From the Guidelines
Nitroglycerin works primarily as a vasodilator by releasing nitric oxide, which relaxes vascular smooth muscle, thereby reducing myocardial oxygen demand and improving myocardial perfusion. The mechanism of action of nitroglycerin involves the reduction of myocardial oxygen requirement and consumption, resulting from the reduction of LV volume and arterial pressure primarily due to reduced preload 1. This is achieved through the dilation of large epicardial coronary arteries and collateral vessels, which improves myocardial perfusion and relieves coronary vasospasm in patients with vasospastic angina.
- Key aspects of nitroglycerin's mechanism of action include:
- Reduction in myocardial oxygen demand and consumption
- Improvement in myocardial perfusion
- Vasodilation of large epicardial coronary arteries and collateral vessels
- Relief of coronary vasospasm in patients with vasospastic angina
- The net effect of nitroglycerin is a reduction in myocardial oxygen demand, making it effective in relieving both demand and supply ischemia 1.
- Additionally, nitroglycerin exerts antithrombotic and antiplatelet effects in patients with stable angina, which can further contribute to its beneficial effects 1.
- It is essential to note that a reflex increase in sympathetic activity may occur in some patients, which can increase heart rate and contractile state, but the overall effect of nitroglycerin is still a reduction in myocardial oxygen demand 1.
From the FDA Drug Label
Mechanism of Action: Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and result in vasodilatation
The mechanism of action (MOA) of Nitroglycerin is through the formation of free radical nitric oxide (NO), which activates guanylate cyclase, leading to an increase in cyclic GMP in smooth muscle and other tissues, resulting in vasodilatation 2.
- The key steps in the MOA are:
- Formation of nitric oxide (NO)
- Activation of guanylate cyclase
- Increase in cyclic GMP
- Vasodilatation due to dephosphorylation of myosin light chains
From the Research
Mechanism of Action of Nitroglycerin
The mechanism of action (MOA) of nitroglycerin (glyceryl trinitrate) involves the relaxation of vascular smooth muscle, leading to vasodilation. The key steps in this process are:
- Nitroglycerin is bioactivated by mitochondrial aldehyde dehydrogenase (mtALDH) to form 1,2-glyceryl dinitrate and nitrite 3
- Nitrite is then converted to nitric oxide (NO), which activates soluble guanylate cyclase (GC) 4
- The activation of GC leads to an increase in intracellular cyclic GMP (cGMP), which initiates Ca extrusion from the smooth muscle cell, causing relaxation 4
- The relaxation of vascular smooth muscle results in vasodilation, which is the primary therapeutic effect of nitroglycerin in the treatment of angina pectoris
Key Factors Influencing the MOA of Nitroglycerin
Some important factors that influence the MOA of nitroglycerin include:
- The presence of sulfhydryl groups, which are required for the bioactivation of nitroglycerin 5
- The activity of mtALDH, which is inhibited in blood vessels made tolerant by nitroglycerin 3
- The formation of a nitrodilator-activated NO store (NANOS) in vascular smooth muscle cells, which can be depleted by repeated use of nitroglycerin and replenished by nitrite 6
- The role of cyclic GMP in initiating Ca extrusion from the smooth muscle cell, which is impaired in tolerance 4
Tolerance to Nitroglycerin
Tolerance to nitroglycerin is a major limitation to its clinical use, and is characterized by a decrease in its vasodilatory efficacy over time. The mechanisms underlying tolerance include: