1. Exogenous nitrates (GTN, ISMN) are converted into nitric oxide (NO).

2. NO and nitrosothiols induce guanylyl cyclase, which converts GTP to cyclic GMP (cGMP).

3. Raised intracellular cGMP has 2 main effects:

• Inhibition of Ca2+ channels on smooth muscle cells, causing reduction in intracellular Ca2+ - this prevents normal binding to calmodulin which normally initiates muscle cell contraction.
• Activation of K+ channels causing efflux of K+ from smooth muscle cells and hyperpolarisation of the membrane - this makes it difficult for an action potential to stimulate contraction.

4. This ultimately causes vascular smooth muscle cell relaxation and vasodilatation.

Veins (capacitance vessels)

Vasodilatation of veins causes venous pooling of blood. This reduces cardiac preload - the pressure at which the right ventricle fills which reduces the wall tension in the myocardium of the ventricles which reduces the O2 requirements of the myocardium. Reducing the O2 demand of the myocardium means it is less likely to become ischaemic. This is the principal mechanism by which nitrates can be used for long-term angina prophylaxis.

In heart failure, long-acting nitrates are used because they cause venous dilatation, which reduces cardiac filling pressures. This can help to reduce the symptoms of pulmonary congestion.

Vasodilatation of veins occurs at low nitrate levels (e.g. with S/L GTN, oral ISMN).

Coronary arteries

Vasodilatation relieves vasospasm in the coronary arteries, which occurs in angina and acute coronary syndromes. Resolution of vasospasm reduces myocardial ischaemia (and therefore chest pain) by restoring coronary blood flow to the myocardium.

NOTE: dilatation of coronary arteries does not occur at therapeutic concentrations of nitrates and the principal mechanism by which they work is by venodilatation.