Adrenergic Receptors (ARs)

could be one of the mechanisms that contrib-

a-Adrenoceptors

uted to a positive effect on DO caused by the

obstruction.

a-ARs may have effects on different locations in

the bladder: the detrusor smooth muscle, the

b-Adrenoceptors

detrusor vasculature, the afferent and efferent

It has been known for a long time that isoprena-

nerve terminal and intramural ganglia. For

some of these possible sites only fragmentary

line, a non subtype selective b-AR agonist, can

information is available.

relax bladder smooth muscle.84 Even if the

Most investigators agree on that there is a low

importance of b-ARs for human bladder func-

expression of these receptors in the derusor

tion still remains to be established,1 this does

muscle.78–80 In the human bladder studies Malloy

not exclude that they can be useful therapeutic

et al.78 found that two-thirds of the a-AR mRNA

targets. All three subtypes of b-ARs (b1, b2, and

expressed was a1D, there was no a1B, and one-

b3) can be found in the detrusor muscle of most

third was a .

species, including humans,1,79 and also in the

1A

human urothelium.85 However, the expression

Nomiya and Yamaguchi81 confirmed the low

expression of a-AR mRNA in normal human

of b3-AR mRNA79,81 and functional evidence

bladder, and further demonstrated that there

indicate a predominant role for this receptor in

was no upregulation of any of the adrenergic

both normal and neurogenic bladders.79,86,87 The

receptors with obstruction. In addition, in func-

human detrusor also contains b2-ARs, and most

tional experiments they found a small response

probably both receptors are involved in the

to phenylephrine at high drug concentrations

physiological effects (relaxation) of noradrena-

with no difference between normal and obs-

line in the bladder.1,79 b3-AR agonists have a pro-

tructed bladders. Thus, in the obstructed human

nounced effect on spontaneous contractions of

bladder, there seemed to be no evidence for a-

isolated detrusor muscle,88 which may be the

AR upregulation. This finding was challenged

basis for their therapeutic effects in OAB/DO.

by Bouchelouche et al.82 who found an increased

It is generally accepted that b-AR-induced

response to a1-AR stimulation in obstructed

detrusor relaxation is mediated by activation of

human bladders. If there is a change of sensi-

adenylyl cyclase with the subsequent formation

tivity to a-AR stimulation in the obstructed

of cAMP.89 However, there is evidence suggest-

bladder of clinical importance (influencing the

ing that in the bladder K+ channels, particularly

response to a-AR blockers) remains to be

BKca channels, may be involved in b-AR medi-

established.

ated relaxation independent of cAMP.90–93

All subtypes of a-ARs can be found in differ-

The in vivo effects of b3-AR agonists on blad-

ent parts of the human vascular tree, and they

der function have been studied in several ani-

all mediate contraction. The expression varies

mal models. It has been shown that b3-AR

with vessel bed and increases with age. In the

agonists increase bladder capacity with no

bladder, the function of the detrusor muscle is

change in micturition pressure and residual vol-

dependent on the vasculature and the perfusion.

ume.94–97 For example, Hicks et al.98 studied the

Hypoxia induced by partial outlet obstruction is

effects of the selective b3-AR agonist,GW427353,

believed to play a major role in both the hyper-

in the anesthetized dog and found that the drug

trophic and degenerative effects of partial outlet

evoked an increase in bladder capacity under

obstruction. Das et al.83 investigated in rats

conditions of acid evoked bladder hyperactivity,

whether doxazosin affected blood flow to the

without affecting voiding.

bladder and reduced the level of bladder dys-

b3-AR selective agonists are currently being

function induced by partial outlet obstruction.

evaluated as potential treatment for OAB/DO in

They found that 4 weeks treatment with dox-

humans.99 One of these, mirabegron (YM187),

azosin increased bladder blood flow in both

which mediated muscle relaxation in human

control and obstructed rats. Furthermore dox-

bladder strips,100 was given to patients with OAB

azosin treatment reduced the severity of the

in a controlled clinical trial.101 The primary effi-

detrusor response to partial outlet obstruction.

cacy analysis showed a statistically significant

Thus, doxazosin could reduce the increase in

reduction in mean micturition frequency, com-

bladder weight in obstructed animals which

pared to placebo, and with respect to secondary