Treatment with Hypotensive Agents Affects the Impaired Relaxation of the Penile Corpus Cavernosum in Hypertensive Rats

Ushiyama, Masayuki; Kuramochi, Tomoya; Katayama, Shigehiro

doi:10.1291/hypres.29.523

Cited by 10 publications

(13 citation statements)

References 23 publications

(32 reference statements)

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“…It has been also reported that treatment with another ARB irbesartan reduced the vascular and cavernosal oxidative stress, and improved the endothelial function of the corpus cavernosum in cholesterol-fed ApoE −/− mice with atherosclerosis (4). In another experimental study, treatment with amlodipine did not change the level of oxidative stress marker (thiobarbiuric acid reactive substance) in corpus cavernosum in the SHR (35). These data are in agreement with our study that treatment with ARBs reduces oxidative stress in the penile tissue.…”

Section: Enos and Nnos Mrnas In The Rat Penile Tissuessupporting

confidence: 92%

“…Additionally, it has been reported that nifedipine augments cGMP production through the activation of cardiac soluble guanylyl cyclase as a negative inotropic effect but does not affect the NOS expression (31). Furthermore, it has been demonstrated that treatment with amlodipine significantly increased nitrate/nitrite and cGMP level in the plasma and corpus cavernosum in the SHR (1,35). Taken together, nifedipine and other L-type calcium channel blockers may be able to increase cGMP production in the penis independently of NOS…”

Section: Enos and Nnos Mrnas In The Rat Penile Tissuesmentioning

confidence: 99%

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

et al. 2014

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Possible effect of olmesartan, an angiotensin II receptor blocker (ARB), or nifedipine, an L-type calcium channel blocker, on penile dysfunction in the spontaneously hypertensive rat (SHR) was investigated in this study. Twelve-week-old male SHRs were treated with olmesartan (1 or 3 mg/ kg, per orally (p.o.)) or nifedipine (30 mg/kg, p.o.) once a day for 6 weeks. Wistar rats and SHRs with vehicle treatment were used as controls. Penile cGMP and malondialdehyde concentrations, and mRNA levels of endothelial and neuronal NO synthase (eNOS and nNOS) were measured. Penile function was evaluated by organ bath studies with norepinephrine-induced contractions and acetylcholine-induced relaxations. The SHR showed significantly increased blood pressure, decreased cGMP concentrations, increased malondialdehyde concentrations, decreased eNOS and nNOS mRNA levels, norepinephrine-induced hyper-contractions, and acetylcholine-induced hyporelaxations in the penile tissue compared to the Wistar rat. Both nifedipine and olmesartan significantly decreased blood pressure, increased cGMP and normalized the hyper-contractions and hypo-relaxations observed in the SHR group. However, not nifedipine but olmesartan improved the malondialdehyde concentrations and increased mRNA levels of eNOS and nNOS in the penis. Our results indicate that the hypertension-associated penile dysfunction might be treated with ARBs such as olmesartan better than calcium channel blockers, such as nifedipine.Hypertension induces vascular remodeling, pathological changes in the penis, and subsequent diminished blood supply to the penile tissue. In addition, hypertension represents one of the major risk factors for the development of vasculogenic erectile dysfunction (ED) (16,28). ED frequently appears in hypertensive patients than in normotensive individuals (10). The extent of ED directly depends on the degree and time of hypertension (8). Clinical studies show that approximately 30% of hypertension patients have ED compared to 9.6% in the common population (12, 28). Thus, antihypertensive therapies in hypertension-related ED patients are necessary in order to reduce the blood pressure and further protect the cavernous tissue. However, some of these therapies did not always improve the symptoms of ED in hypertensive patients (22,23). In clinical studies, the older antihypertensive drugs, i.e., diuretics and β-adrenoreceptor blockers, may exert detrimental effect on ED. On the other hand, more recent drugs have neutral (calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors) or favorable (angiotensin II type 1 receptor (AT1R) blockers (ARBs)) effects (11,22). These data suggest that blood pressure control may not be the only treatment strategy to improve erec-

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Section: Enos and Nnos Mrnas In The Rat Penile Tissuessupporting

confidence: 92%

Section: Enos and Nnos Mrnas In The Rat Penile Tissuesmentioning

confidence: 99%

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

et al. 2014

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“…Ushiyama et al. [32,33] showed that ED in hypertensive rats results from impairment of the relaxation evoked by neurogenic CO and NO. Shamloul and Wang [34] demonstrated an increased intracavernosal pressure response in hypertensive rats after chronic hemin treatment.…”

Section: Discussionmentioning

confidence: 99%

Effect of Hemin and Carbon Monoxide Releasing Molecule (CORM-3) on cGMP in Rat Penile Tissue

Aziz

El-Asmar

Mostafa

et al. 2008

The Journal of Sexual Medicine

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Introduction Cyclic guanosine monophosphate (cGMP) levels can be regulated by heme oxygenase-1 and 2 (HO-1 and HO-2)-derived carbon monoxide (CO). Aims Assessment of the effect of upregulating CO in rat corpora cavernosa (CC) on cavernous cGMP. Methods Three experimental groups were studied: first group (N=40), short-term HO induction over 2 weeks by injection of intraperitoneal increasing doses of hemin; the second group (N=40) was subjected to intracavernosal injection of CO donor, CORM-3, or its inactive form (iCORM-3) over 2 weeks; the third group (N=60) was subdivided into three subgroups: the first one received a combined hemin and CORM-3, the second one received hemin and its inhibitor stannus mesoporphyrin (SnMP), and third one received a combined hemin, CORM-3, and SnMP. Main Outcome Measures In CC, HO-1 and HO-2 gene expression, Northern blot and Western blot, cGMP levels, and HO enzyme activity. Results In the first group, maximum induction of HO-1 gene expression, HO enzyme activity, and cGMP occurred with 4-mg hemin dose with a successive increase over 2 weeks. In the second group, CORM-3 increased cGMP by twofold compared with iCORM-3, and also increased HO-1 protein. In the third group, SnMP inhibited the enhancing effect of CORM-3 and HO on erectile signaling molecules; i.e., HO-1 gene, enzyme activity, and cGMP. Conclusions CORM-3- or hemin-mediated CO release could increase cavernous tissue cGMP.

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“…The spontaneous treatment of hypertensive rats with amlodipine or imidapril for 4 weeks induced a relaxation increase in the response to EFS of the corpus cavernosum. 18 Treating hypercholesterolemic rats with irbesartan also improved endothelial function. 22 In clinical trials, preliminary data from several randomized and open studies have suggested that angiotensin type 1 receptor antagonists may be associated with improvement in sexual function.…”

Section: Discussionmentioning

confidence: 98%

“…Several investigational and clinical reports have suggested that some types of medication, including antihypertensive drugs, alpha-adrenergic blockers and hypolipidemic agents, can help treat ED. In vitro studies examining alpha-adrenergic blockers, 14,15 calcium channel blockers 16,17 and angiotensin-converting enzyme inhibitors 18 have shown direct relaxation or induced increased relaxation in response to electrical field stimulation (EFS). Angiotensin receptor blockers have also been shown to improve sexual function 19--21 in clinical trials and have improved endothelial function in hypercholesterolemic rats.…”

Section: Introductionmentioning

confidence: 99%

The effects of the combined use of a PDE5 inhibitor and medications for hypertension, lower urinary tract symptoms and dyslipidemia on corporal tissue tone

et al. 2012

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ED is closely associated with its comorbidities (hypertension, dyslipidemia and lower urinary tract symptoms (LUTS)). Therefore, several drugs have been prescribed simultaneously with PDE5 inhibitors. If a specific medication for ED comorbidities has enhancing effects on PDE5 inhibitors, it offers alternative combination therapy in nonresponders to monotherapy with PDE5 inhibitors and allows clinicians to treat ED and its comorbidities simultaneously. To establish theoretical basis of choosing an appropriate medication for ED and concomitant disease, we examined the effects combining a PDE5 inhibitor with representative drugs for hypertension, dyslipidemia and LUTS on relaxing the corpus cavernosum of rabbits using the organbath technique. The effect of mirodenafil on relaxing phenylephrine-induced cavernosal contractions was significantly enhanced by the presence of 10 À4 M losartan, 10 À6 M nifedipine, 10 À6 M amlodipine, 10 À7 M doxazosin and 10 À9 M tamsulosin (Po0.05). The maximum relaxation effects were 47.2 ± 3.8%, 57.6 ± 2.6%, 64.0 ± 3.7%, 76.1 ± 5.7% and 71.7 ± 5.4%, respectively. Enalapril and simvastatin had no enhancing effects. The relaxation induced by sodium nitroprusside alone (39.0±4.0%) was significantly enhanced in the presence of the 10 À4 M losartan (66.0 ± 6.0%, Po0.05). Tetraethylammonium (1 mM) significantly inhibited the enhancement effects of tamsulosin and doxazosin on mirodenafil-induced relaxation (doxazosin: 76.1 ± 5.7% vs 45.3 ± 2.3%; tamsulosin: 71.7±5.4% vs 48.1±3.5%). On the basis of these findings, losartan seemed to induce synergistic effects through an interaction with nitric oxide. In addition, K þ channel activation could be one of the mechanisms for the synergistic effect of combining mirodenafil with doxazosin or tamsulosin. We believe that the combination of a PDE5 inhibitor with losartan, nifedipine, amlodipine, doxazosin or tamsulosin could be a pharmacologic strategy for simultaneously treating ED and its comorbidities and increasing response rates to PDE5 inhibitors.International Journal of Impotence Research (2012) 24, 221--227; doi:10.1038/ijir.2012; published online 5 July 2012Keywords: comorbidity; ED; PDE5 inhibitor INTRODUCTION ED is a common condition, with a reported prevalence of 52% in men aged 40--70 years in the United States 1 and 49% in men aged 50--80 years in Europe.2 It can affect patients' lives in different ways, including disrupting interpersonal relationships, interfering with sexual life, causing problems with partners and increasing stress, all of which make ED a major quality of life issue.

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Treatment with Hypotensive Agents Affects the Impaired Relaxation of the Penile Corpus Cavernosum in Hypertensive Rats

Abstract: Treatment of erectile dysfunction (ED) in hypertensive subjects remains to be formally established. There is currently no standardized treatment for ED in hypertensive subjects. In this study, we tested our hypoth-

Cited by 10 publications

References 23 publications

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

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

Effect of Hemin and Carbon Monoxide Releasing Molecule (CORM-3) on cGMP in Rat Penile Tissue

The effects of the combined use of a PDE5 inhibitor and medications for hypertension, lower urinary tract symptoms and dyslipidemia on corporal tissue tone

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