Effects of doxazosin on blood flow and mRNA expression of nitric oxide synthase in the spontaneously hypertensive rat genitourinary tract

Abstract

Hypertension may impact pelvic arterial blood flow resulting in reduction of nitric oxide synthase (NOS) levels. Although doxazosin, an alpha(1)-adrenoceptor antagonist, has been shown to improve erectile dysfunction as well as benign prostatic hyperplasia (BPH) and hypertension, it is not clear whether these improvements using doxazosin are primarily due to direct actions on the prostate, urinary bladder and penis, possibly via inhibition of vascular alpha(1)-adrenoceptors, or other sites of actions. Therefore, we investigated effects of doxazosin to the spontaneously hypertensive rat (SHR) on blood flow and NOS levels in the genitourinary tract. Four groups of rats were assessed: group 1, SHRs treated with doxazosin (30 mg/kg/day) for 4 weeks; group 2, SHRs treated with nifedipine (30 mg/kg/day) for 4 weeks; group 3, untreated SHRs; and group 4, untreated Wistar-Kyoto (WKY) rats. Blood flow to the ventral prostate, dorsolateral prostate, urinary bladder and penis was determined using a fluorescent microsphere infusion technique. Expression levels of nNOS and eNOS mRNAs were quantified by real-time RT-PCR using SYBR Green I. Blood flow to the ventral prostate, dorsolateral prostate, urinary bladder and penis was significantly lower in untreated SHRs than WKY rats. Treatment with doxazosin increased blood flow to each tissue studied in SHRs. RT-PCR data indicated that untreated SHRs had lower mRNA expression levels of nNOS in the bladder and penis and eNOS in the penis than WKY rats and that administration of doxazosin to the SHR caused an increase in expression levels of these genes, i.e., up-regulation of nNOS in the bladder and penis and eNOS in the penis. However, nifedipine had no significant effects on blood flow and NOS levels in the SHR genitourinary tract. Our data demonstrate that doxazosin treatment causes differential alterations in blood flow and NOS levels in the SHR genitourinary tract. These findings may provide insight into the beneficial effects of alpha(1)-adrenoceptor antagonists, on prostate, bladder and penile function, when used to treat symptoms of BPH and elevated blood pressure.

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

“…Results of this study showed that NO-cGMP signalling was more affected by Doxa-treatment independent of its duration. The results about stimulated transcription of constitutive nitric oxide synthases (Nos1, Nos3) are in line with recent findings that administration of Doxa (30 mg/kg BW/day for 4 weeks) to the spontaneously hypertensive rats caused an up-regulation of NOS1 in the bladder and penis and NOS3 in the penis (Yono et al, 2007).…”

Effect of an angiotensin II receptor blocker and a calcium channel blocker on hypertension associated penile dysfunction in a rat model

“…These data are in agreement with our study that treatment with ARBs reduces oxidative stress in the penile tissue. Yono et al demonstrated that nifedipine had no significant effects on eNOS and nNOS mRNA levels in the penis in the SHR (36). In our study, treatment with nifedipine had no change in the eNOS and nNOS mRNA levels, while the treatment significantly increased the penile cGMP which is the second messenger of NO derived by NOS.…”

“…The model exhibits the substantial morphological changes such as vascular remodeling on penile tissue, and diminished blood flow to the erectile tissue (6,7,36). Also, hypertrophy of corpus cavernous smooth muscle and vascular smooth muscle has been confirmed in the SHR (32).…”

“…Furthermore, eNOS and nNOS are important factors for penile erection to produce NO from L-arginine in the corpus cavernosum. The impairment of NOS and NO availability should lead to develop ED (30,36). Mazza et al reported that treatment with an ARB, candesartan, improved cavernous sinusoidal eNOS and acetylcholine-induced hypo-relaxation in the SHR (25).…”

PDE5 inhibitors for LUTS

“…83 Their effects may be secondary to relaxation of smooth muscle present in the prostate, urethra, and bladder neck, as well as their vascular supply. [84][85][86][87] In vitro studies have also shown that NO donor drugs and PDE5 inhibitors may stimulate anti-proliferative or apoptotic effects in the prostate, improved pelvic blood flow, and effects on afferent nerves from the prostate or bladder, resulting in their improvement of LUTS symptoms. 88,89 A recent study by Dmochowski et al 90 examined LUTS and urodynamic parameters in 200 men (baseline IPSSX13) randomized to tadalafil (20 mg) treatment or placebo for 12 weeks.…”