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Thermogenesis, electro-chemical physiology (ECP), and electro-mechanical activities (EMAs) are fundamental facets of cellular functioning that are associated with powering, coherence, homeostasis, sensing, and response to stimuli. The classical Hodgkin–Huxley–Katz purview of ECP is derived from Nernst-based foundations for dilute solutions, whereas cellular milieus are mostly highly packed colloidal coacervates, with various types/levels of macromolecules (ions), interactions, and ordering of water. It has also been established that trans-membrane potential (TMP) manifestation can also be affected by adsorption of ions and effective charge separation (1e processes), necessitating the questioning and expansion of classical purviews. Further, we have demonstrated that the traditional explanation of electrogenic/stoichiometric and vitally deterministic bidirectional pumping/channeling of ions by membrane proteins (such as Na,K-ATPase) as the rationale for resting/dynamic TMP variations is untenable. In stark contrast, the murburn purview of ECP-EMAs acknowledges the complexity and discretization of the organization of water, ions, and macromolecules within the cell and does not solicit selective ion-pumping or TMP-based powering/propagation rationales. Herein, we summarize the murburn rationale for the molecular to macroscopic integration of processes such as thermogenesis, kinetic Na–K differentiation at the cell membrane, visual signal transduction and neuronal impulse relay, Complex V mediated mechano-chemostat function, flagella-based motility, etc., and discuss the alteration of cellular volume/tenor in muscle cell contraction. We assert that the membrane-embedded proteins/enzymes cannot use ATP to work against the natural laws of physics. Therefore, the classical perception of membrane-based ion pumps must be jettisoned to make way for the thermodynamics-friendly murburn purview. [ABSTRACT FROM AUTHOR]

The redox metabolic paradigm of murburn concept advocates that diffusible reactive species (DRS, particularly oxygen‐centric radicals) are mainstays of physiology, and not mere pathological manifestations. The murburn purview of cellular function also integrates the essential principles of bioenergetics, thermogenesis, homeostasis, electrophysiology, and coherence. In this context, any enzyme that generates/ modulates/utilizes/sustains DRS functionality is called a murzyme. We have demonstrated that several water‐soluble (peroxidases, lactate dehydrogenase, hemogoblin, etc.) and membrane‐embedded (Complexes I–V in mitochondria, Photosystems I/II in chloroplasts, rhodopsin/transducin in rod cells, etc.) proteins serve as murzymes. The membrane protein of Na,K‐ATPase (NKA, also known as sodium‐potassium pump) is the focus of this article, owing to its centrality in neuro‐ cardio‐musculo electrophysiology. Herein, via a series of critical queries starting from the geometric/spatio‐temporal considerations of diffusion/mass transfer of solutes in cells to an update on structural/distributional features of NKA in diverse cellular systems, and from various mechanistic aspects of ion‐transport (thermodynamics, osmoregulation, evolutionary dictates, etc.) to assays/explanations of inhibitory principles like cardiotonic steroids (CTS), we first highlight some unresolved problems in the field. Thereafter, we propose and apply a minimalist murburn model of trans‐membrane ion‐differentiation by NKA to address the physiological inhibitory effects of trans‐dermal peptide, lithium ion, volatile anesthetics, confirmed interfacial DRS + proton modulators like nitrophenolics and unsaturated fatty acid, and the diverse classes of molecules like CTS, arginine, oximes, etc. These explanations find a pan‐systemic connectivity with the inhibitions/uncouplings of other membrane proteins in cells. [ABSTRACT FROM AUTHOR]

Venular endothelial cells can release nitric oxide (NO) in response to intraluminal flow both in isolated venules and in vivo. Experimental studies suggest that venular endothelium-released NO causes dilation of the adjacent paired arteriole. In the vascular wall, NO stimulates its target hemoprotein, soluble guanylate cyclase (sGC), which relaxes smooth muscle cells. In this study, a computational model of NO transport for an arteriole and venule pair was developed to determine the importance of the venular endothelium-released NO and its transport to the adjacent arteriole in the tissue. The model predicts that the tissue NO levels are affected within a wide range of parameters, including NO-red blood cell reaction rate and NO production rate in the arteriole and venule. The results predict that changes in the venular NO production affected not only venular endothelial and smooth muscle NO concentration but also endothelial and smooth muscle NO concentration in the adjacent arteriole. This suggests that the anatomy of microvascular tissue can permit the transport of NO from arteriolar to venular side, and vice versa, and may provide a mechanism for dilation of proximal arterioles by venules. These results will have significant implications for our understanding of tissue NO levels in both physiological and pathophysiological conditions. vasodilation; shear stress; microcirculation; nitric oxide; mathematical model

Nitric oxide (NO) plays many important physiological roles, including the regulation of vascular smooth muscle tone. In response to hemodynamic or agonist stimuli, endothelial cells produce NO, which can diffuse to smooth muscle where it activates soluble guanylate cyclase (sGC), leading to cGMP formation and smooth muscle relaxation. The close proximity of red blood cells suggests, however, that a significant amount of NO released will be scavenged by blood, and thus the issue of bioavailability of endothelium-derived NO to smooth muscle has been investigated experimentally and theoretically. We formulated a mathematical model for NO transport in an arteriole to test the hypothesis that transient, burst-like NO production can facilitate efficient NO delivery to smooth muscle and reduce NO scavenging by blood. The model simulations predict that 1) the endothelium can maintain a physiologically significant amount of NO in smooth muscle despite the presence of NO scavengers such as hemoglobin and myoglobin; 2) under certain conditions, transient NO release presents a more efficient way for activating sGC and it can increase cGMP formation severalfold; and 3) frequency- rather than amplitude-dependent control of cGMP formation is possible. This suggests that it is the frequency of NO bursts and perhaps the frequency of [Ca.sup.2+] oscillations in endothelial cells that may limit cGMP formation and regulate vascular tone. The proposed hypothesis suggests a new functional role for [Ca.sup.2+] oscillations in endothelial cells. Further experimentation is needed to test whether and under what conditions in silico predictions occur in vivo. mathematical model; vascular regulation; microcirculation; diffusion; blood substitutes

Administration of hemoglobin-based oxygen carriers (HBOCs) frequently results in vasoconstriction that is primarily attributed to the scavenging of endothelium-derived nitric oxide (NO) by cell-free hemoglobin. The ensuing pressor response could be caused by the high NO reactivity of HBOC in the vascular lumen and/or the extravasation of hemoglobin molecules. There is a need for quantitative understanding of the NO interaction with HBOC in the blood vessels. We developed a detailed mathematical model of NO diffusion and reaction in the presence of an HBOC for an arteriolarsize vessel. The HBOC reactivity with NO and degree of extravasation was studied in the range of 2-58 x [10.sup.6] [M.sup.-1] * [s.sup.-1] and 0-100%, respectively. The model predictions showed that the addition of HBOC reduced the smooth muscle (SM) NO concentration in the activation range (12-28 nM) for soluble guanylate cyclase, a major determinant of SM contraction. The SM NO concentration was significantly reduced when the extravasation of HBOC molecules was considered. The myoglobin present in the parenchymal cells scavenges NO, which reduces the SM NO concentration. mathematical model; microcirculation; extravasation; vasoconstriction; myoglobin