AReceptor Subtypes

There are differences between the receptors on nerves (presynaptic receptors) and those on effector cells (postsynaptic receptors). Furthermore, some a-agonists and antagonists exhibit selectivity for one of these receptor types. Terminology classifies receptors as either aj or a2. arReceptors are those whose stimulation has traditionally been associated with the postsynaptic a-receptors of smooth muscle, while a2-receptors are those originally associated with the presynaptic a-re-ceptors of peripheral nerves. However, the designation of receptors as either aj or a2 cannot be categorized strictly by anatomical location (i.e., presynaptic or post-synaptic), since evidence now indicates that a2-recep-tors occupy, in addition to peripheral nerves, a variety of sites including smooth muscle, adrenal medullary cells, the brain, and melanocytes.

The existence of a-receptor subclasses and the receptor selectivity exhibited by certain a-blocking agents have therapeutic implications. Phentolamine is a disappointing antihypertensive drug because its administration results in a reflex increase in both heart rate and contractile force; these effects tend to negate the reduction in blood pressure that it produces. In contrast, prazosin is an effective antihypertensive drug because the reflex cardiac stimulation it induces is much less. The differing he-modynamic effects produced by phentolamine and pra-zosin appear to be related to their relative degree of selectivity for a1- and a2- receptors. Phentolamine is a relatively nonselective receptor blocking agent, since in addition to blocking postsynaptic a1-receptors, it will block presynaptic a2-receptors; the latter action enhances release of norepinephrine, hence augments cardiac rate and contractile force. Blockade of a2-receptors may actually potentiate the cardiac effects of sympathetic nerve stimulation. Prazosin, in contrast to phentolamine, is relatively selective for a1-receptors; that is, it preferentially blocks responses mediated by the postsynaptic a1-receptors in the blood vessels without having a substantial effect on presynaptic a2-receptors. Thus, prazosin stimulates the heart less than does phentolamine.

Absolute selectivity of action for a1- or a2-receptors does not exist for any available a-agonists and antagonists. Furthermore, as is the case with (3-receptors, a given effector tissue may contain more than one a-receptor subtype. Recent evidence suggests that in addition to a1-receptors, vascular smooth muscle may possess a2-receptors. Although the functional importance of a2-re-ceptors in blood vessels seems to be less than that of a1-receptors, this can account for certain clinical observations, as for example the pressor response that occurs upon initiation of treatment with the a2-agonist clonidine.

It is becoming increasingly clear that neither a1- nor a2-receptors are homogeneous. There seem to be at least three subtypes of both a1- and a2-receptors, that is, a1A, a1B, a1D, a2A, a2B and a2C. At this point, the pharmacology and therapeutic usefulness of the major a-antagonists can be reasonably well explained by considering their relative selectivity for the two main classes of a-receptors, a1 and a2. This is beginning to change, however. For example, tamsulosin (Flomax), a recently introduced a-antagonist, reportedly exhibits some selectivity for a1A-receptors, which are rich in the prostate, as compared to a1B-receptors, which are more plentiful in vascular smooth muscle. This may provide some advantage to tamsulosin as an agent for treatment of patients with benign prostate hypertrophy (discussed later).

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