RECEPTORS ON THE AUTONOMIC EFFECTOR CELLS
The receptors for acetylcholine and related drugs (cholinoreceptors) and for norepinephrine and related drugs (adrenoceptors) are different. Acetylcholine will not interact with receptors for norepinephrine, and nor-epinephrine will not interact with cholinoreceptors. These receptors are selective not only for their respec-tive agonists but also for their respective antagonist drugs; that is, drugs that antagonize or block acetyl-choline at cholinoreceptors will not antagonize norepi-nephrine at adrenoceptors and vice versa.
The action of administered acetylcholine on effector systems innervated by parasympathetic postganglionic neurons (smooth muscle cells, cardiac muscle cells, and exocrine gland cells) resembled the actions produced by the naturally occurring plant alkaloid muscarine. The actions of both acetylcholine and muscarine on the vis-ceral effectors are similar to those produced by parasympathetic nerve stimulation. Furthermore, the effects of acetylcholine, muscarine, and parasympa-thetic nerve stimulation on visceral effectors are antag-onized by atropine, another plant alkaloid.
The administration of acetylcholine mimics the stimulatory effect of nicotine, the alkaloid from the to-bacco plant, on autonomic ganglia and the adrenal medulla. It has become common practice to refer to the effects of acetylcholine on visceral effectors as the mus-carinic action of acetylcholine and to its effects on theautonomic ganglia and adrenal medulla as the nicotinic action of acetylcholine. The respective receptors are called the muscarinic and nicotinic cholinoreceptors or the muscarinic and nicotinic receptors of acetylcholine.
The action of acetylcholine at the skeletal muscle motor end plate resembles that produced by nicotine. Thus, the cholinoreceptor on skeletal muscle is a nico-tinic receptor. Based on antagonist selectivity, however, the autonomic and somatic nicotinic receptors are not pharmacologically identical .
Acetylcholine can stimulate a whole family of re-ceptors. However, these receptors are sufficiently chem-ically diverse that different exogenous agonists and antagonists can distinguish among them. Great thera-peutic benefit has been obtained from this diversity be-cause it allows the development of therapeutic agents that can selectively mimic or antagonize actions of acetylcholine. Such a diversity of receptor subtypes ex-ists for other neurotransmitters in addition to acetyl-choline.
Adrenoceptors interact not only with norepinephrine but also with the adrenal medullary hormone epineph-rine and a number of chemically related drugs. However, the responses produced by the drugs in dif-ferent autonomic structures differ quantitatively or qualitatively from one another.
On the basis of the observed selectivity of action among agonists and antagonists, it was proposed that two types of adrenoceptors exist. These were designated as α- and β-adrenoceptors. Subsequently, it has become necessary to classify the adrenoceptors further into α 1-, α 2-, β 1-, and β 2-receptor subtypes. Table 9.1 indicates present knowledge of the distribution of the subtypes of adrenoceptors in various tissues.
The α 1-adrenoceptors are located at postjunctional (postsynaptic) sites on tissues innervated by adrenergic neurons. α 2-Adrenoceptors having a presynaptic (i.e., neuronal) location are involved in the feedback inhibi-tion of norepinephrine release from nerve terminals (discussed later). α 2-Receptors also can occur postjunc-tionally. The β 1-adrenoceptors are found chiefly in the heart and adipose tissue, while β 2-adrenoceptors are lo-cated in a number of sites, including bronchial smooth muscle and skeletal muscle blood vessels, and are asso-ciated with smooth muscle relaxation.
Activation of α1-adrenoceptors in smooth muscle of blood vessels leads to vasoconstriction, while activation of β 2-adrenoceptors in blood vessels of skeletal muscle produces vasodilation. Activation of β 1-adrenoceptors on cardiac tissue produces an increase in the heart rate and contractile force.
Norepinephrine and epinephrine are potent α- adrenoceptor agonists, while isoproterenol, a synthetic adrenomimetic, is selective for β 1- and β 2-adrenocep-tors. Norepinephrine and epinephrine are thus potent vasoconstrictors of vascular beds that contain predomi-nantly α-adrenoceptors, while isoproterenol has little effect in these vessels.
Isoproterenol and epinephrine are potent β2-adrenoceptor agonists; norepinephrine is a relatively weak β2-adrenoceptor agonist. Isoproterenol and epi-nephrine produce vasodilation in skeletal muscle, but norepinephrine does not; rather it produces vasocon-striction through the α1-adrenoceptors. Isoproterenol, epinephrine, and norepinephrine are potent β1-adreno-ceptor agonists; thus, all three can stimulate the heart (Table 9.1).
The existence of a β 3-adrenoceptor has recently been demonstrated in human adipose tissue along with the β 1-adrenoceptor. This observation raises the possi-bility that eventually therapeutic drugs may selectively alter lipid metabolism and therefore provide therapeu-tic management of obesity. The β 3-receptor and the re-cently identified subtypes within the α 1- and α 2-receptor groups ( α1A, α 1B, etc.) also have not been included in thetable, since as yet few therapeutic drugs distinguish among these further subtypes. One exception is tam-sulosin, an antagonist with some selectivity for α 1A-receptors in the urinary tract.
Presynaptic or prejunctional receptors are located on the presynaptic nerve endings and function to control the amount of transmitter released per nerve impulse and in some instances to affect the rate of transmitter synthesis through some as yet undetermined feedback mechanism. For instance, during repetitive nerve stimu-lation, when the concentration of transmitter released into the synaptic or junctional cleft is relatively high, the released transmitter may activate presynaptic receptors and thereby reduce the further release of transmitter. Such an action may prevent excessive and prolonged stimulation of the postsynaptic cell. In this case, the ac-tivation of the presynaptic receptor would be part of a negative feedback mechanism.
The presynaptic receptors may have pharmacologi-cal significance, since several drugs may act in part ei-ther by preventing the transmitter from reaching the presynaptic receptor, thus causing excessive transmitter release, or by directly stimulating presynaptic receptors and thereby diminishing the amount of transmitter re-leased per impulse.
The inhibitory presynaptic α-adrenoceptors found on noradrenergic neurons are of the α 2-subtype. Adrenoceptors of the β2 subclass also occur presynap-tically, and activation of these receptors leads to en-hanced norepinephrine release. The physiological and pharmacological importance of these presynaptic β2-receptors is less certain than it is for presynaptic α2-receptors.
Presynaptic receptors for nonadrenomimetic sub-stances (e.g., acetylcholine, adenosine) also have been found on the sympathetic presynaptic nerve ending. Their importance and role in the modulation of neuro-transmission have not been definitively established.