[Categorization of adrenergic alpha 1 receptors in detrusor of patients with obstructive BPH. Initial study on experimental animal model].
BACKGROUND
The action of alpha 1-adrenergic receptor antagonists in ameliorating irritation and obstruction in patients with bladder outlet obstruction (due to Benign Prostatic Hyperplasia-BPH) has been demonstrated. Although it is well known that alpha 1-a receptors are responsible for prostate smooth muscle relaxation, the mechanism by which irritative bladder symptoms are improved is unknown. Different alpha 1 receptor subtypes may be involved. The objective of this study is to investigate the changes in the alpha-adrenergic receptor populations in the obstructed detrusor, and to determine which subtype is proportionally increased in this situation (bladder outlet obstruction).


METHODS
This was an in vivo study in an experimental model: male NZ (New Zealand) rabbits. The bladder neck of one group of rabbits was obstructed surgically using the technique proposed by Levin et al. Subsequent to bladder catherization with a 8Fr catheter, the bladder neck was exposed by means of a low medial abdominal incision. The bladder neck was tied with a 2/0 silk thread below the ureteral orifices. The catheter was taken out at the end of the intervention. The rabbits were sacrificed after 4 weeks using intracardiac pentothal and cystectomy was performed. A control group that did not undergo bladder obstruction were also sacrificed at this time, for the comparative study. Part of the detrusor was used for a pathological study and the rest for a physio-pharmacological study in which the organ was placed in a bath of adrenoceptor agonists (phenylephrine and noradrenaline) and antagonists WB101, AH11101A and BMY7378 (antagonists of the alpha 1a, b, d, respectively).


RESULTS
The findings of the pathological study show that the bladder wall was thicker in the rabbits that underwent bladder obstruction. The physio-pharmacological studies demonstrate that the detrusor response to the selective alpha-1 adrenergic agonist was greater in the rabbits that underwent bladder obstruction, however detrusor contractility was decreased (KPSS). With bladder obstruction the alpha 1d receptors were increased.


CONCLUSIONS
Receptor-binding studies (Malloy et al) aim to differentiate the alpha-adrenoreceptor populations. These studies identify and quantitate the different receptor subtypes in tissue without taking into account their activity. The isometric and physio-pharmacological tests evaluate active receptors, i.e. those that respond to agonist and antagonist stimuli. This enables detrusor activity to be evaluated accurately. The results obtained in this investigational study support the hypothesis that there is a high statistically significant increase in the alpha 1 adrenergic receptors in the obstructed detrusor. Furthermore, in agreement with previous molecular studies, during prostate obstruction alpha 1d is the predominate sub-population in the bladder. These findings may have patho-physiological, clinical and pharmacological implications. If this hypothesis which has been demonstrated in an experimental model, is also demonstrated in studies in humans, pharmacological development should not only be focussed on selective alpha 1a receptor antagonists (prostate) but also on those of alpha 1d, for relieving symptoms in patients with bladder outlet obstruction (BPH and prostatism).
González Enguita
C
C
Cátedra y Servicio de Urología, Fundación Jiménez Díaz, Universidad Autónoma, Madrid.
Vela Navarrete
R
R
Salcedo de Diego
A
A
Pérez Martínez
F
F
Ramírez Pérez del Yerro
M
M
Cancho Gil
M J
MJ
Crespí Martínez
F
F
Bravo Fernandez
I
I
Cabrera Pérez
J
J
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000378:metabolism*; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis / Q000302:isolation & purification*; D001748:Urinary Bladder Neck Obstruction / Q000378:metabolism*
D018340:Receptors, Adrenergic, alpha-1