A 69-year-old man comes to the office due to a 6-month history of chest tightness when he walks uphill or climbs stairs. The discomfort radiates to his throat and lasts 5-10 minutes before slowly subsiding. Medical history is significant for hyperlipidemia and type 2 diabetes mellitus. His father had coronary artery bypass surgery at age 60 and his mother suffered a stroke. Vital signs are normal. Cardiac examination reveals no murmurs or additional heart sounds. The patient is prescribed a medication that is metabolized to S-nitrosothiols in the vascular smooth muscle cells, and he reports rapid and significant symptom relief. Which of the following components of the cardiovascular system is most susceptible to the medication prescribed to this patient?

Question

A 69-year-old man comes to the office due to a 6-month history of chest tightness when he walks uphill or climbs stairs.  The discomfort radiates to his throat and lasts 5-10 minutes before slowly subsiding.  Medical history is significant for hyperlipidemia and type 2 diabetes mellitus.  His father had coronary artery bypass surgery at age 60 and his mother suffered a stroke.  Vital signs are normal.  Cardiac examination reveals no murmurs or additional heart sounds.  The patient is prescribed a medication that is metabolized to S-nitrosothiols in the vascular smooth muscle cells, and he reports rapid and significant symptom relief.  Which of the following components of the cardiovascular system is most susceptible to the medication prescribed to this patient?

Quizplus · Accepted Answer

This patient has stable angina pectoris and experienced rapid symptomatic relief following receipt of a nitrate. Pharmacologic nitrates (eg, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) are metabolized to nitric oxide and S-nitrosothiols via mitochondrial aldehyde dehydrogenase within vascular smooth muscle cells. These compounds in turn activate guanylate cyclase and promote the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which leads to dephosphorylation of myosin light chains and causes vascular smooth muscle relaxation. Nitrates predominantly affect the large veins, where smooth muscle relaxation leads to venodilation and increased venous capacitance. Cardiac venous return (preload) is reduced, leading to a reduction in left ventricular end-diastolic volume and pressure and a consequent decrease in left ventricular wall stress. Decreased myocardial oxygen demand leads to relief of anginal symptoms. (Choice A) Both beta blockers and nondihydropyridine calcium channel blockers (eg, verapamil) are negative inotropic and chronotropic agents. They exert antianginal effects via direct actions on cardiac myocytes to reduce myocardial contractility and heart rate, and thereby decrease myocardial oxygen demand. Nitrates have no direct effect on cardiac myocytes. (Choice B) Sodium nitroprusside generates nitric oxide while in the bloodstream (rather than within vascular smooth muscle cells) and is much less selective for the large veins than nitrates. It causes relatively balanced vasodilation of both the large arteries and veins, and is useful for reducing blood pressure in patients with hypertensive emergency. (Choice D) Precapillary sphincters are bands of smooth muscle that regulate blood flow from arterioles into mesenteric capillary beds. The effect of nitrates on precapillary sphincters is minimal compared to that on the large veins. (Choice E) Dihydropyridine calcium channel blockers (eg, nifedipine, amlodipine, nicardipine) block L-type calcium channels in vascular smooth muscle cells to trigger vasodilation. This effect is exerted on small arteries and arterioles in both the peripheral and coronary circulation, resulting in 2 therapeutic effects on stable angina. The peripheral vasodilation reduces afterload leading to a decrease in cardiac work and myocardial oxygen demand, and the coronary vasodilation increases myocardial oxygen supply. Educational objective: Pharmacologic nitrates (eg, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) are metabolized to nitric oxide and S-nitrothiols in vascular smooth muscle cells, leading to an increase in cyclic guanosine monophosphate (cGMP) that stimulates vasodilation. Large veins are predominantly affected, leading to increased venous capacitance and reduced venous return (preload), which decreases left ventricular wall stress and myocardial oxygen demand to relieve anginal symptoms. __________ References: Mechanisms of action of nitrates. (http://www.ncbi.nlm.nih.gov/pubmed/7873467) Identification of the enzymatic mechanism of nitroglycerin bioactivation. (http://www.ncbi.nlm.nih.gov/pubmed/12048254)

A 69-Year-Old Man Comes to the Office Due to a 6-Month