A 53-year-old man comes to the emergency department with shortness of breath and chest tightness. The patient was playing in a poker tournament when his symptoms first began. He has a history of hypertension and is not compliant with his medications. His last medical follow-up was a year ago. Blood pressure is 195/115 mm Hg and pulse is 90/min and regular. Lung examination reveals bibasilar crackles. Nitroglycerin infusion is started and results in significant symptomatic improvement. Repeat blood pressure is 165/90 mm Hg. Which of the following intracellular events is most likely responsible for the beneficial effects of this patient's treatment?
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This patient's clinical presentation is consistent with acute pulmonary edema due to severely elevated blood pressure (hypertensive emergency). In such cases, intravenous vasodilators (nitroglycerine, sodium nitroprusside) are often used to improve the acute heart failure by reducing preload and afterload.
Nitrates are metabolized within vascular smooth muscle cells to nitric oxide, which activates guanylate cyclase and promotes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Increased levels of cGMP lead to decreased intracellular calcium (reduces the activity of myosin light-chain kinase) and activation of myosin light chain phosphatase. This promotes myosin light-chain dephosphorylation and vascular smooth muscle relaxation.
(Choice A) Actin phosphorylation has no role in smooth or skeletal muscle relaxation. In smooth muscle, a stimulus to contract leads to increased intracellular calcium, which leads to myosin phosphorylation. Once myosin is phosphorylated, it is able to bind directly to actin and cause muscle contraction.
(Choice B) Calcium release from sarcoplasmic reticulum would lead to increased contraction of the cardiac myocytes. It is not involved in the mechanism of action of nitrates on vascular smooth muscle cells.
(Choice C) Nitrates do not cause an increase in cyclic mononucleotide degradation. On the contrary, they activate guanylate cyclase and promote conversion of GTP to cGMP, which ultimately leads to smooth muscle relaxation.
(Choice D) Inositol triphosphate binds to its receptor on the endoplasmic reticulum and leads to the release of Ca2+ into the cytoplasm. In vascular smooth muscle cells, this increased concentration of cytoplasmic Ca2+ results in increased smooth muscle contraction.
(Choice F) Tyrosine kinases play a role in a wide variety of intracellular processes and pathways. The effects of insulin and insulin-like growth factor occur via activation of receptor tyrosine kinases, which in turn cause phosphorylation of tyrosine residues on intracellular proteins important for signal transduction.
Educational objective:
Nitrates (via conversion to nitric oxide) activate guanylate cyclase and increase intracellular levels of cyclic guanosine monophosphate (cGMP). Increased levels of cGMP lead to myosin light-chain dephosphorylation, resulting in vascular smooth muscle relaxation.