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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
Smooth Muscle
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
A decrease in intracellular Ca++ produces relaxation. Ca++ is taken up by the sarcoplasmic reticulum in an active process driven by ATP and modulated by receptor activity. In addition, myosin phosphatase dephosphorylates myosin light chain kinase and detaches phosphate from the myosin head, resulting in smooth muscle relaxation. This process controls the rate of relaxation.
Gastrodin attenuates angiotensin II-induced vascular contraction and MLCK/p-MLC2 pathway activation
Published in Pharmaceutical Biology, 2023
Zhi Guo, Xuan Yang, Meizhu Wu, Aling Shen, Jiapeng Li, Xiuli Zhang, Ying Cheng, Qiurong Xie, Jun Peng
Excessive activation of the renin–angiotensin–aldosterone system (RAAS) contributes to the initiation and progression of hypertension (Romero et al. 2015; Te Riet et al. 2015; Rossier et al. 2017; Schutten et al. 2017). Angiotensin II (Ang II) is the primary active component of the RAAS. Ang II binds to angiotensin type 1 receptor (AT1R) and triggers downstream signalling involving highly specific fluctuations in Ca2+ signalling, thereby resulting in contraction of vascular smooth muscle cells (VSMCs) and elevation of blood pressure (Te Riet et al. 2015; Bennett et al. 2016). As an important secondary messenger, intracellular Ca2+ is essential for vascular smooth muscle contraction (Harraz and Jensen 2021). In VSMCs, increased intracellular Ca2+ levels induce contraction by binding to calmodulin (CaM) and then activating myosin light chain kinase (MLCK) and phosphorylating the Ser18 and Thr19 residues of myosin light chain 2 (MLC2) (Kim et al. 2008; Touyz et al. 2018). Phosphorylated myosin binds to actin fibres, leading to fibre contraction and changes in vessel tension and vascular diameter (Bravo-Sagua et al. 2020). Accordingly, the inhibition of the MLCK/phospho-myosin light chain 2 (p-MLC2) pathway and resulting vascular contraction represents a potential strategy for treating hypertension and vascular dysfunction.
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].