Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Part II: Sites and mechanisms of action of dopamine receptor agonists.

Relatively selective dopamine receptor agonists, like bromocriptine, lergotrile, pergolide and N,N-di-n-propyl-dopamine, lower arterial pressure in conscious spontaneously hypertensive rats and in several anesthetized animal preparations. This effect has been attributed to stimulation of dopamine receptors since it can be specifically antagonized by several dopamine receptor blocking agents (domperidone, haloperidol, pimozide, sulpiride). The two main mechanisms which can theoretically intervene in the antihypertensive effects of dopamine agonists are direct smooth muscle relaxation mediated by stimulation of post junctional DA1-dopamine receptors and the reduction of the neural release of norepinephrine resulting from activation of of DA2-dopamine receptors on ganglionic bodies or sympathetic nerve terminals. Other accessory mechanisms of undoubted interest might be a natriuretic effect or a decrease of aldosterone release. On the basis of the presently available pharmacological results in experimental animals, it is not unreasonable to advance the hypothesis that agonists of DA1- and DA2-dopamine receptors produce cardiovascular changes most compatible with an antihypertensive activity being due to a fall in peripheral resistance. However, before any of these compounds can become of therapeutic interest further research in this field is necessary to explore whether it is possible to minimize or even entirely avoid certain unwanted effects (vomiting, nausea, endocrinological alterations) that appear to be intimately associated particularly with those agents stimulating the DA2-dopamine receptors subtype. A more thorough pharmacological characterization of human dopamine receptors would be useful to provide an insight into whether novel chemical approaches can solve some of these problems. Finally, the ideal profits of future dopamine receptor agonists aimed at the treatment of elevated arterial pressure is discussed.