A 65-year-old man with type 2 diabetes mellitus comes to the office due to decreased sexual performance over the last 6 months. The patient says his libido, muscle strength, and energy level are normal, but his erections are inconsistent, weak, and of inadequate duration for sexual activity. Past medical history is positive for hypertension, but he has no history of coronary artery disease and no suspicious chest pain. Bilateral ankle brachial index testing is within normal limits. The patient is treated with sildenafil, which gives significant improvement in his sexual performance. The intracellular signaling of this drug is most similar to that of which of the following substances?

Question

A 65-year-old man with type 2 diabetes mellitus comes to the office due to decreased sexual performance over the last 6 months.  The patient says his libido, muscle strength, and energy level are normal, but his erections are inconsistent, weak, and of inadequate duration for sexual activity.  Past medical history is positive for hypertension, but he has no history of coronary artery disease and no suspicious chest pain.  Bilateral ankle brachial index testing is within normal limits.  The patient is treated with sildenafil, which gives significant improvement in his sexual performance.  The intracellular signaling of this drug is most similar to that of which of the following substances?

Quizplus · Accepted Answer

Atrial and brain natriuretic peptides (ANP and BNP) are polypeptide hormones that exert their effect by binding ANP receptors. These transmembrane receptors are linked to a guanylyl cyclase that converts guanosine 5′-triphosphate to cyclic guanosine 3′,5′-monophosphate (cGMP). cGMP then activates a downstream cGMP-dependent protein kinase, leading to relaxation of vascular smooth muscle and subsequent vasodilation. Nitric oxide activates the same cGMP second messenger system by binding a cytosolic guanylyl cyclase. Penile erection is initiated by release of acetylcholine and nitric oxide (NO) from parasympathetic fibers, leading to a rise in intracellular cGMP and vasodilation of the arteries supplying the corpus cavernosum. Sildenafil is a phosphodiesterase-5 inhibitor that decreases degradation of cGMP, enhancing the effect of parasympathetic activation in erectile tissues. Because vasodilatory nitrates (eg, nitroglycerin, isosorbide mononitrate) work by releasing NO, coadministration of sildenafil with nitrates can lead to excessive cGMP-induced vasodilation and severe hypotension. (Choice A) 1,25-dihydroxycholecalciferol is the active form of vitamin D; it is a sterol vitamin that freely crosses cell membranes and interacts with a receptor that primarily resides in the nucleus. (Choice C) Gamma-aminobutyric acid is an inhibitory neurotransmitter that acts to hyperpolarize nerve cells by binding ligand-gated ion channels or metabotropic receptors. (Choice D) The insulin receptor consists of 2 alpha and 2 beta subunits. The alpha subunits are extracellular and provide the binding site for insulin. The beta subunits are intracellular and contain tyrosine kinase domains. (Choice E) Interleukin-2 (IL-2) receptor is a transmembrane protein complex that acts via a multipathway system, including a JAK-STAT signaling component, a MAP kinase pathway, and phosphoinositide 3-kinase. (Choice F) Platelet-derived growth factor stimulates cell growth and division, including angiogenesis. It acts via a tyrosine kinase receptor. Educational objective: Atrial natriuretic peptide, brain natriuretic peptide, and nitric oxide activate guanylyl cyclase and increase conversion of guanosine 5′-triphosphate to cyclic guanosine 3′,5′-monophosphate (cGMP). Phosphodiesterase inhibitors (eg, sildenafil) decrease the degradation of cGMP. Elevated intracellular cGMP levels lead to relaxation of vascular smooth muscle and vasodilation. __________ References: Sildenafil: efficacy, safety, tolerability and mechanism of action in treating erectile dysfunction. (http://www.ncbi.nlm.nih.gov/pubmed/16922643)

A 65-Year-Old Man with Type 2 Diabetes Mellitus Comes to the Office