A-2-Adrenoceptors

Catecholamines. The catecholamines, epinephrine (EPl adrenaline) (85), norepinephrine (NE noradrenaline) (86) (see Epinephrine and norepinephrine), and dopamine (DA) (2), are produced from tyrosine by the sequential formation of L-dopa, DA, NE, and finally EPl. EPl and NE produce their physiological effects via CC- and -adrenoceptors, a-Adrenoceptors can be further divided into CC - and a2-subtypes which in turn are divided... 

Fig. 10. The postulated interaction of a-adrenoceptor agonists with the receptor. The Easson-Stedman hypothesis suggests that (R)-noradrenaline is most potent owing to its three points of attachment () to the adrenoceptor, whereas dopamine and (5)-noradrenaline are equal in activity, but less active...

Correlation between clinical effectiveness and receptor affinities, however, can be seen with other receptors in addition to the dopamine D2 receptor. These include other dopaminergic receptors, as well as noradrenergic and serotonergic receptors. For example, most antipsychotics also have high affinity for a -adrenoceptors and 5-HT2 receptors (225). Some antipsychotics have been shown to be selective for the adrenoceptor versus the a -adrenoceptor, for example, spiperone [749-02-0] (226) and risperidone (61) (221]... 

As of the mid-1990s, use of MAOIs for the treatment of depression is severely restricted because of potential side effects, the most serious of which is hypertensive crisis, which results primarily from the presence of dietary tyramine. Tyramine, a naturally occurring amine present in cheese, beer, wine, and other foods, is an indirecdy acting sympathomimetic, that is, it potently causes the release of norepinephrine from sympathetic neurons. The norepinephrine that is released interacts with adrenoceptors and, by interacting with a-adrenoceptors, causes a marked increase in blood pressure the resultant hypertension may be so severe as to cause death. 

The cardiovascular adverse effects associated with quinidine therapy are hypotension and tachycardia, both of which are related to its a-adrenoceptor blocking actions. The tachycardia may be a reflex adjustment to the fall in blood pressure or may also be a direct action of the dmg on sympathetic nerve terminals leading to an increased release of NE. Quinidine also produces ringing in the ears (cinchonism) (1,2). 

Phenylephrine. Phenylephrine hydrochloride is an a -adrenoceptor agonist. Phenylephrine produces powerful vasoconstrictor and hypertensive responses. This results in baroreceptor activation of a reflex bradycardia and thus is useful in the treatment of supraventricular tachyarrhythmias. Unlike epinephrine [51-43-4] the actions of which are relatively transient, phenylephrine responses are more sustained (20 min after iv dosing and 50 min after subcutaneous dosing) (86). 

Patients having high plasma renin activity (PRA) (>8 ng/(mLh)) respond best to an ACE inhibitor or a -adrenoceptor blocker those having low PRA (<1 ng/(mLh)) usually elderly and black, respond best to a calcium channel blocker or a diuretic (184). -Adrenoceptor blockers should not be used in patients who have diabetes, asthma, bradycardia, or peripheral vascular diseases. The thiazide-type diuretics (qv) should be used with caution in patients having diabetes. Likewise, -adrenoceptor blockers should not be combined with verapamil or diltiazem because these dmgs slow the atrioventricular nodal conduction in the heart. Calcium channel blockers are preferred in patients having coronary insufficiency diseases because of the cardioprotective effects of these dmgs. 

OC-Adrenoceptor Blockers. Nonselective a-adrenoceptor blockers (Table 6), such as phentolamine, which block both a - and a2 adrenoceptors, produce vasodilation by antagonizing the effects of endogenous norepinephrine. They also produce severe tachycardia and have been replaced by selective a -adrenoceptor blockers, such as prazosin, terazosin, and doxazosin, which do not usually cause severe tachycardia. 

Prazosin, a selective a -adrenoceptor antagonist, exerts its antihypertensive effect by blocking the vasoconstrictor action of adrenergic neurotransmitter, norepinephrine, at a -adrenoceptors in the vasculature (200,227,228). Prazosin lowers blood pressure without producing a marked reflex tachycardia. It causes arteriolar and venular vasodilation, but a significant side effect is fluid retention. Prazosin increases HDL cholesterol, decreases LDL cholesterol, and does not cause glucose intolerance. 

Terazosin is selective a -adrenoceptor blocker having hypotensive efficacy equal to that of prazosin. Terazosin has a longer duration of action and better gastrointestinal absorption profile than prazosin. 

Diltiazem inhibits calcium influx via voltage-operated channels and therefore decreases intracellular calcium ion. This decreases smooth muscle tone. Diltiazem dilates both large and small arteries and also inhibits a-adrenoceptor activated calcium influx. It differs from verapamil and nifedipine by its use dependence. In order for the blockade to occur, the channels must be in the activated state. Diltiazem has no significant affinity for calmodulin. The side effects are headache, edema, and dizziness. 

Adenosine A1 Adenosine A2a Adenosine A3 aja-adrenoceptor ocib-adrenoceptor a2a-adrenoceptor a2b-adrenoceptor a -adrenoceptor Pi-adrenoceptor P2-adrenoceptor Angiotensin AT] Bradykinin B] Bradykinin B2 CGRP... 

FIGURE 9.14 Effects of adenosine receptor agonist 2-chloro-adenosine on vascular perfusion pressure of isolated perfused rat kidneys. Minor effects seen in untreated kidneys (filled circles) and pronounced vasoconstriction while vasodilatation in kidneys coperfused with subthreshold concentrations of a-adrenoceptor vasoconstrictor methoxamine and vasodilatatory activation of adenylyl cyclase with forskolin (open circles). Redrawn from [49]. 

FIGURE 9.21 Changes in heart rate (ordinates) for agonist-induced changes in cardiac inotropy (changes in rate of ventricular pressure) in anesthetized cats. Responses shown to isoproterenol (filled circles) and dobutamine (open circles), (a) Response in normal cats shows inotropic selectivity (less tachycardia for given changes in inotropy) for dobutamine over isoproterenol, (b) The inotropic selectivity of dobutamine is reduced by previous a-adrenoceptor blockade by phentolamine. From [61],... 

Causalgia is burning pain evoked by the activation of sympathetic efferent fibres. The likely mechanism underlying this syndrome involves ectopic expression of a-adrenoceptors on nociceptive afferents following peripheral injury or disease. 

Cotransmission is transmission through a single synapse by means of more than one transmitter. For example, to elicit vasoconstriction, postganglionic sympathetic neurones release their classical transmitter noradrenaline (which acts on smooth muscle a-adrenoceptors) as well as ATP (which acts on smooth muscle P2 receptors) and neuropeptide Y (which acts on smooth muscle Yx receptors). 

Hypotension is defined as abnormally low blood pressure. In most cases, hypotension is adequately treated with general measures (e.g. physical exercise), dtug treatment is rarely required. Drugs used for the treatment of hypotension include a-adrenoceptor agonists and compounds which activate both a and (3 adrenoceptors. 

In sympathetically innervated tissues, such as vas deferens or blood vessels, ATP produces fast responses mediated by P2X receptors followed by a slower component mediated by G protein-coupled a-adrenoceptors (Fig. 2) NPY usually acts as a pre-or postjunctional modulator of the release and/or action of NA and ATP. Similarly, for parasympathetic nerves supplying the urinary bladder, ATP provokes a fast, short-lasting twitch response via P2X receptors, whereas the slower component is mediated by G... 

Several clinically used drags, e.g. salbirtamol (a/ -adrenoceptor agonist), propanol (a j3-adrenoceptor antagonist) and the 2-arylpropiotric acids (NSAIDs) are employed in... 

While the amount of noradrenaline released from the terminals can be increased by nerve stimulation, it can be increased much more by drugs, like phenoxybenzamine, which block presynaptic a-adrenoceptors. These receptors are normally activated by increased noradrenaline in the synapse and trigger a feedback cascade, mediated by... 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

In addition to changes within the nerve, sympathetic afferents become able to activate sensory afferents via as yet poorly characterised a-adrenoceptors. These interactions between adjacent sensory and autonomic nerve axons and between ganglion cells result in excitation spreading between different nerve fibres. These peripheral ectopic impulses can cause spontaneous pain and prime the spinal cord to exhibit enhanced evoked responses to stimuli, which themselves have greater effects due to increased sensitivity of the peripheral nerves. 

Milani S, Djavan B. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia latest update on a, adrenoceptor antagonists. BJU Int 2005 95(Suppl 4) 29—36. 

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