EFS
Embryonal Fyn-associated substrate (hEFS) (Cas scaffolding protein family member 3) [CASS3]
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The prevalence of urinary dysfunction increases with age, yet therapies are often suboptimal. Incomplete understanding of the linkages between system, organ, and tissue domains across lifespan remains a knowledge gap. If tissue-level changes drive the aging bladder phenotype, parallel changes should be observed across these domains. In contrast, a lack of inter-domain correlation across age groups would support the hypothesis that urinary performance is a measure of the physiologic reserve, dependent on centrally-mediated adaptive mechanisms in the aging system. Male and female mice across four age groups underwent sequential voiding spot assays, pressure/flow cystometry, bladder strip tension studies, histology, and quantitative PCR analyses. The primary objective of this study was to test the impact of age on the cortical, autonomic, tissue functional and structural, and molecular domains, and identify inter-domain correlations among variables showing significant changes with age within these domains. Behavior revealed diminished peripheral voiding and spot size in aged females. Cystometry demonstrated increased postvoid residual and loss of volume sensitivity, but the preservation of voiding contraction power, with almost half of oldest-old mice failing under cystometric stress. Strip studies revealed no significant differences in adrenergic, cholinergic, or EFS sensitivity. Histology showed increased detrusor and lamina propria thickness, without a change in collagen/muscle ratio. Adrb2 gene expression decreased with age. No consistent inter-domain correlations were found across age groups. Our findings are consistent with a model in which centrally-mediated adaptive failures to aging stressors are more influential over the aging bladder phenotype than local tissue changes.
MeSH Terms
- Adrenergic beta-Agonists
- Aging
- Animals
- Carbachol
- Cholinergic Agonists
- Electric Stimulation
- Female
- Isoproterenol
- Male
- Mice
- Mucous Membrane
- Muscle Contraction
- Myography
- Phenotype
- Receptor, Muscarinic M3
- Receptors, Adrenergic, beta-2
- Urinary Bladder
- Urination
Keywords
- aging
- control physiology
- resilience
- urinary dysfunction
To evaluate the functional and molecular alterations of contractile and relaxant machinery in the bladder and urethra that lead to the underactive bladder (UAB) in old female mice. Female young (3-months) and old (18-months) C57BL/6 mice were used. Urodynamic was assessed in awake and anaesthetized mice. Electrical-field stimulation (EFS) and concentration-response curves to contractile and relaxing agents in isolated bladders and urethras were performed. Messenger RNA (mRNA) expressions of muscarinic, adrenergic, and transient receptor potential vanilloid-4 (TRPV4), and of the enzymes tyrosine hydroxylase and neuronal nitric oxide synthase (nNOS) were determined. Bladder cyclic adenosine monophosphate (cAMP) levels were measured. Cystometry in old mice showed incapacity to produce bladder emptying. On filter paper, old mice showed reduced urinary spots. Compared to the young group, bladder contractions induced by EFS and carbachol were lower in old mice. The β -adrenoceptor agonist mirabegron promoted higher bladder relaxation and elevation of cAMP levels in old mice. In old mice urethras, the α -adrenoceptor agonist phenylephrine produced higher contractions, but no differences were found for the NO donor sodium nitroprusside-induced relaxations. In old mice, increased mRNA expressions of β - and α -adrenoceptors in bladder and urethra were found, respectively, whereas the muscarinic M and M receptors and β -adrenoceptors did not change between groups. Reduced mRNA expressions of tyrosine hydroxylase and nNOS were found in old mouse urethras. Additionally, TRPV4 expression was reduced in bladder urothelium from old mice. Age-associated mouse UAB is the result of autonomic dysfunction at multiple levels leading to the less sensitive and overrelaxed bladder, along with urethral hypercontractility.
MeSH Terms
- Aging
- Animals
- Autonomic Nervous System
- Cyclic AMP
- Electric Stimulation
- Female
- Mice
- Mice, Inbred C57BL
- Muscle Contraction
- Receptors, Adrenergic
- Receptors, Muscarinic
- Urethra
- Urinary Bladder
- Urinary Bladder, Underactive
- Urodynamics
Keywords
- TRPV4
- aging
- muscarinic receptors
- neuronal nitric oxide synthase
- voiding dysfunction
- α1-adrenoceptors
- β-adrenoceptors
The pathophysiology of the genuine empty follicle syndrome (EFS) is still debated. Ovarian aging has been contested as a cause of this condition. Our aim was to investigate the occurrence of the genuine EFS in cases of a low number of mature follicles in a prospective manner. Ninety-five infertile women were recruited and evaluated following conventional controlled ovarian stimulation (COS) with ≤ six follicles of ≥14 mm diameter on the day of hCG administration. Enrolled women were 37.5 ± 5.2 years of age with basal FSH level of 9.1 ± 3.7 mIU/L, antral follicle count (AFC) of 6.9 ± 4.6, and number of ≥14 mm follicles (on the day of hCG) of 3.4 ± 1.5. Among the 95 women, four were complicated by the genuine EFS (4.2%) with features of the depleted ovarian reserve. Comparison between these four cases and the 91 controls revealed significant differences between age, AFC, number of ≥14 mm follicles, and serum E level corresponding to 41.8 ± 1.7 versus 37.4 ± 5.2 years, 1.7 ± 0.6 versus 7.1 ± 4.5, 2.0 ± 0.8 versus 3.4 ± 1.5 follicles, and 356 ± 200 versus 975 ± 557 pg/mL, respectively. Post hoc analysis revealed that 56 among the 95 women fulfilled the Bologna criteria for poor ovarian response and all four cases matched the definition of the genuine EFS raising its incidence to 7.1% in this group. A logistic regression analysis showed that AFC was a significant factor in the development of the genuine EFS. We conclude that the genuine EFS complicates infertile women characterized by a low number of mature follicles. Our findings suggest that the mechanism behind this occurrence is associated with a more exhausted ovarian reserve.
MeSH Terms
- Adult
- Case-Control Studies
- Chorionic Gonadotropin, beta Subunit, Human
- Female
- Humans
- Infertility, Female
- Ovarian Follicle
- Ovarian Reserve
- Ovulation Induction
- Prospective Studies
- Syndrome
- Treatment Failure
Keywords
- Assisted reproduction
- empty follicle syndrome
- low ovarian reserve
- ovarian aging
- poor ovarian response
The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs), neuronal nitric oxide synthase (nNOS)-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years). The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP) 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF), nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005) and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, P<0.001), while endomysial area of circular muscle did not significantly decrease. The proportions of NOS-immunoreactive cells and c-Kit-immunoreactive areas declined with aging (6 week vs 2 year; P<0.001 and P = 0.004, respectively), but there was no significant change of PGP 9.5-immunopositiviy. The expressions of nNOS, c-Kit and SCF mRNA also reduced with aging (6 week vs 2 year; P = 0.006, P = 0.001 and P = 0.006, respectively), while the change of PGP 9.5 mRNA expression was not significant. Western blot showed the significant decreases of nNOS and c-Kit protein expression with aging (6 week vs 2 year; P = 0.008 and P = 0.012, respectively). The EFS-induced esophageal contractions significantly decreased in 2-yr-old rat compared with 6-wk-old rats, however, L-NG-Nitroarginine methylester did not significantly increase the spontaneous and EFS-induced contractions in the 6-wk- and 2-yr-old rat esophagus. In conclusion, an increase of lamina propria thickness, a decrease of endomysial area, c-Kit, SCF and NOS expression with preserved total enteric neurons, and contractility in aged rat esophagus may explain the aging-associated esophageal dysmotility.
MeSH Terms
- Aging
- Animals
- Blotting, Western
- Esophagus
- Interstitial Cells of Cajal
- Male
- Neurons
- Nitric Oxide Synthase Type I
- Proto-Oncogene Proteins c-kit
- Rats
- Rats, Inbred F344
- Real-Time Polymerase Chain Reaction
- Stem Cell Factor
Frailty has been proposed by geriatricians as an indicator of functional age. The Edmonton Frail Scale (EFS) is a 15-point incremental scale; it is quick (<5 min), and simple to administer. We conducted an exploratory study to establish if the EFS add utility to clinician's expertise by determining if there was an association between EFS and receipt of chemotherapy in colorectal cancer (CRC) patients. The EFS was administered to stage II-IV CRC patients ≥70 years. EFS assessment was completed by one of the investigators, with the treating oncology team blinded to the results. A total of 46 patients were enrolled, and the EFS was reproduced in 32 patients at two visits (r=0.81; 95% CI: 0.64-0.90, P<0.0001). There was no correlation between the EFS and receipt of chemotherapy for the study population as a whole; however, exclusion of stage II patients showed a reduced likelihood of receiving chemotherapy with higher EFS scores (odds ratio 0.56; 95% CI: 0.37-0.85, P<0.01 per unit increment). A similar effect was observed after multivariable analysis (adjusting for performance status, age, stage and gender, odds ratio 0.41 95% CI: 0.18-0.96, P<0.05 per unit increment). This exploratory study suggests that EFS can identify patients that oncologists may have thought were too frail for chemotherapy, independent of PS. Therefore, the EFS has the potential to add a reproducible, and quantifiable measure of frailty to the clinician's decision making toolset. A follow up study will employ the EFS in real-time, and determine if using the EFS can minimize complications and unplanned health care utilization in elderly cancer patients.
Keywords
- Elderly
- chemotherapy
- colorectal cancer (CRC)
- frailty
- geriatrics
Dexmedetomidine is a selective α2 adrenergic agonist. Although dexmedetomidine is widely used for sedation and analgesia, it frequently produces hypotension and bradycardia. The present study aimed to evaluate the effects of dexmedetomidine on cardiac function and coronary circulation using Langendorff-perfused guinea pig hearts. Coronary perfusion pressure (CPP) and left ventricular pressure (LVP) were continuously monitored, and electric field stimulation (EFS) was applied to stimulate sympathetic nerve terminals. Dexmedetomidine almost completely inhibited the EFS-induced increase in LVP at all ages. The effect of dexmedetomidine on coronary artery resistance varied according to postnatal age, i.e., dexmedetomidine had little effect on CPP in young hearts (<4 weeks) but increased CPP by 10 mmHg at 4-8 weeks and by 15 mmHg at >8 weeks. The increase in CPP in adult hearts was inhibited by imiloxan, an α2B antagonist, and prazosin, an α1 antagonist. The results suggest that dexmedetomidine acts on α2 adrenergic receptors at sympathetic nerve terminals to suppress the release of norepinephrine. In addition, the findings suggest that dexmedetomidine directly affects α1 adrenoceptors and/or α2B adrenoceptors on coronary smooth muscles to increase CPP. The age-related changes in α adrenoceptor subtypes may be linked to the cardiodepressant effects of dexmedetomidine.
MeSH Terms
- Adrenergic alpha-2 Receptor Agonists
- Aging
- Analgesics, Non-Narcotic
- Animals
- Coronary Circulation
- Coronary Vessels
- Dexmedetomidine
- Guinea Pigs
- Heart
- Heart Rate
- Hypnotics and Sedatives
- In Vitro Techniques
- Myocardial Contraction
- Ventricular Function, Left
Keywords
- Cardiac function
- Coronary circulation
- Dexmedetomidine
- Langendorff perfusion
- α(2)-adrenoceptor
The aim of this study was determine whether intracavernosal injection (ICI) of insulin-like growth factor-1 (IGF-1) protein can improve corpus cavernosal smooth muscle relaxation in aging rats. Ten young (4-month-old) and 30 old (24-month-old) Sprague-Dawley male rats were enrolled in the study. The old rats were divided into three groups: vehicle-only (n = 10), IGF-1 1 µg/kg (n = 10) and IGF-1 10 µg/kg treatment groups (n = 10). After 4 weeks of single IGF-1 injection treatment, strips of corporal tissue were precontracted with phenylephrine, and dose-response curves were generated to evaluate endothelial-dependent [acetylcholine (ACh)], endothelial-independent [sodium nitroprusside (SNP)] and electrical field stimulation (EFS) vasoreactivity. The changes in percentage of cavernosal smooth muscle and the concentration of nitric oxide (NO) in penile tissue were also evaluated. After IGF-1 treatment, the vasoreactivity was significantly improved in both the 1 µg/kg and the 10 µg/kg treatment groups compared with the vehicle-only group at 4 weeks in response to ACh, SNP and EFS (all p < 0.05). The percentage of cavernosal smooth muscle was increased in the IGF-1 treatment groups. The NO concentrations were increased after IGF-1 treatment. These data demonstrate that ICI of IGF-1 can improve vasoreactivity via endothelium-dependent and endothelial-independent mechanisms in the corpus cavernosum of the aging rat.
MeSH Terms
- Acetylcholine
- Aging
- Animals
- Dose-Response Relationship, Drug
- Electric Stimulation
- Injections, Intramuscular
- Insulin-Like Growth Factor I
- Male
- Models, Animal
- Muscle Relaxation
- Muscle, Smooth, Vascular
- Nitric Oxide
- Nitroprusside
- Penis
- Rats
- Rats, Sprague-Dawley
- Vasodilator Agents
Keywords
- Cavernosal smooth muscle
- insulin-like growth factor-1
- intracavernosal injection
- rats
- vasoreactivity
Obestatin is a 23-amino acid peptide encoded by the ghrelin gene. We have investigated the effect of obestatin on intestinal contractility in rats ranging from the suckling period till adolescence. Duodenal and middle jejunum whole-thickness preparations from neonatal and adult rats were studied in an organ bath, for isometric recording under treatment with obestatin (1μmolL(-1)) in the presence of acetylocholine (ACh), atropine and tetradotoxin (TTX). Both the EFS and ACh-stimulated contractile response, as well as spontaneous contractile activity is age-dependent and specific for the segment of jejunum. Except for the middle jejunum of 7day old rats, treatment with obestatin caused a significant TTX-sensitive increase in the amplitude of EFS-stimulated off-contraction of both intestinal segments studied. Following injection of obestatin, the amplitude of spontaneous contraction in the duodenum increased in 7day old rats. In the middle jejunum, treatment with obestatin significantly increased both the amplitude and frequency of spontaneous contraction in rats till the 28th day of life, whereas in adult rats the observed effect of obestatin was the opposite (P<0.001 and P<0.0001, respectively). The effects of treatment with obestatin on stimulation with increasing doses of ACh were only observed in the preparations from suckling rats. ACh-stimulated contractility in the duodenum was decreased while in the middle jejunum the observed effect was opposite. These results indicate the importance of peripheral obestatin in the cholinergic control of intestinal contractility in both neonatal and adult rats.
MeSH Terms
- Acetylcholine
- Aging
- Animals
- Duodenum
- Electric Stimulation
- Ghrelin
- In Vitro Techniques
- Intestines
- Jejunum
- Male
- Muscle Contraction
- Rats, Wistar
Keywords
- Contractility
- Intestine
- Neonates
- Obestatin
Aging is associated with erectile dysfunction (ED), in which nitric oxide synthase (NOS) activity and NO bioavailability are reduced due to deficiencies of NOS cofactor (tetrahydrobiopterin, BH(4)) and substrate (L-arginine). We determined whether the prolonged treatment with sodium nitrite (NaNO(2)) as a storage form of NO ameliorates ED in aged rats. Male Sprague-Dawley rats were divided: younger, aged and NaNO(2)-treated (20 mg/kg per day) aged groups. The erectile (intracavernosal pressure [ICP]/mean arterial pressure [MAP]) and corpus cavernous (CC) responses were evaluated after 12 weeks. The ICP/MAP in aged rats was lower than in young controls, which was not improved by the NaNO(2) treatment. Immunohistochemical (IHC) staining for endothelial NOS and collagen deposition was performed. We assayed NO indirectly by measuring the level of its stable end products, nitrite/nitrate, using the Griess reagent. The relaxations to ACh and EFS in the aged group were considerably less than in the younger group, which were normalized by acute incubations of l-arginine or BH(4) of aged CC. In conclusion, NaNO(2) treatment did not restore erectile response while nitrate levels were enhanced in aged penis. The cofactor or substrate administrations, but not chronic exogenous modulation of NO system may be beneficial in aged men with ED.
MeSH Terms
- Aging
- Animals
- Arginine
- Biopterin
- Dose-Response Relationship, Drug
- Erectile Dysfunction
- Male
- Nitrates
- Nitric Oxide Synthase Type III
- Nitrites
- Penile Erection
- Penis
- Rats, Wistar
- Sodium Nitrite
Keywords
- Aging
- NaNO2 treatment
- corpus cavernosum
- erectile dysfunction
- nitric oxide
Erectile dysfunction (ED) is very prevalent in the older population, although the ageing-related mechanisms involved in the development of ED are poorly understood. We propose that age-induced differences in nerve- and endothelium-mediated smooth muscle contractility in the corpus cavernosum (CC) could be found between a senescent-accelerated mouse prone (SAMP8) and senescent-accelerated mouse resistant (SAMR1) strains. We analysed the changes in muscle tension induced by electrical field stimulation (EFS) or agonist addition 'in vitro', assessing nerve density (adrenergic, cholinergic and nitrergic), the expression of endothelial nitric oxide synthase (eNOS), cGMP accumulation and the distribution of interstitial cells (ICs) by immunofluorescence. We observed no change in both the nerve-dependent adrenergic excitatory contractility at physiological levels of stimulation and in the nitrergic inhibitory response in SAMP8 animals. Unlike cholinergic innervation, the density of adrenergic and nitrergic nerves increased in SAMP8 mice. In contrast, smooth muscle sensitivity to exogenous noradrenaline (NA) was slightly reduced, whereas cGMP accumulation in response to EFS and DEA/NO, and relaxations to DEA/NO and sildenafil, were not modified. No changes in the expression of eNOS and in the distribution of vimentin-positive ICs were detected in the aged animals. The ACh induced atropine-sensitive biphasic endothelium-dependent responses involved relaxation at low concentrations that turned into contractions at the highest doses. CC relaxation was mainly because of the production of NO together with some relaxant prostanoid, which did not change in SAMP8 animals. In contrast, the contractile component was considerably higher in the aged animals and it was completely inhibited by indomethacin. In conclusion, a clear imbalance towards enhanced production of contractile prostanoids from the endothelium may contribute to ED in the elderly. On the basis of these data, we propose the senescence-accelerated mouse model as a reliable tool to analyse the basic ageing mechanisms of the CC.
MeSH Terms
- Aging
- Animals
- Cyclic GMP
- Electric Stimulation
- Erectile Dysfunction
- Male
- Mice
- Models, Animal
- Muscle Contraction
- Muscle Relaxation
- Muscle, Smooth
- Nitric Oxide Synthase Type III
- Piperazines
- Purines
- Sildenafil Citrate
- Sulfones
Keywords
- SAMP8 mouse
- adrenergic
- ageing
- cholinergic
- corpus cavernosum
- endothelium-dependent tone
- erectile dysfunction
- nerve-mediated contractility
- nitrergic
Incidences of gastrointestinal (GI) motility disorders increase with age. However, there is a paucity of knowledge about the aging mechanisms leading to GI dysmotility. Motility in the GI tract is a function of smooth muscle contractility, which is modulated in part by the enteric nervous system (ENS). Evidence suggests that aging impairs the ENS, thus we tested the hypothesis that senescence in the GI tract precipitates abnormalities in smooth muscle and neurally mediated contractility in a region-specific manner. Jejunal and colonic circular muscle strips were isolated from young (4-10 years) and old (18 years) baboons. Myogenic responses were investigated using potassium chloride (KCl) and carbachol (CCh). Neurally mediated contractile responses were evoked by electrical field stimulation (EFS) and were recorded in the absence and presence of atropine (1 μM) or NG-Nitro-l-arginine methyl ester (l-NAME; 100 μM). The myogenic responses to KCl in the jejunum and colon were unaffected by age. In the colon, but not the jejunum, CCh-induced contractile responses were reduced in aged animals. Compared to young baboons, there was enhanced EFS-induced contractility of old baboon jejunal smooth muscle in contrast to the reduced contractility in the colon. The effect of atropine on the EFS response was lower in aged colonic tissue, suggesting reduced participation of acetylcholine. In aged jejunal tissue, higher contractile responses to EFS were found to be due to reduced nitregic inhibition. These findings provide key evidence for the importance of intestinal smooth muscle and ENS senescence in age-associated GI motility disorders.
MeSH Terms
- Aging
- Animals
- Colon
- Electric Stimulation
- Gastrointestinal Motility
- Jejunum
- Models, Animal
- Muscle, Smooth
- Myenteric Plexus
- Papio
Keywords
- enteric neurodegeneration
- myenteric plexus
- non-human primate
- normal aging
Little is known about the time course of aging on interstitial cells of Cajal (ICC) of colon. The aim of this study was to investigate the change of morphology, ICC, and neuronal nitric oxide synthase (nNOS)-immunoreactive cells in the aged rat. The proximal colon of 344 Fischer rats at four different ages (6, 31, 74 wk, and 2 yr) were studied. The immunoreactivity of c-Kit, nNOS, anti-protein gene product 9.5, and synaptophysin were counted after immunohistochemistry. The c-kit, stem cell factor (ligand of Kit), and nNOS mRNA were measured by real-time PCR. c-Kit and nNOS protein were assessed by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The area of intramuscular fat deposition significantly increased with age after 31 wk. c-Kit-immunoreactive ICC and nNOS-immunoreactive neurons and nerve fibers significantly declined with age. mRNA and protein expression of c-kit and nNOS decreased with aging. The functional study showed that the spontaneous contractility was decreased in aged rat, whereas EFS responses in the presence of atropine and L-NG-Nitroarginine methyl ester were increased in aged rat. In conclusion, the decrease of proportion of proper smooth muscle, the density of ICC and nNOS-immunoreactive neuronal fibers, and the number of nNOS-immunoreactive neurons during the aging process may explain the aging-associated colonic dysmotility.
MeSH Terms
- Adipose Tissue
- Aging
- Animals
- Cellular Senescence
- Colon
- Enteric Nervous System
- Gastrointestinal Motility
- Immunohistochemistry
- Interstitial Cells of Cajal
- Muscle Contraction
- Muscle, Smooth
- Nitric Oxide Synthase Type I
- Proto-Oncogene Proteins c-kit
- Rats
- Rats, Inbred F344
- Stem Cell Factor
Keywords
- aging
- colon
- inbred F344
- interstitial cells of Cajal
- neuronal nitric oxide synthase
- rats
The aim of this study was to investigate the effect of pravastatin treatment on diminished corpus cavernosum (CC) function associated with aging. Male rats were divided into three groups as adult rats (12-14 weeks old), aged rats (72-80 weeks old) and aged rats given 10 mg/kg/d pravastatin in drinking water for six weeks. Blood pressure was measured by tail-cuff method. Total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides and testosterone levels were estimated in blood. Changes in expression levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) (Ser-1177), neuronal nitric oxide synthase (nNOS), NADPH oxidase subunit gp91(phox), Rho A and Rho kinase (ROCK2) in CC were assessed by immunohistochemistry. Nitric oxide (NO)-mediated endothelium-dependent and neurogenic CC relaxation were evaluated by acetylcholine (ACh, 0.1 nM-100 µM) and electrical field stimulation (EFS; 30 V, 5 ms, 2-32 Hz), respectively. In aged rats, NO-mediated, both endothelium-dependent and neurogenic CC relaxation, were significantly impaired as compared to adult rats. Besides, eNOS, p-eNOS and nNOS expressions decreased significantly in CC from aged rats, while gp91(phox), RhoA and ROCK2 expressions increased significantly. The diminished relaxation in response to ACh or EFS as well as the changes in expression of these proteins in aged rats were significantly improved by pravastatin treatment. Pravastatin improves NO-mediated CC relaxations of aged rats probably by inhibiting NADPH oxidase/Rho kinase pathways, and this effect does not seem to be associated with lipid lowering effect of this drug.
MeSH Terms
- Aging
- Animals
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Male
- Nitric Oxide
- Nitric Oxide Synthase
- Penile Erection
- Penis
- Pravastatin
- Rats, Wistar
Keywords
- Aging
- NADPH oxidase
- corpus cavernosum
- nitric oxide
- pravastatin
- rho kinase
INTRODUCTION.: Prevalence of erectile dysfunction (ED) increases progressively with aging, but the ED pathophysiology at its early stages is still poorly investigated. AIM.: This study aimed to evaluate the functional and molecular alterations of erectile function at middle age, focusing on the contribution of oxidative stress in erectile tissue for the ED. METHODS.: Young (3.5-month) and middle-aged (10-month) male Wistar rats were used. Rat corpus cavernosum (RCC) was dissected free and mounted in 10-mL organ baths containing Krebs solution. Intracavernosal pressure (ICP) in anesthetized rats was evaluated. MAIN OUTCOME MEASURES.: Concentration-response curves to endothelium-dependent and endothelium-independent agents, as well as to electrical field stimulation (EFS), were obtained in RCC strips. Measurement of cyclic guanosine monophosphate (cGMP) and expressions of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS), gp91(phox) and superoxide dismutase-1 (SOD-1) expressions in RCC were evaluated. RESULTS.: ICP was significantly reduced in middle-aged compared with young rats. RCC relaxations to acetylcholine (10(-8) to 10(-2) M), sodium nitroprusside (10(-8) to 10(-2) M), sildenafil (10(-9) to 10(-5) M), BAY 41-2272 (10(-9) to 10(-5) M), and EFS (4-32 Hz) were decreased in middle-aged group, which were nearly normalized by apocynin (NADPH oxidase inhibitor; 10(-4) M) or SOD (75 U/mL). Prolonged treatment with apocynin (85 mg/rat/day, 4 weeks) also restored the impaired relaxations in middle-aged rats. Relaxations to 8-bromoguanosine 3',5'-cyclic monophosphate sodium salt (8-Br-cGMP; 10(-8) to 3 × 10(-4) M) remained unchanged between groups. Basal and stimulated cGMP production were lower in middle-aged group, an effect fully restored by apocynin and SOD. Protein expression of nNOS and phosphorylated eNOS (p-eNOS) (Ser-1177) reduced, whereas gp(91phox) mRNA expression increased in RCC from middle-aged rats. CONCLUSIONS.: ED in middle-aged rats is associated with decreased NO bioavailability in erectile tissue due to upregulation of NADPH oxidase subunit gp91(phox) and downregulation of nNOS/p-eNOS. Antioxidant therapies may be a good pharmacological approach to prevent ED at its early stages.
MeSH Terms
- Acetophenones
- Acetylcholine
- Aging
- Animals
- Blood Pressure
- Cyclic GMP
- Down-Regulation
- Electric Stimulation
- Endothelium, Vascular
- Enzyme Inhibitors
- Erectile Dysfunction
- Free Radical Scavengers
- Male
- Membrane Glycoproteins
- Muscle Relaxation
- NADPH Oxidase 2
- NADPH Oxidases
- Nitric Oxide Synthase
- Nitroprusside
- Penile Erection
- Phosphodiesterase 5 Inhibitors
- Piperazines
- Purines
- Pyrazoles
- Pyridines
- RNA, Messenger
- Rats
- Sildenafil Citrate
- Sulfones
- Superoxide Dismutase
- Superoxide Dismutase-1
- Up-Regulation
- Vasodilator Agents