Guanylate cyclase stimulators are medications that influence the cardiovascular system. They work by interacting with a specific enzyme found within cells, particularly in blood vessels and the heart. Their primary action is to promote the relaxation and widening of blood vessels, which improves blood flow and reduces pressure. This approach addresses conditions where blood vessel function is impaired.
The Role in the Nitric Oxide Pathway
The enzyme soluble guanylate cyclase (sGC) regulates vascular tone within cells. The body naturally produces nitric oxide (NO), a gas that binds to sGC within cells. This binding activates sGC, causing it to convert guanosine-5′-triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). Cyclic GMP acts as a messenger within the cell, triggering events that lead to smooth muscle relaxation and vasodilation in blood vessel walls.
In certain medical conditions, the natural production or availability of nitric oxide can be reduced, which impairs sGC activity. Guanylate cyclase stimulators work by directly interacting with the sGC enzyme, even when nitric oxide levels are low. They can stimulate sGC independently of nitric oxide and also enhance the enzyme’s sensitivity to any available nitric oxide. This dual mechanism of action results in increased cGMP production. Elevated cGMP levels promote vasodilation and improved blood flow.
Conditions Treated by Guanylate Cyclase Stimulators
Guanylate cyclase stimulators are primarily prescribed for conditions involving high blood pressure in the lung arteries, known as pulmonary hypertension. One such condition is chronic thromboembolic pulmonary hypertension (CTEPH), where persistent blood clots or scar-like tissue block or narrow the pulmonary arteries. These blockages increase pressure in the lung arteries, making the heart work harder. For patients with inoperable CTEPH or persistent symptoms after surgery, these medications dilate pulmonary arteries and reduce blood flow resistance.
Another condition treated is pulmonary arterial hypertension (PAH), involving narrowing of small lung arteries. This narrowing elevates blood pressure in the pulmonary arteries, straining the right side of the heart and potentially leading to heart failure. By promoting vasodilation, guanylate cyclase stimulators reduce this pressure, easing blood flow through the lungs and improving heart pumping efficiency. They are also used in specific types of chronic heart failure, especially in symptomatic patients after a recent hospitalization or requiring intravenous diuretics.
Common Guanylate Cyclase Stimulator Medications
Two main medications in the guanylate cyclase stimulator class are approved for use: Riociguat and Vericiguat. Riociguat (Adempas) was the first approved drug in this class. It treats both pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat improves exercise capacity and functional class in adults with these lung conditions.
Vericiguat (Verquvo) is another medication in this category. This drug is approved for adults with symptomatic chronic heart failure who have a reduced ejection fraction. Vericiguat reduces the risk of cardiovascular death and heart failure hospitalizations, especially after a recent hospitalization or need for intravenous diuretics. While both medications stimulate soluble guanylate cyclase, they are prescribed for different primary conditions.
Potential Side Effects and Safety Considerations
Like all medications, guanylate cyclase stimulators can cause side effects. Common side effects include low blood pressure (hypotension), headache, and dizziness. Gastrointestinal issues like indigestion, nausea, vomiting, and diarrhea can also occur. Anemia has also been reported.
Safety considerations exist for these medications. Guanylate cyclase stimulators are contraindicated in pregnancy due to the risk of fetal harm. For this reason, Riociguat (Adempas) is available only through a restricted program, the Adempas REMS Program. This program requires certified prescribers, monthly pregnancy testing, and contraception for females of reproductive potential to minimize pregnancy exposure. These drugs must not be taken with other vasodilators, such as nitrates or phosphodiesterase-5 (PDE-5) inhibitors like sildenafil or tadalafil, as this combination can lead to a severe drop in blood pressure.