, systemic vascular resistance, cardiac output, and pulse wave velocity did not differ between the groups.

Conclusions

Two weeks of daily liquorice consumption increased extracellular volume, amplified pressure wave reflection from the periphery, and elevated central systolic and diastolic blood pressure.

Trial Registration

EU Clinical Trials Register EudraCT 2006-002065-39</url>ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01742702","term_id":"NCT01742702"}}NCT01742702     

Mixed acid-base disorders, hydroelectrolyte imbalance and lactate production in hypercapnic respiratory failure: the role of noninvasive ventilation

Background

Hypercapnic Chronic Obstructive Pulmonary Disease (COPD) exacerbation in patients with comorbidities and multidrug therapy is complicated by mixed acid-base, hydro-electrolyte and lactate disorders. Aim of this study was to determine the relationships of these disorders with the requirement for and duration of noninvasive ventilation (NIV) when treating hypercapnic respiratory failure.

Methods

Sixty-seven consecutive patients who were hospitalized for hypercapnic COPD exacerbation had their clinical condition, respiratory function, blood chemistry, arterial blood gases, blood lactate and volemic state assessed. Heart and respiratory rates, pH, PaO₂ and PaCO₂ and blood lactate were checked at the 1st, 2nd, 6th and 24th hours after starting NIV.

Results

Nine patients were transferred to the intensive care unit. NIV was performed in 11/17 (64.7%) mixed respiratory acidosis–metabolic alkalosis, 10/36 (27.8%) respiratory acidosis and 3/5 (60%) mixed respiratory-metabolic acidosis patients (p = 0.026), with durations of 45.1±9.8, 36.2±8.9 and 53.3±4.1 hours, respectively (p = 0.016). The duration of ventilation was associated with higher blood lactate (p<0.001), lower pH (p = 0.016), lower serum sodium (p = 0.014) and lower chloride (p = 0.038). Hyponatremia without hypervolemic hypochloremia occurred in 11 respiratory acidosis patients. Hypovolemic hyponatremia with hypochloremia and hypokalemia occurred in 10 mixed respiratory acidosis–metabolic alkalosis patients, and euvolemic hypochloremia occurred in the other 7 patients with this mixed acid-base disorder.

Conclusions

Mixed acid-base and lactate disorders during hypercapnic COPD exacerbations predict the need for and longer duration of NIV. The combination of mixed acid-base disorders and hydro-electrolyte disturbances should be further investigated.     

Cardiovascular actions of l-cysteine and l-cysteine sulfinic acid in the nucleus tractus solitarius of the rat

The sulfur-containing excitatory amino acid (EAA) l-cysteine sulfinic acid (CSA), a neurotransmitter candidate, is endogenously synthesized from l-cysteine (Cys). Exogenous Cys administration into the brain produces cardiovascular effects; these effects likely occur via synaptic stimulation of central nervous system (CNS) neurons that regulate peripheral cardiovascular function. However, the cardiovascular responses produced by CNS Cys administration could result from CSA biosynthesized in synapse. The present study examined the role of CSA in Cys-induced cardiovascular responses within the nucleus tractus solitarius (NTS) of anesthetized rats. The NTS receives input from various visceral afferents that gate autonomic reflexes, including cardiovascular reflexes. Within the NTS, both Cys and CSA microinjections produced decrease responses in arterial blood pressure and heart rate that were similar to those produced by l-glutamate. Co-injection of the ionotropic EAA receptor antagonist kynurenic acid abolished Cys-, but not CSA-, induced cardiovascular responses. This finding suggests that only Cys-induced cardiovascular responses are mediated by kynurenate-sensitive receptors. This study provides the first demonstration that Cys- and CSA-induced cardiovascular responses occur via different mechanisms in the NTS of rats. Further, this study also indicates that Cys-induced cardiovascular responses do not occur via CSA. Thus, within the NTS, endogenous Cys and/or CSA might be involved in cardiovascular regulation.     

Choline Administration Reverses Hypotension In Spinal Cord Transected Rats: The Involvement of Vasopressin

Intracerebroventricular (i.c.v.) choline (50–150 g) increased blood pressure and decreased heart rate in spinal cord transected, hypotensive rats. Choline administered intraperitoneally (60 mg/kg), also, increased blood pressure, but to a lesser extent. The pressor response to i.c.v. choline was associated with an increase in plasma vasopressin. Mecamylamine pretreatment (50 g; i.c.v.) blocked the pressor, bradycardic and vasopressin responses to choline (150 g). Atropine pretreatment (10 g; i.c.v.) abolished the bradycardia but failed to alter pressor and vasopressin responses. Hemicholinium-3 [HC-3 (20 g; i.c.v.)] pretreatment attenuated both bradycardia and pressor responses to choline. The vasopressin V1 receptor antagonist, (-mercapto-, -cyclopenta-methylenepropionyl¹, O-Me-Tyr², Arg⁸)-vasopressin (10 g/kg) administered intravenously 5 min after choline abolished the pressor response and attenuated the bradycardia-induced by choline. These data show that choline restores hypotension effectively by activating central nicotinic receptors via presynaptic mechanisms, in spinal shock. Choline-induced bradycardia is mediated by central nicotinic and muscarinic receptors. Increase in plasma vasopressin is involved in cardiovascular effects of choline.     

Modeling left ventricular diastolic dysfunction: classification and key indicators

Background

Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported.

Methods

We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5^th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations.

Results

IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O₂ and CO₂ differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD.

Conclusion

The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease.     

Cardiovascular effects produced by injections of thyrotropin-releasing hormone in specific preoptic and hypothalamic nuclei in the rat

Microinjection of 1.4 pmol TRH (0.5 ng; 50–150 nl) into both the preoptic suprachiasmatic nucleus (pos) and the A6800–7000 region of the medial preoptic nucleus (pom) produced increases in blood pressure and heart rate of 7% and 19%, respectively; heart rate responses in these two areas were higher than those occurring in other areas tested. TRH induced a significant increase in blood pressure and heart rate in the posterior hypothalamic nucleus (nhp) and increased heart rate only in the anterior (nha) and dorsomedial (ndm) hypothalamic nuclei. A small decrease in both blood pressure and heart rate resulted with TRH injections in the A7050–7400 region of the pom. No changes in respiratory rate or rectal temperature were observed at any site with this dose of TRH. Preliminary studies into the mechanism of the cardiovascular actions of TRH suggested that inhibition of the parasympathetic nerves to the heart make a partial contribution to the TRH-induced heart rate increase in the pos and that adrenal catecholamine release mediates the TRH response in the nhp. Neither methylatropine pretreatment nor adrenalectomy prevented the response to TRH injected into the nha, suggesting that activation of the cardiac sympathetic nerves may mediate TRH actions in this region. In the ndm, neither methylatropine nor adrenalectomy prevented the response to TRH; however, there was a tendency for the response to be less after methylatropine. Therefore, both inhibition of the parasympathetic and activation of the sympathetic nervous systems may contribute to the response observed, but no adrenal involvement could be demonstrated. Discrete injections of 0.8 nmol TRH produced increases in heart rate and blood pressure in all preoptic and hypothalamic nuclei tested with accompanying changes in respiratory rate and rectal temperature in some areas. Lateral cerebral ventricle injections of as little as 2.8 pmol TRH produced increases in blood pressure and heart rate; cardiovascular responses to higher doses (0.8–22 nmol) in the ventricle were often accompanied by arousal, piloerection, “wet dog” shakes and changes in respiratory rate and rectal temperature. Previous immunohistochemical demonstration of nerve cells and fibers in the preoptic-hypothalamic area and the present finding of specific sites responsive to low dose TRH injections (1.4 pmol) both support a physiological role for this peptide in central control of the cardiovascular system.     

Intracellular pH during daily torpor inPeromyscus maniculatus

Summary Intracellular and extracellular acid-base parameters during normothermy and daily torpor were examined in deer mice (Peromyscus maniculatus). [¹⁴C]Dimethyloxazolidinedione and [³]inulin were used to assess intracellular pH in liver, heart, skeletal muscle, and brain. Buffering capacities were determined using tissue homogenates. A significant increase in plasma and during daily torpor indicates a respiratory acidosis. All tissues experienced a reduction in the calculated dissociation ratio of histidine imidazole groups (_imid) during daily torpor (16.5% for brain, approximately 10% for other tissues). Based on comparisons with physicochemical tissue buffering capacities, metabolic compensation of the respiratory acidosis occurred in liver, heart, and plasma, while brain was more acidotic than predicted. The more extensive change in brain _imid might influence a regulated decrease in body temperature. Comparison of acid-base parameters during daily torpor and hibernation suggests that the magnitude of acid-base modifications in mammals may be associated with the level of dormancy.Abbreviations _imid dissociation ratio of histidine imidazole groups - physicochemical non-bicarbonate buffer value - ' apparent (in vivo) buffer value - bicarbonate bicarbonate values corrected to a temperature of 25 °C - pH pH values corrected to a temperature of 25 °C - pH _i intracellular pH - pK _imid pK of histidine imidazole groups - T _b body temperature