Intracellular angiotensin II as a regulator of muscle tone in vascular resistance vessels. Pathophysiological implications

The influence of intracellular angiotensin II on the regulation of potassium current and membrane potential of smooth muscle cells of mesenteric arteries and its relevance for the regulation of vascular tone was reviewed. The presence of components of the renin angiotensin system (RAS) in different cells of the cardiovascular system, was discussed including their presence in the nuclei and mitochondria. Emphasis was given to the opposite effects of intracellular and extracellular angiotensin II (Ang II) on the regulation of potassium current, membrane potential and contractility of vascular resistance vessels and its implication to vascular physiology and pathology and the possible role of epigenetic factors on the expression of angiotensin II (Ang II) and renin in vascular resistance vessels as well as its possible pathophysiological role in hypertension and other cardiovascular diseases.     

Metabolic Enzyme Alterations and Astrocyte Dysfunction in a Murine Model of Alexander Disease With Severe Reactive Gliosis

Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAP^Tg;Gfap^+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAP^Tg;Gfap^+/R236H versus wild-type mice confirmed upregulation of the glutathione metabolism pathway and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which had not been reported previously in AxD. Relative protein-level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8-deficient mice exhibit a phenotype similar to GFAP^Tg;Gfap^+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAP^Tg;Gfap^+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAP^Tg;Gfap^+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap⁺ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAP^Tg;Gfap^+/R236H mice. Last, to determine whether the findings in GFAP^Tg;Gfap^+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant fourfold upregulation of FABP7. However, immunohistochemistry analysis showed that UGT8 accumulates in AxD patient subpial brain regions where abundant amounts of Rosenthal fibers are located, which was not observed in the GFAP^Tg;Gfap^+/R236H mice.     

On measurements of the higher harmonics of transmembrane current

The higher harmonics of the current caused by an alternating voltage applied to bilayer lipid membranes made of diphytanoyl phosphatidylcholine (DPhPC) in decane and tetradecane were measured. A universal relation between the amplitudes of harmonics was proposed and experimentally verified. This allowed the coefficients of expansion of the capacitance in even powers of voltage to be calculated for the DPhPC membrane in tetradecane; it also permitted comparison of the inhomogeneity in the thickness of the DPhPC membranes in decane and tetradecane.     

Water and ion permeability of a native collagen membrane

With the help of a ribonucleoprotein it is possible to precipitate collagen in a layer of fibers with a 700 Å period. As collagen is a constituent of many membrane systems in the body, it seemed interesting to investigate the permeability of ions and water through a native collagen membrane.The experiments were carried out with the help of an acryl glass apparatus, where an osmotic pressure, a hydrostatic pressure difference or both can be maintained between the two bulk phases separated by the membrane. The diffusion coefficients for NaCl and KCl were found to be comparable with those in other biological membranes (D_s = 9 · 10⁻⁷cm² · s⁻¹) whereas there is difference of more than three orders of magnitude in the hydraulic permeability (L_p = 6 cm⁴ · J⁻¹ · s⁻¹).Volume flow measurements caused by an osmotic gradient indicated that the reflection coefficient for NaCl and KCl is very small. In hydrostatic pressure experiments, the membrane shows a preferred direction for volume flows which seems to have something to do with the mode of preparation of the membrane.     

Intracellular calcium release mediated by two muscarinic receptor subtypes

Four subtypes of muscarinic acetylcholine receptor (mAChR) were stably expressed in neuroblastoma-glioma hybrid cells (NG108-15). By combining fluorescent indicator dye (fura-2) studies with electrophysiological measurements it is shown that stimulation of mAChR I and mAChR III readily leads to release of calcium from intracellular stores and to associated conductance changes, whereas stimulation of mAChR II and mAChR IV exerts no such effect. Dose-response curves describing the amplitude or the delay of the calcium rise induced by acetylcholine suggest that the apparent affinity of mAChR III for its agonist is higher by about one order of magnitude than that of mAChR I. Ionic substitution experiments and current fluctuation analysis indicate that calcium activates a K⁺-specific conductance of ‘small’ single-channel amplitude similar to the SK type [1]. Furthermore, an outward current (M current) suppressed by activation of mAChR I and mAChR III has a single-channel amplitude corresponding to a conductance of approximately 3 pS.     

PACEMAKER OSCILLATIONS IN HEART AND BRAIN: A KEY ROLE FOR HYPERPOLARIZATION-ACTIVATED CATION CHANNELS

Rhythmic activity of single cells or multicellular networks is a common feature of all organisms. The oscillatory activity is characterized by time intervals of several seconds up to many hours. Cellular rhythms govern the beating of the heart, the swimming behavior of sperm, cycles of sleep and wakefulness, breathing, and the release of hormones. Many neurons in the brain and cardiac cells are characterized by endogenous rhythmic activity, which relies on a complex interplay between several distinct ion channels. In particular, one type of ion channel plays a prominent role in the control of rhythmic electrical activity since it determines the frequency of the oscillations. The activity of the channels is thus setting the “pace” of the oscillations; therefore, these channels are often referred to as “pacemaker” channels. Despite their obvious important physiological function, it was not until recently that genes encoding pacemaker channels have been identified. Because both hyperpolarization and cyclic nucleotides are key elements that control their activity, pacemaker channels have now been designated hyperpolarization-activated and cyclic nucleotide–gated (HCN) channels. The molecular identification of the channels and the upcoming studies on their properties in heterologous systems will certainly enhance our understanding of “pacemaking” in physiological systems. This review gives a brief insight into the physiological importance of these channels and sums up what we have learned since the first cloning of genes succeeded (for recent reviews, see also Clapham 1998; Luüthi and McCormick 1998a; Biel et al. 1999; Ludwig, Zong, Hofmann, et al. 1999; Santoro and Tibbs 1999). (Chronobiology International, 17(4), 453–469, 2000)     

The extracranial arterial system in the heads of beaked whales,with implications on diving physiology and pathogenesis

Beaked whales are medium‐sized toothed whales that inhabit depths beyond the continental shelf; thus beaked whale strandings are relatively infrequent compared to those of other cetaceans. Beaked whales have been catapulted into the spotlight by their tendency to strand in association with naval sonar deployment. Studies have shown the presence of gas and fat emboli within the tissues and analysis of gas emboli is suggestive of nitrogen as the primary component. These findings are consistent with human decompression sickness (DCS) previously not thought possible in cetaceans. Because, tissue loading with nitrogen gas is paramount for the manifestation of DCS and nitrogen loading depends largely on the vascular perfusion of the tissues, we examined the anatomy of the extracranial arterial system using stranded carcasses of 16 beaked whales from five different species. Anatomic regions containing lipid and/or air spaces were prioritized as potential locations of nitrogen gas absorption due to the known solubility of nitrogen in adipose tissue and the nitrogen content of air, respectively. Attention was focused on the acoustic fat bodies and accessory sinus system on the ventral head. We found much of the arterial system of the head to contain arteries homologous to those found in domestic mammals. Robust arterial associations with lipid depots and air spaces occurred within the acoustic fat bodies of the lower jaw and pterygoid air sacs of the ventral head, respectively. Both regions contained extensive trabecular geometry with small arteries investing the trabeculae. Our findings suggest the presence of considerable surface area between the arterial system, and the intramandibular fat bodies and pterygoid air sacs. Our observations may provide support for the hypothesis that these structures play an important role in the exchange of nitrogen gas during diving. J. Morphol. 277:5–33, 2016. © 2015 Wiley Periodicals, Inc.