Tamsulosin is an alpha-1A and alpha-1B adrenergic receptor antagonist used to treat benign prostatic hyperplasia, ureteral stones, prostatitis, and female voiding dysfunction. Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors but about 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. Alpha-1A adrenergic receptor are coupled to the Gq signaling cascade. When these receptors are activated, it leads to the activation of phospholipase C, which converts Phosphatidylinositol (3,4,5)-trisphosphate to inositol (3,4,5)-trisphosphate (IP3) and diacylglycerol (DAG). IP3 activates IP3 receptors on the sarcoplasmic reticulum leading to the release of stored calcium into the cytosol. DAG activates protein kinase C (PKC). One of the downstream effects of PKC include activation of calcium channels on the membrane, leading to influx of calcium ions into the cytosol. Both IP3 and DAG increase cytosolic levels of calcium which then binds to calmodulin to create a calcium-calmodulin complex. Muscle contraction and relaxation are controlled by the enzymes myosin kinase and myosin phosphatase. Myosin kinase phosphorylates myosin light chain, leading to interaction between actin and myosin, producing muscle contraction. Myosin phosphorylase dephosphorylates the phosphorylated myosin light chain, preventing interaction with actin, producing muscle relaxation. The calcium-calmodulin activates myosin kinase, leading to increased phosphorylation of myosin light chain and more muscle contraction. By inhibiting alpha-1A receptors in the prostate, tamsulosin decreased cytosolic calcium and prevents activation of myosin kinase, thereby causing more dephosphorylation and allowing muscle relaxation. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. Alpha-1D receptors are also Gq coupled and may produce muscle relaxation in a similar mechanism to alpha-1A receptors. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas.

Tamsulosin Pathway References