Effect of doxazosin on rat urinary bladder function after partial outlet obstruction.
Hypoxia induced by partial outlet obstruction is believed to play a major role in both the hypertrophic and degenerative effects of partial outlet obstruction. Doxazosin (dox) is a clinically effective alpha-adrenergic antagonist used in the treatment of symptomatic benign prostatic hyperplasia (BPH). Although the major therapeutic effect of the agent is believed to occur on the smooth muscle components of the prostate by reducing prostatic urethral resistance and thus improving emptying, dox may have part of its clinical action via effects mediated by other actions, including via spinal alpha-adrenergic receptors or direct effects on the bladder, possibly via inhibition of vascular alpha receptors. The specific aim of the current study was to determine whether dox pretreatment on rats affects blood flow to the bladder and reduces the level of bladder dysfunction induced by partial outlet obstruction. In part 1, eight rats were separated into two groups of four rats each. Group 1 received oral administration of dox (30 mg/kg) for 4 weeks; group 2 received vehicle (5% dimethyl sulfoxide). After 4 weeks of treatment, blood flow studies were performed using fluorescent microspheres and the bladders excised, frozen, and submitted to Interactive Medical Technologies (IMT) for blood flow analysis. In part 2, 32 adult male rats were separated into four groups of eight rats each. Groups 1 and 2 received oral administration of dox (30 mg/kg) for 4 weeks, groups 3 and 4 received vehicle (5% dimethyl sulfoxide). At 4 weeks, the rats in groups 1 and 3 received partial outlet obstructions and treatment continued for an additional 2 weeks. After 6 weeks of treatment (total), each rat was anesthetized, the bladder excised, weighed, and isolated strips mounted and contractility studies performed. 1) Four weeks pretreatment of rats with dox increased blood flow to the bladder in both the control and obstructed groups. 2) Partial outlet obstruction induced a mild decrease in blood flow. 3) The magnitude of the increased bladder weight in the vehicle-treated obstructed group was significantly greater than in the dox-treated obstructed group. 4) Partial outlet obstruction resulted in significant decreases in the contractile response to field stimulation in both treated and non-treated rats. The magnitude of the decreased response was significantly greater in the non-treated rats. 5) The response to potassium chloride was significantly reduced by partial outlet obstruction in the vehicle-treated group but not in the dox-treated group. 6) The time to maximal tension was significantly increased in response to carbachol, adenosine triphosphate, and potassium chloride. However, the magnitude of the increase was significantly greater for the vehicle-treated obstructed groups stimulated by potassium chloride than for the dox-treated groups. Dox treatment of rats increased blood flow to the bladder and reduced the severity of the response to partial outlet obstruction. These beneficial effects would be due to pharmacological effects on alpha-adrenergic systems outside those present in the prostate. These include effects on blood flow to the bladder, effects on the micturition centers of the central nervous system, spinal reflexes, and alpha-adrenergic receptors in the urethra and bladder.
Das
Anurag K
AK
Division of Urology, Albany Medical College, Albany, New York 12208, USA.
Leggett
Robert E
RE
Whitbeck
Catherine
C
Eagen
George
G
Levin
Robert M
RM
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D017292:Doxazosin / Q000008:administration & dosage / Q000494:pharmacology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction; D009929:Organ Size; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D012016:Reference Values; D001743:Urinary Bladder / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D001748:Urinary Bladder Neck Obstruction / Q000473:pathology / Q000503:physiopathology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D018679:Cholinergic Agonists; D014665:Vasodilator Agents; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D002217:Carbachol; D017292:Doxazosin