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Does it make sense to develop new centrally acting cardiovascular drugs?

Bousquet P, Monassier L, Feldman J.

Summary

The autonomic nervous system plays a pivotal role in modulating all the components of the cardiovascular regulation. Therefore, one can assume that drugs targeting this system may be useful in the management of several cardiovascular diseases. Drugs acting on central nervous system centers seem to be modulators rather than blockers; as such, they are expected to preserve the contraregulatory processes and to generate only a few side effects. Because the sympathetic nervous system is largely involved in the regulation of vasomotor tone, centrally acting antihypertensive drugs were developed first. Recently, new leader compounds selective for nonadrenergic imidazoline receptors have been synthetized. Although such drugs have no capacity to activate α₂-adrenoceptors, they have been proven to be hypotensive. These drugs are expected to be even better tolerated than the currently available centrally acting drugs.

Clin Exp Pharmacol Physiol. 2001;28:976-978

Commentary

Clonidine and α-methyl-dopa, developed in the 1960s, are the prototypes of centrally acting antihypertensive drugs. Their antihypertensive efficacy is beyond any doubt, but their position in the management of hypertension has been greatly weakened because of their side-effect profile. This situation may be improved by the introduction of newer drugs which are as effective as antihypertensives as the classical drugs, but are better tolerated. Examples of
this development are the newer agents which interact with imidazoline I₁ receptors, such as rilmenidine and moxonidine.
The question then arises as to whether it is indeed useful to develop new centrally acting agents. This matter was discussed exhaustive and critically by Bousquet et al in the present paper.
On theoretical grounds centrally acting drugs which cause peripheral sympatho-inhibition (and possibly also some activation of the parasympathomimetic system) may offer certain hemodynamic/pathophysiological advantages.

Important cardiovascular diseases, such as hypertension, and even more so congestive heart failure, are known to be associated with an activated sympathetic nervous system.Suppression of this activated system, starting at the origin (the central nervous system) therefore seems a logical approach.

Besides hypertension and heart failure, other pathologic targets can be thought of, such as certain types of cardiac tachyarrhythmias. It should be realized that several mechanisms and receptor systems are involved in the central nervous regulation of the sympathetic system and the cardiovascular system, such as NO, GABA, and muscarinic receptors, besides the already mentioned α₂-adrenoceptors and imidazoline I₁ receptors. Since only the α₂- and I₁ receptors have been investigated as clinically beneficial drug targets, many alternative possibilities can be thought of for the further development of new centrally acting drugs. Considering the potential advantages of centrally acting drugs, such investigations would appear well worthwhile.