Endocrine and fluid metabolism in males and females of different ages after bedrest, acceleration and lower body negative pressure

Space shuttle flight simulations were conducted to determine the effects of weightlessness, lower body negative pressure (LBNP), and acceleration of fluid and electrolyte excretion and the hormones that control it. Measurements were made on male and female subjects of different ages before and after bedrest. After admission to a controlled environment, groups of 6 to 14 subjects in the age ranges 25 to 35, 35 to 45, 45 to 55 to 65 years were exposed to +3 G sub z for 15 minutes (G1) and to LBNP (LBNP1) on different days. On 3 days during this prebedrest period, no tests were conducted. Six days of bedrest followed, and the G sub z (G2) and LBNP (LBNP2) tests were run again. Hormones, electrolytes, and other parameters were measured in 24-hour urine pools throughout the experiment. During bedrest, cortisol and aldosterone excretion increased. Urine volume decreased, and specific gravity and osmolality increased. Urinary electrolytes were statistically unchanged from levels during the non-stress control period. During G2, cortisol increased significantly over its control and bedrest levels. Urine volume, sodium, and chloride were significantly lower; specific gravity and osmolality were higher during the control period or bedrest. The retention of fluids and electrolytes after +G sub z may at least partially explain decreased urine volume and increased osmolality observed during bedrest in this study. There were some who indicated that space flight would not affect the fluid and electrolyte metabolism of females or older males any more severely than it has affected that of male astronauts

Capsaicin- resistant arterial baroreceptors

BACKGROUND: Aortic baroreceptors (BRs) comprise a class of cranial afferents arising from major arteries closest to the heart whose axons form the aortic depressor nerve. BRs are mechanoreceptors that are largely devoted to cardiovascular autonomic reflexes. Such cranial afferents have either lightly myelinated (A-type) or non-myelinated (C-type) axons and share remarkable cellular similarities to spinal primary afferent neurons. Our goal was to test whether vanilloid receptor (TRPV1) agonists, capsaicin (CAP) and resiniferatoxin (RTX), altered the pressure-discharge properties of peripheral aortic BRs. RESULTS: Periaxonal application of 1 μM CAP decreased the amplitude of the C-wave in the compound action potential conducting at <1 m/sec along the aortic depressor nerve. 10 μM CAP eliminated the C-wave while leaving intact the A-wave conducting in the A-δ range (<12 m/sec). These whole nerve results suggest that TRPV1 receptors are expressed along the axons of C- but not A-conducting BR axons. In an aortic arch – aortic nerve preparation, intralumenal perfusion with 1 μM CAP had no effect on the pressure-discharge relations of regularly discharging, single fiber BRs (A-type) – including the pressure threshold, sensitivity, frequency at threshold, or maximum discharge frequency (n = 8, p > 0.50) but completely inhibited discharge of an irregularly discharging BR (C-type). CAP at high concentrations (10–100 μM) depressed BR sensitivity in regularly discharging BRs, an effect attributed to non-specific actions. RTX (≤ 10 μM) did not affect the discharge properties of regularly discharging BRs (n = 7, p > 0.18). A CAP-sensitive BR had significantly lower discharge regularity expressed as the coefficient of variation than the CAP-resistant fibers (p < 0.002). CONCLUSION: We conclude that functional TRPV1 channels are present in C-type but not A-type (A-δ) myelinated aortic arch BRs. CAP has nonspecific inhibitory actions that are unlikely to be related to TRV1 binding since such effects were absent with the highly specific TRPV1 agonist RTX. Thus, CAP must be used with caution at very high concentrations

Modeling the differentiation of A- and C-type baroreceptor firing patterns

The baroreceptor neurons serve as the primary transducers of blood pressure for the autonomic nervous system and are thus critical in enabling the body to respond effectively to changes in blood pressure. These neurons can be separated into two types (A and C) based on the myelination of their axons and their distinct firing patterns elicited in response to specific pressure stimuli. This study has developed a comprehensive model of the afferent baroreceptor discharge built on physiological knowledge of arterial wall mechanics, firing rate responses to controlled pressure stimuli, and ion channel dynamics within the baroreceptor neurons. With this model, we were able to predict firing rates observed in previously published experiments in both A- and C-type neurons. These results were obtained by adjusting model parameters determining the maximal ion-channel conductances. The observed variation in the model parameters are hypothesized to correspond to physiological differences between A- and C-type neurons. In agreement with published experimental observations, our simulations suggest that a twofold lower potassium conductance in C-type neurons is responsible for the observed sustained basal firing, whereas a tenfold higher mechanosensitive conductance is responsible for the greater firing rate observed in A-type neurons. A better understanding of the difference between the two neuron types can potentially be used to gain more insight into the underlying pathophysiology facilitating development of targeted interventions improving baroreflex function in diseased individuals, e.g. in patients with autonomic failure, a syndrome that is difficult to diagnose in terms of its pathophysiology.Comment: Keywords: Baroreflex model, mechanosensitivity, A- and C-type afferent baroreceptors, biophysical model, computational mode

Modeling the Afferent Dynamics of the Baroreflex Control System

In this study we develop a modeling framework for predicting baroreceptor firing rate as a function of blood pressure. We test models within this framework both quantitatively and qualitatively using data from rats. The models describe three components: arterial wall deformation, stimulation of mechanoreceptors located in the BR nerve-endings, and modulation of the action potential frequency. The three sub-systems are modeled individually following well-established biological principles. The first submodel, predicting arterial wall deformation, uses blood pressure as an input and outputs circumferential strain. The mechanoreceptor stimulation model, uses circumferential strain as an input, predicting receptor deformation as an output. Finally, the neural model takes receptor deformation as an input predicting the BR firing rate as an output. Our results show that nonlinear dependence of firing rate on pressure can be accounted for by taking into account the nonlinear elastic properties of the artery wall. This was observed when testing the models using multiple experiments with a single set of parameters. We find that to model the response to a square pressure stimulus, giving rise to post-excitatory depression, it is necessary to include an integrate-and-fire model, which allows the firing rate to cease when the stimulus falls below a given threshold. We show that our modeling framework in combination with sensitivity analysis and parameter estimation can be used to test and compare models. Finally, we demonstrate that our preferred model can exhibit all known dynamics and that it is advantageous to combine qualitative and quantitative analysis methods

C-terminal Tail of β-Tubulin and its Role in the Alterations of Dynein Binding Mode

Dynein is a cytoskeletal molecular motor protein that moves along the microtubule (MT) and transports various cellular cargos during its movement. Using standard Molecular Dynamics (MD) simulation, Principle Component Analysis (PCA), and Normal Mode Analysis (NMA) methods, this investigation studied large-scale movements and local interactions of dynein’s Microtubule Binding Domain (MTBD) when bound to tubulin heterodimer subunits. Examination of the interactions between the MTBD segments, and their adjustments in terms of intra- and intermolecular distances at the interfacial area with tubulin heterodimer, particularly at α-H16, β-H18 and β-tubulin C-terminal tail (CTT), was the main focus of this study. The specific intramolecular interactions, electrostatic forces and the salt-bridge residue pairs were shown to be the dominating factors in orchestrating movements of the MTBD and MT interfacial segments in the dynein’s low-high affinity binding modes. Important interactions included β-Glu447 and β-Glu449 (CTT) with Arg3469 (MTBD-H6), Lys3472 (MTBD-H6-H7 loop) and Lys3479 (MTBD-H7); β-Glu449 with Lys3384 (MTBD-H8), Lys3386 and His3387 (MTBD-H1). The structural and precise position, orientation, and functional effects of the CTTs on the MT-MTBD, within reasonable cut-off distance for non-bonding interactions and under physiological conditions, are unavailable from the previous studies. The absence of the residues in the highly flexible MT-CTTs in the experimentally solved structures is perhaps in some cases due to insufficient data from density maps, but these segments are crucial in protein binding. The presented work contributes to the information useful for the MT-MTBD structure refinement

Functional properties of peptides derived from seminalplasmin: Binding to monospecific anti-seminalplasmin immunoglobulins G and calmodulin.

Seminalplasmin was specifically hydrolysed employing the proteinases Lys-C and Glu-C. A set of peptides of seminalplasmin were obtained which were used to study their interaction with monospecific anti-seminalplasmin IgGs as well as calmodulin. Two peptides P4 (position 38-47) and P9 (position 4-32) strongly interacted with the polyclonal anti-seminalplasmin IgGs, indicating that a C-terminal (P4) as well as a N-terminal region of seminalplasmin represent major antigenic sites of the polypeptide. From the panel of peptides only peptide P9 was found to bind to calmodulin with high affinity. Thus, the structural requirements for the strong and specific interaction of calmodulin with seminalplasmin apparently reside in the N-terminal sequence 3-32 of the latter

Functional properties of peptides derived from seminalplasmin: Binding to monospecific anti-seminalplasmin immunoglobulins G and calmodulin.

Seminalplasmin was specifically hydrolysed employing the proteinases Lys-C and Glu-C. A set of peptides of seminalplasmin were obtained which were used to study their interaction with monospecific anti-seminalplasmin IgGs as well as calmodulin. Two peptides P4 (position 38-47) and P9 (position 4-32) strongly interacted with the polyclonal anti-seminalplasmin IgGs, indicating that a C-terminal (P4) as well as a N-terminal region of seminalplasmin represent major antigenic sites of the polypeptide. From the panel of peptides only peptide P9 was found to bind to calmodulin with high affinity. Thus, the structural requirements for the strong and specific interaction of calmodulin with seminalplasmin apparently reside in the N-terminal sequence 3-32 of the latter