What is the role of nitrates in managing hypertension?

From the Guidelines

Nitrates should be avoided in the management of hypertension, particularly in patients with heart failure with preserved ejection fraction (HFpEF), due to a signal of harm associated with their use 1.

Role of Nitrates in Hypertension Management

The use of nitrates in hypertension management is limited and should be approached with caution. According to the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline, nitrates are not recommended for the treatment of hypertension in patients with HFpEF due to the potential for harm 1.

Specific Situations for Nitrate Use

While nitrates are not first-line agents for chronic hypertension management, they may be considered in specific situations such as:

• Hypertensive emergencies or resistant hypertension
• Angina with concurrent hypertension
• Patients with coronary artery disease, where nitrates can be used to relieve symptoms of ischemia and pulmonary congestion 1

Important Considerations

When using nitrates, it is essential to be aware of the potential for:

• Tolerance development with continuous use, necessitating a nitrate-free interval
• Common side effects such as headache, dizziness, and hypotension
• Risk of severe hypotension when used with phosphodiesterase inhibitors like sildenafil
• Contraindications, such as right ventricular infarction or hemodynamic instability 1

From the FDA Drug Label

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy Severe hypotension, particularly with upright posture, may occur with small doses of nitroglycerin This drug should therefore be used with caution in patients who may be volume-depleted or who, for whatever reason, are already hypotensive.

The role of nitrates in managing hypertension is not explicitly stated as a primary use. However, nitrates can cause severe hypotension, particularly in patients who are already hypotensive or volume-depleted. Therefore, nitrates should be used with caution in these patients. 2

From the Research

Role of Nitrates in Managing Hypertension

• Nitrates are highly effective in terminating acute attacks of angina pectoris and in the prophylaxis of symptomatic and asymptomatic myocardial ischemia 3
• The prevailing mechanism of nitrates in patients with chronic stable angina is preload reduction by venodilatation, which distinguishes them from beta and calcium-channel blockers 3
• Nitrates dilate coronary arteries not only in pre- and poststenotic vessels but also in eccentric lesions, and seem to be a physiological substitute for endothelium-derived relaxing factor in patients with endothelial dysfunction 3

Nitrate Tolerance and Rebound

• Nitrate tolerance develops rapidly in patients with coronary artery disease and/or congestive heart failure, and can be prevented or minimized by providing nitrate-free or low-nitrate intervals 3, 4
• Rebound phenomena, such as rest angina in patients with ischemic heart disease, can occur during nitrate-free periods 4
• Intermittent nitrate therapy can prevent the development of tolerance, but may not be suitable for treating unstable angina due to rebound angina during nitrate-free periods 4

Antihypertensive Effects of Nitrates

• Restoring nitric oxide activity by using nitrite and nitrate has been considered a potential therapeutic strategy to treat hypertension 5
• Dietary inorganic nitrate may be beneficial for lowering blood pressure and reducing cardiovascular disease risks, but the evidence is insufficient to support or refute its use 6
• Dietary inorganic nitrate has been shown to reduce blood pressure and improve vascular function in hypertension, with its efficacy dependent on the degree of blood pressure elevation and vascular dysfunction 7

Mechanisms and Clinical Relevance

• The enterosalivary cycle of nitrate, where nitrate is converted to nitrite by nitrate-reducing bacteria in the oral cavity, plays a crucial role in the bioactivation of nitrates 5
• Agents such as dietary and smoking-derived thiocyanate, antiseptic mouthwash, proton pump inhibitors, ascorbate at high concentrations, and xanthine oxidoreductase inhibitors can impair the blood pressure responses to nitrite and nitrate 5
• The use of nitrates in combination with other medications, such as hydralazine, may improve survival in patients with heart failure, but its effectiveness as a first-line therapy is limited by the development of tolerance 4