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Pathway Description
Ritodrine B2-Adrenergic Myometrial Smooth Muscle Relaxation Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2023-05-16
Last Updated: 2023-10-25
Ritodrine is a adrenergic beta agonist used for the treatment and prophylaxis of premature labour. Beta-2 adrenergic receptors are located at sympathetic neuroeffector junctions of many organs, including uterus. Ritodrine is beta-2 adrenergic agonist. It stimulates beta-2 adrenergic receptor, increases cAMP level and decreases intracellular calcium concentration. The decrease of calcium concentration leads to a relaxation of uterine smooth muscle and, therefore, a decrease in premature uterine contractions. Ritodrine binds to receptors on outer membrane of myometrial cells. Once ritodrine is administered and it binds to the beta-2 adrenergic receptor, the G protein signalling cascade begins. The alpha and beta/gamma subunits of the G protein separate and GDP is replaced with GTP on the alpha subunit. This alpha subunit then activates adenylyl cyclase which converts ATP to cAMP. cAMP then activates protein kinase A (PKA) which in turn phosphorylates targets and inhibits MLCK through decreased calcium levels causing muscle relaxation. PKA can phosphorylate certain Gq-coupled receptors as well as phospholipase C (PLC) and thereby inhibit G protein-coupled receptor (GPCR) -PLC-mediated phosphoinositide (PI) generation, and thus calcium flux. PKA phosphorylates the inositol 1,4,5-trisphosphate (IP3) receptor to reduce its affinity for IP3 and further limit calcium mobilization. PKA phosphorylates myosin light chain kinase (MLCK) and decreases its affinity to calcium calmodulin, thus reducing activity and myosin light chain (MLC) phosphorylation. Inhibits the phosphorylation of myosin. There are two mechanisms by which KCa++ channels can be activated in these cells, the first being when PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization, and the second being directly by the G proteins by direct gating. Phosphorylation of ATP-sensitive potassium channels occurs as well. Since myosine light chain kinase is not activated, Serine/threonine-protein phosphatase continues to dephosphorylate myosin LC-P, and more cannot be synthesized so myosin remains unbound from actin causing muscle relaxation. This relaxation of the smooth muscles in the uterus causes the uterine muscles to relax which causes a decrease in premature contractions, effectively treating premature labour. In summary, ritodrine is able to complete this through its activation of beta-2 adrenergic receptors, activation of ATP-sensitive potassium channels, and activation of calcium activated potassium channels. Ritodrine is typically administered via intravenous injection, or as an oral tablet. Some side effects of using ritodrine may include chest pain or tightness, dizziness or lightheadedness, flushed and dry skin, and increased urination.
References
Ritodrine B2-Adrenergic Myometrial Smooth Muscle Relaxation Pathway References
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