Miscellaneous Drugs during Pregnancy
“Bert” Bertis Britt Little in 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).
Stimulus-Secretion Coupling: Intracellular Proteins and Nucleotides
Stephen W. Carmichael, Susan L. Stoddard in The Adrenal Medulla 1986 - 1988, 2017
The effects of purified myosin light-chain kinase on myosin light-chain phosphorylation and catecholamine secretion in digitonin-permeabilized chromaffin cells were investigated by Lee, Holz and Hathaway (1987). In the absence of exogenous myosin light-chain kinase, calcium enhanced phosphorylation of the myosin light-chain. In the presence of calcium, myosin light-chain kinase caused an approximately 2-fold increase in myosin light-chain phosphorylation. Under the same conditions, secretion was unaltered by myosin light-chain kinase. These experiments indicate that the phosphorylation of myosin light-chain by myosin light-chain kinase is not a limiting factor in secretion in digitonin-treated chromaffin cells. Lee et al. (1987) suggested that the activation of myosin is not directly involved in secretion from the cells.
REGULATORY MECHANISMS
David M. Gibson, Robert A. Harris in Metabolic Regulation in Mammals, 2001
endothelial cells, in response to the binding of acetylcholine to "muscarinic" plasma membrane receptors. In certain blood vessels acetylcholine causes relaxation of vascular smooth muscle cells which underlie the endothelial layer. NO is the link in this signal transmission by diffusing across cell boundaries from endothelial cells into adjacent smooth muscle cells. The intracellular NO sensor is a cytosolic enzyme guarnivi cyclase which synthesizes cyclic GMP to activate a cGMP-dcpcndcnt protein kinase (PKG). (Compare with ANT which binds to a plasma membrane receptor guanylyl cyclase, item one.) A PKG phosphorylation step dampens the myosin light chain kinase contractile system of smooth muscle. Opposing accumulation of cGMP is a cGMP-specific phosphodiesterase. Pharmaceutical agents have been developed that cause vascular dilation through the inhibition of this enzyme. The drug nitroglycerin is prescribed to clfcct prompt dilation of cardiac \asculaturc during episodes of anginal pain through the release ol NO in ■situ.
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].
Related Knowledge Centers
- Enzyme
- Muscle
- Myosin
- Phosphorylation
- Serine/Threonine-Specific Protein Kinase
- Myosin Light Chain
- Mylk
- Mylk2
- Mylk3
- Mylk4