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Miscellaneous Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Beta-adrenergic tocolytic drugs bind to beta-adrenergic receptors on the outer myometrial cell membrane and activate adenylate cyclase, which catalyzes conversion of ATP to cAMP. Increased intracellular cAMP levels activate cAMPase-dependent protein kinase and decreases intracellular calcium concentration, reducing myometrial contractility (Caritis et al., 1989; Roberts, 1984). Phosphorylation of myosin light chain kinase, another pathway, inactivates the enzyme, thus inhibiting subsequent phosphorylation of the myosin light chain. Maternal metabolic abnormalities (gluconeogenesis, hypokalemia, and hyperglycemia), and cardiopulmonary complications (tachycardia, hypotension, arrhythmias, myocardial ischemia, pulmonary edema) are associated with beta-agonist tocolysis (Box 15.2). Apprehension, electrocardiogram (EKG/ECG) changes (S-T segment depression) and maternal death are associated with beta-adrenergic agonist tocolytic agents. Every beta-agonist is associated with an increased frequency of pulmonary edema, occurring among <5 percent of pregnant women who use these drugs (Boyle, 1995; McCombs, 1995).
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
The relaxant effects of β2-adrenoceptor agonists have, until the last 5 years, been thought to be fully explained by PKA-dependent phosphorylation of proteins associated with intracellular regulation of calcium levels, including inhibition of inositol phosphate hydrolysis following phospholipase C activation, increased sodium/calcium exchange, and increased calcium reuptake (Figure 1). Inhibition of myosin light chain kinase activity is an additional site of action of PKA.98
General Aspects of Endocrine Physiology
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Calmodulin is an intracellular binding protein that acts as a second messenger. A number of peptide hormones increase intracellular calcium, either by opening calcium channels following receptor activation or secondary to the phosphatidylinositol system. Calcium ions bind to calmodulin, leading to a conformational change. The calmodulin–calcium complex binds to and activates various enzymes. For example, it activates myosin light-chain kinase, and this results in the phosphorylation of myosin, causing smooth muscle contraction.
Angiotensin-converting enzyme inhibitor induced angioedema: not always a class effect? A case report and short narrative review
Published in Current Medical Research and Opinion, 2021
Guillaume Becker, Fabien Rougerie, Amelia-Naomi Sabo, Marie-Caroline Dalmas, Estelle Ayme-Dietrich, Laurent Monassier
The bradykinin mechanism has been associated with the highest mortality rate, potentially triggering angioedema-related asphyxia3. This phenomenon is not related to the activation of mast cells but rather to the uncontrolled generation of bradykinin by the kinin–kallikrein system. Bradykinin promotes vasodilation by stimulating the production of nitric oxide and other relaxing factors by the endothelium4. It is thus assumed that most of the specific effects of bradykinin are mediated by its type 2 receptor (B2R). B2R is a G-protein-coupled receptor mainly stimulating phospholipase-C via activated Gq proteins. Thus, its stimulation rapidly releases calcium from the endoplasmic reticulum. In endothelial cells, calcium can activate various enzymatic systems directly (phospholipase A2) or indirectly by binding to calmodulin which, in turn, activates endothelial nitric oxide synthase and myosin light chain kinase. All these intracellular couplings lead to the relaxation of arteriolar smooth muscle cells. Moreover, the activated myosin light chain kinase induces the contraction of actin–myosin cytoskeleton, leading to endothelial cell retraction, vascular endothelial barrier permeabilization and fluid extravasation5. Otherwise, by stimulating constitutive B2 receptors in smooth muscle cells, extraluminal bradykinin mediates inositol phosphate accumulation and the subsequent Ca2+ influx, which acts as a transducing mechanism for the bradykinin-stimulated contraction of vascular smooth muscle cells6.
Efficacy and safety of netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma and ocular hypertension
Published in Expert Review of Ophthalmology, 2019
Jefferson D. Berryman, Gary D. Novack
Structurally, the TM is composed of the uveal meshwork, corneoscleral meshwork, and juxtacanalicular (JCT) tissue. According to Zhang et al., these trabecular meshwork cells contain cytoskeletal structures that have the ability to undergo cellular contraction and relaxation through various intracellular mechanisms including Rho-associated signaling pathways. Downstream effectors, such as Rho-associated protein kinases (Rho kinases, ROCKs), participate in signal transductions that lead to phosphorylation of myosin light chain kinase which participates in the regulation of actin-myosin-related changes in cellular motility, size, and differentiation. These ROCK pathways ultimately act to increase the contractile state and stiffness of cells in the TM. ROCK inhibitors have been found to lower IOP by relaxing both the ciliary muscle and TM to increase aqueous outflow [9,10].
Gut permeability and osteoarthritis, towards a mechanistic understanding of the pathogenesis: a systematic review
Published in Annals of Medicine, 2021
Giorgio Guido, Guido Ausenda, Veronica Iascone, Emanuele Chisari
If such changes do occur, progressively, innate immune receptors in the gut get activated by microbial products and stimulate pro-inflammatory mediators production. Pro-inflammatory cytokines, in turn, dysregulate TJs formation creating a vicious cycle. TNFα, for instance, is known to be involved in occludin internalisation, while IFNγ reduces both ZO-1 and occludin expression. Myosin light chain kinase (MLCK) seems to be important in the cytokine-mediated regulation of TJ complexes [61]. As a general view, TJ dysregulation may be induced by cytokines, by immune cells, by NSAIDs, or alcohol chronic use, as well as by pathogens in the context of a dysbiotic microbiome [62].