Generality
Vasodilators are drugs that exert a relaxing action on the muscles of the blood vessels, with consequent dilation of the same.
Vasodilator drugs, therefore, are mainly used in the treatment of hypertension.
More specifically, the dilators of the arteries decrease the systemic vascular resistance, reducing the afterload on the left ventricle; for this reason, they are mostly used in the treatment of heart failure, angina and pulmonary systemic hypertension.
The dilators of the veins, on the other hand, decrease the pre-load of the heart and reduce the hydrostatic pressure of the capillaries, thus counteracting the onset of edema. These vasodilators are sometimes used in the treatment of heart failure, but are more useful in the treatment of the systemic and pulmonary edema caused by it.
Vasodilator drugs can be divided into different classes, both according to their chemical structure and according to the mechanism of action through which they carry out their action.
These classes will be briefly described below.
Antagonists of the Lenti del Calcium channels
These particular vasodilator drugs work by antagonizing L-type voltage-gated calcium channels (otherwise referred to as slow calcium channels), found mainly in the smooth muscle of blood vessels. In doing so, these drugs counteract the vascular constriction and induce vasodilation.
This is possible because calcium plays a fundamental role in the contraction mechanisms of smooth muscle. In fact, following the increase in intracellular levels of calcium ions, these same cations form a complex with calmodulin, a particular type of plasma protein. This complex causes the activation of the kinase which induces the phosphorylation of the myosin light chain, the which consequence consists in the contraction of the vascular smooth muscle.
Therefore, by blocking L-type calcium channels, s "upstream inhibits the signal cascade that leads to muscle contraction, thus favoring the appearance of vasodilation.
This category of vasodilators includes active ingredients such as:
- Dihydropyridines such as amlodipine (Norvasc®), nimodipine (Nimotop®) and nifedipine (Adalat®). In particular, this last active principle exerts its vasodilating action mainly at the level of the coronary arteries.
- Verapamil (Isoptin®) and diltiazem (Altiazem®). It should be noted that these calcium channel blockers are also used in the treatment of cardiac arrhythmias; for this reason they are sometimes grouped within the category of antiarrhythmic drugs.
Nitro-derivatives with vasodilating action
These particular types of vasodilator drugs exert their action, of relaxation of the vascular smooth muscle, through the release of nitrogen monoxide (NO).
Nitrogen monoxide is a gas with strong vasodilating properties, which is naturally produced by the endothelium cells of blood vessels. Once released, NO is able to promote the production of cyclic GMP (cyclic guanosine monophosphate), the which gives rise to a cascade of chemical signals that leads to smooth muscle relaxation.
Therefore, the nitro-derivative compounds, once taken, undergo transformations that lead to the synthesis of NO, the direct responsible of the vasodilating activity of which these drugs are endowed.
Sodium nitroprusside (Sodio Nitroprussiato®) belongs to this category of vasodilator drugs.
Potassium channel activators
The vasodilators belonging to this category are able to exert their action through the activation of the ATP-sensitive potassium channels, present on the vascular smooth muscles. Thanks to the opening of these channels, in fact, an increase in leakage occurs. of potassium ions from the cell, which causes membrane hyperpolarization. In turn, cell membrane hyperpolarization causes voltage-gated calcium channels to close, resulting in decreased plasma calcium levels. All this ultimately leads to the relaxation of smooth muscles, and therefore to vasodilation.
Active ingredients such as pinacidil, nicorandil and minoxidil belong to this category of vasodilators. This last active ingredient, however, is no longer used as a vasodilating agent because it causes a particular type of side effect: hypertrichosis. Currently, in fact, minoxidil is available in pharmaceutical formulations suitable for cutaneous use and is used in the treatment of alopecia of various origins and nature.
Finally, diazoxide is also an active ingredient that can fall into the category of potassium channel activating vasodilators. However, more than for its vasodilating properties, this active principle is exploited for its ability to increase blood glucose levels and is currently used in the treatment of hypoglycemia.
Phosphodiesterase inhibitors
Phosphodiesterases are particular types of enzymes whose task is to break the phosphodiester bonds.
There are at least eleven different isoforms of the phosphodiesterase enzyme. From the point of view of vasodilation of smooth muscle, the isoforms of interest are type 3 phosphodiesterases (or PDE3, located in vascular smooth muscle and heart) and type 5 phosphodiesterases. (or PDE5, localized both in the vascular smooth muscle and in the corpora cavernosa of the penis).
Type 3 phosphodiesterases have the task of degrading cyclic AMP (cyclic adenosine monophosphate), thus generating vasoconstriction.
In fact, cyclic AMP normally carries out a vasodilatory action, through the activation of the dephosphorylation mechanism of the myosin light chain which causes the relaxation of the vascular smooth muscles.
Therefore, PDE3 inhibitors induce an increase in the availability of cyclic AMP, resulting in vasodilation.
Active ingredients such as amrinone, milrinone and enoximone belong to the selective PDE3 inhibitory vasodilators.
Type 5 phosphodiesterases are also present on vascular smooth muscle but their task, unlike PDE3, is to degrade cyclic GMP. Therefore, PDE5 inhibitors favor vasodilation through an increase in cyclic GMP levels (see the mechanism of action exerted by nitro-derived vasodilators).
However, selective PDE5 inhibitors - although they were initially conceived as antihypertensive drugs - are currently used mostly in the treatment of erectile dysfunction, precisely because they exert a "vasodilating action also in the corpora cavernosa of the penis."
PDE5 inhibitors used in therapy include sildenafil (Viagra®), tadalafil (Cialis®) and vardenafil (Levitra®).
Hydralazine
Hydralazine is an active ingredient belonging to the family of vasodilating drugs, but having a rather unique mechanism of action of its kind and still not fully understood.
In any case, from the studies conducted it seems that this active ingredient is able to induce the dilation of the vascular smooth muscle through different mechanisms, such as:
- Hyperpolarization of the cell membrane through the opening of potassium channels;
- Inhibition of the activity of IP3 (inositol triphosphate), a second messenger responsible for the release of calcium ions from the sarcoplasmic reticulum;
- Stimulation of nitrogen monoxide (NO) synthesis.
The vasodilator effect of hydralazine is highly specific for arterial vessels and is regarded as a direct acting vasodilator drug.
Side effects
The type of side effects that may occur following treatment with vasodilators may vary according to the type of active ingredient used and according to the chosen route of administration.
However, it can be said that many of the aforementioned vasodilator drugs can induce undesirable effects such as:
- Reflex tachycardia and increased cardiac contractile force, caused by the heart's baroreceptor reflex that occurs in response to vasodilation and hypotension exerted by vasodilator drugs.
- Hypotension, including orthostatic hypotension.
- Renal sodium retention.
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