The ocReceptors

Comparatively little was known about a-receptors or their structural requirements as recently as the 1970s. A 60-page review on molecular geometry and adrenergic activity dealt with a-receptors in less than one page (Patil et al., 1974). More recent research has increased understanding of this area considerably. Better understanding of receptors and their subtypes allows the development of ever more selectivity in agonists and antagonists, initially for increased depth of receptor research and, subsequently, of clinically useful drugs. In areas where multiple receptors seem to abound, it is multiple interactions of nonselective drugs that may be responsible for the bulk of side effects that arise.

In the brief overview to follow it is not possible to detail all the research.12 Until the mid-1970s a-adrenoceptors in smooth muscles were viewed as functioning by increasing cell membrane permeability to cations on stimulation. Intestinal muscle cells show increased K+ entry. Relaxation then follows due to hyperpolarization. Elsewhere it is the influx of Na+ and Ca2+ that increase, the voltage drops, and contraction results from the excitation. More recently two concepts regarding a-adrenoceptors developed more or less simultaneously. One was that two types of a-receptors exist, and are now named a, and a2. The other was the demonstration that in vitro and in vivo NE released by a sympathetic neuron following its stimulation was itself inhibited by this liberated NE by activating inhibitory a-adrenoceptors located on the varicosities of this prejunctional neuron. In other words, an inhibitory feedback mechanism was operative. Such autoreceptors were initially classified as a2. In this arrangement autoreceptors must by their very function be presynaptic since they respond to NE molecules released into the synaptic cleft. It is therefore now apparent that synaptic NE levels are under dual control: neuronal stimulation and feedback inhibition. It seemed obvious—and convenient—to refer to the presynaptic inhibitor adrenoceptors as a2, and those on postsynaptic effector cells (the "classic" a-receptors) as a^ The assumption was simply that all postsynaptic a-adrenoceptors would be subtype a^ This anatomical classification, however, did not hold up long. It was soon shown not to be true in vascular smooth muscle of rats and cats, a-Adrenoceptors that mediated vasoconstriction as expected were not blocked by the known selective a!-adrenoceptor drug prazocin (see Chapter 10). The finding was soon verified on human artery tissues. It thus became apparent that not all a2-receptors were presynaptic. This has since been substantiated by other researchers. Figure 9-10 schematically illustrates the system as it is presently believed to function. The presynaptic fiber releases NE into the synaptic cleft following stimulation. The neurotransmitter produces the expected vasoconstriction and other effects by stimulating postsynaptic a-receptors (a! or a2). The NE can also stimulate the presynaptic a-receptors (aj or a2), inhibiting NE

12 For such detail see Timmermans, 1987.

Varicosity

Sympathetic Nerve impulse induce* C-fiber exocytotic NA release

'Presynaptic a -receptor

Vesicle containing NA

Sympathetic Nerve impulse induce* C-fiber exocytotic NA release

'Presynaptic a -receptor

Synaptic gap t NA

Synaptic gap t NA

-Effector cell

(e.g.,vescul»r smooth muscle)

Response (contraction)

Figure 9-10. Pre- and postsynaptic a adrenoceptors of noradrenergic synapses. (From Timmermen and Van Zwieten, 1972). NA = norepinephrine.

-Effector cell

(e.g.,vescul»r smooth muscle)

Response (contraction)

Figure 9-10. Pre- and postsynaptic a adrenoceptors of noradrenergic synapses. (From Timmermen and Van Zwieten, 1972). NA = norepinephrine.

release from subsequent impulses. These presynaptic receptors reside on the membranes of vesicles or varicosities of the presynaptic neuron. The process, then, constitutes a negative feedback system and is not unique to adrenergic neurons. There is now also evidence of similar effects in cholinergic, dopaminergic, ^-adrenergic, and other systems. The presynaptic a-adrenoceptors exist at most of the noradrenergic neurons they were expected to be. Activity ratios between pre- and postsynaptic agonists and antagonists have been determined for many tissues. Measurements for presynaptic agonists determine the concentration of drug that will inhibit tritium-labeled NE (3H-NE) overflow; postsynaptic activity measures the concentration of drug needed to induce a smooth muscle constriction (Starke, 1981).

It was determined that methoxamine and phenylephrine are predominantly (but not totally) postsynaptic a-agonists. Methyl-NE, tramazoline, and clonidine show presynaptic preference (a2). Prazocin has very definite postsynaptic antagonist (0^) action. The alkaloids yohimbine and rauwolscine exhibit high presynaptic a-adrenoceptor affinity, thereby acting as antagonists. It must be remembered that a-adrenoceptors whose characteristics are those of presynaptic a2 receptors have been found on nona-drenergic nerve terminals and even at postjunctional sites. In general, though, presynaptic a2-receptors occur at nonadrenergic neurons where there are postsynaptic a-receptors. Sympathetically innervated organs contain postsynaptic a] adrenoceptors. Postsynaptic a2-receptors have been identified in both vascular smooth muscle as well as in the pancreas (islets), platelets, and the CNS, as well as in the eye and kidney (Timmermans and van Zwieten, 1982).

The CNS is now recognized as having a complex control system over the autonomic nervous system by way of both at and a2 adrenoceptors. Their stimulation or blockade by drugs results in a variety of effects that can have clinical import. Many of these are not yet well understood, and those that are will be addressed.

A limited representative (Table 9-4) lists a few drugs in the various ab a2, and mixed categories for both agonists and antagonists. Those whose chemistry was not previously considered (antihypertensives) will be dealt with in the next chapter.

Table 94. Representative ai and a2 Agonist and Antagonist Drugs

Agonists a2

(Xi/OCT

Phenylephrine Methoxamine

Clonidine" Guanabenz

Guanfacine

Noradrenaline

Adrenaline a-Methylnor-adrenaline" Tramazolineb Naphazoline Oxymetazoline

Antagonists a, a2

Prazocin Trimazocin Labetalold Corynthanine6

Yohimbine^ Rauwolscine*

Phentolamine Tolazocine Phenoxybenzamine Piperoxan'1

" There are disagreements on exact classification; thus Clonidine is variously listed a a2 or (X|.

b A nasal decongestant related to naphazoline.

c Active metabolite of methyldopa.

' Yohimbine epimer.

1 Yohimbine and related alkaloids in this are powerful adrenergic blockers not used in therapy now.

g a-Yohimbine.

* Obsolete adrenergic antagonist to circulating EP (Nickerson, 1949).

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