Erectile Dysfunction: Key Role of Cavernous Smooth Muscle Cells.

Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile erection. This disorder is related to psychosocial factors such as anxiety, depression, and low self-esteem, to organic factors such as the presence of preexisting conditions like hypertension, diabetes and dyslipidemia. The pathophysiology of the disease is related to changes in the neurotransmission of the autonomic or the non-cholinergic non-adrenergic nervous system, as well as the release of local mediators, such as thromboxane A2 and endothelin, and hormonal action. These changes lead to impaired relaxation of cavernous smooth muscle, which reduces local blood flow and impairs penile erection. Currently, therapy is based on oral vasodilation, such as sildenafil, tadalafil, vardenafil and iodenafil, or by direct administration of these agents into the corpus cavernosum or by intraurethral route, such as alprostadil and papaverine. Despite this, studies that consolidate the understanding of its pathophysiological process contribute to the discovery of new more efficient drugs for the treatment of erectile dysfunction. In this sense, in the present work an extensive survey was carried out of the mechanisms already consolidated and the most recent ones related to the development of erectile dysfunction.

Ionic Channels as Potential Therapeutic Targets for Erectile Dysfunction: A Review.

Erectile dysfunction (ED) is a prevalent condition, especially in men over 40 years old, characterized by the inability to obtain and/or maintain penile erection sufficient for satisfactory sexual intercourse. Several psychological and/or organic factors are involved in the etiopathogenesis of ED. In this context, we gathered evidence of the involvement of Large-conductance, Ca2+-activated K+ channels (BKCa), Small-conductance, Ca2+-activated K+ channels (SKCa), KCNQ-encoded voltage-dependent K+ channels (KV7), Transient Receptor Potential channels (TRP), and Calcium-activated Chloride channels (CaCC) dysfunctions on ED. In addition, the use of modulating agents of these channels are involved in relaxation of the cavernous smooth muscle cell and, consequent penile erection, suggesting that these channels are promising therapeutic targets for the treatment of erectile dysfunction.

Toxicological and Pharmacological Activities of Leptohyptis macrostachys (Benth.) Harley and J.F.B.Pastore (Lamiaceae) on Intestinal Smooth Muscle.

Leptohyptis macrostachys, previously known as Hyptis macrostachys Benth., is used in folk medicine to relieve the symptoms of asthma, cough, and bronchitis. Recently, we showed that the ethanol extract obtained from Leptohyptis macrostachys has selective spasmolytic activity on guinea pig ileum. Therefore, the aim of this study was to characterize the spasmolytic mechanism of this extract, investigated whether it presents toxicological and antidiarrheal activities. Therefore, the crude ethanolic extract of Leptohyptis macrostachys was analyzed by high-performance liquid chromatographic-diode array detection (HPLC-DAD). The spasmolytic effect was evaluated on guinea pig ileum, toxicological activity using rats and antidiarrheal activity using male and female mice. In HPLC-DAD analysis, Rosmarinic acid (5.44%) was the most abundant phenolic compound, being considered as a chemical marker. The spasmolytic potency of the extract on histamine-induced contraction was reduced in the presence of 1 mM TEA+, a selective big-conductance K+ channels blocker (BKCa). The extract produces a dose-dependent antidiarrheal activity, inhibiting equipotently defecation frequency and liquid stool formation. In addition, the extract has inhibited in a dose-dependent manner both castor oil-induced intestinal transit and intestinal fluid content. Thus, the spasmolytic activity of the extract involves positive modulation of BKCa and its antidiarrheal activity is related to inhibition of intestinal motility and secretion.

Potential Therapeutic Role of Dietary Supplementation with Spirulina platensis on the Erectile Function of Obese Rats Fed a Hypercaloric Diet.

Spirulina platensis, an important source of bioactive compounds, is a multicellular, filamentous cyanobacterium rich in high-quality proteins, vitamins, minerals, and antioxidants. Due to its nutrient composition, the alga is considered a complete food and is recognized for its anti-inflammatory, antioxidant, antiobesity, and reproprotective effects. All of which are important for prevention and treatment of organic and metabolic disorders such as obesity and erectile dysfunction. The aim of this study was to investigate the modulatory role of Spirulina platensis food supplementation and the mechanisms of action involved in reversing the damage caused by a hypercaloric diet on the erectile function of rats. The animals were divided into a standard diet group (SD, n = 5); a hypercaloric diet group (HCD, n = 5); a hypercaloric diet group supplemented with S. platensis at doses of 25 (HCD+SP25, n = 5), 50 (HCD+SP50, n = 5), and 100 mg/kg (HCD+SP100, n = 5); and a hypercaloric diet group subsequently fed a standard diet (HCD+SD, n = 5). In the rats fed a hypercaloric diet, dietary supplementation with S. platensis effectively increased the number of erections while decreasing latency to initiate penile erection. Additionally, S. platensis increases NO bioavailability, reduces inflammation by reducing the release of contractile prostanoids, enhances the relaxation effect promoted by acetylcholine (ACh), restores contractile reactivity damage and cavernous relaxation, reduces reactive oxygen species (ROS), and increases cavernous total antioxidant capacity (TAC). Food supplementation with S. platensis thus restores erectile function in obese rats, reduces production of contractile prostanoids, reduces oxidative stress, and increases NO bioavailability. Food supplementation with S. platensis thus emerges as a promising new therapeutic alternative for the treatment of erectile dysfunction as induced by obesity.

Spirulina platensis prevents oxidative stress and inflammation promoted by strength training in rats: dose-response relation study.

The purpose of this study was to evaluate the effects of Spirulina Platensis supplementation on selected blood markers of oxidative stress, muscle damage, inflammation, and performance in trained rats. Rats (250 g - 300 g) were submitted to a strength training program (eight weeks), divided into four groups: control (GT) (trained without supplementation), trained with daily-supplementation of 50 mg/kg (GT50), 150 mg/kg (GT150) and 500 mg/kg (GT500). Training consisted of a jump protocol in PVC-cylinder containing water, with increasing load over experimental weeks. We evaluated the markers of oxidative stress (malondialdehyde - MDA and antioxidant capacity) and inflammation (C-reactive protein) at the end of the training. Among groups submitted to strength training, concentration of C-reactive protein decreased after 8 weeks of intervention in the trained group and GT500. Strength training enhanced plasma MDA concentration of malondialdehyde with supplementation of S. platensis in GT150 and GT500. In plasma analysis, strength training enhanced the percentage of oxidation inhibition, with spirulina supplementation in rates of 150 and 500 mg/kg. Spirulina supplementation for 8 weeks (in a dose-effect manner) improved antioxidant capacity as well as attenuated exercise-induced increases in ROS and inflammation. As a practical application, the use as high doses did not cause a reduction in positive physiological adaptations to exercise training. Additional studies are necessary to test the application of Spirulina Platensis in other contexts, as collective sports (basketball, football, soccer).

Virgin Coconut Oil Supplementation Prevents Airway Hyperreactivity of Guinea Pigs with Chronic Allergic Lung Inflammation by Antioxidant Mechanism.

Asthma is a chronic inflammatory disease of the airways characterized by immune cell infiltrates, bronchial hyperresponsiveness, and declining lung function. Thus, the possible effects of virgin coconut oil on a chronic allergic lung inflammation model were evaluated. Morphology of lung and airway tissue exhibited peribronchial inflammatory infiltrate, epithelial hyperplasia, and smooth muscle thickening in guinea pigs submitted to ovalbumin sensitization, which were prevented by virgin coconut oil supplementation. Additionally, in animals with lung inflammation, trachea contracted in response to ovalbumin administration, showed a greater contractile response to carbachol (CCh) and histamine, and these responses were prevented by the virgin coconut oil supplementation. Apocynin, a NADPH oxidase inhibitor, did not reduce the potency of CCh, whereas tempol, a superoxide dismutase mimetic, reduced potency only in nonsensitized animals. Catalase reduced the CCh potency in nonsensitized animals and animals sensitized and treated with coconut oil, indicating the participation of superoxide anion and hydrogen peroxide in the hypercontractility, which was prevented by virgin coconut oil. In the presence of L-NAME, a nitric oxide synthase (NOS) inhibitor, the CCh curve remained unchanged in nonsensitized animals but had increased efficacy and potency in sensitized animals, indicating an inhibition of endothelial NOS but ineffective in inhibiting inducible NOS. In animals sensitized and treated with coconut oil, the CCh curve was not altered, indicating a reduction in the release of NO by inducible NOS. These data were confirmed by peribronchiolar expression analysis of iNOS. The antioxidant capacity was reduced in the lungs of animals with chronic allergic lung inflammation, which was reversed by the coconut oil, and confirmed by analysis of peribronchiolar 8-iso-PGF2α content. Therefore, the virgin coconut oil supplementation reverses peribronchial inflammatory infiltrate, epithelial hyperplasia, smooth muscle thickening, and hypercontractility through oxidative stress and its interactions with the NO pathway.

Supplementation with Spirulina platensis Modulates Aortic Vascular Reactivity through Nitric Oxide and Antioxidant Activity.

The possible mechanism is involved in the effects of Spirulina platensis on vascular reactivity. Animals were divided into sedentary group (SG) and sedentary groups supplemented with S. platensis at doses of 50 (SG50), 150 (SG150), and 500 mg/kg (SG500). To evaluate reactivity, cumulative concentration-response curves were constructed for phenylephrine and acetylcholine. To evaluate the involvement of the nitric oxide (NO) pathway, aorta tissue was preincubated with L-NAME and a new curve was then obtained for phenylephrine. Biochemical analyses were performed to evaluate nitrite levels, lipid peroxidation, and antioxidant activity. To contractile reactivity, only SG500 (pD2 = 5.6 ± 0.04 vs. 6.1 ± 0.06, 6.2 ± 0.02, and 6.2 ± 0.04) showed reduction in phenylephrine contractile potency. L-NAME caused a higher contractile response to phenylephrine in SG150 and SG500. To relaxation, curves for SG150 (pD2 = 7.0 ± 0.08 vs. 6.4 ± 0.06) and SG500 (pD2 = 7.3 ± 0.02 vs. 6.4 ± 0.06) were shifted to the left, more so in SG500. Nitrite was increased in SG150 and SG500. Lipid peroxidation was reduced, and oxidation inhibition was increased in all supplemented groups, indicating enhanced antioxidant activity. Chronic supplementation with S. platensis (150/500 mg/kg) caused a decrease in contractile response and increase in relaxation and nitrite levels, indicating greater NO production, due to decreased oxidative stress and increased antioxidant activity.

A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress.

Asthma is a heterogeneous disease of the airways characterized by chronic inflammation associated with bronchial and smooth muscle hyperresponsiveness. Currently, different murine models for the study of asthma show poor bronchial hyperresponsiveness due to a scarcity of smooth muscle and large airways, resulting in a failure to reproduce smooth muscle hyperreactivity. Thus, we aimed to standardize a guinea pig model of chronic allergic lung inflammation mimicking airway smooth muscle hyperreactivity observed in asthmatics (Asth). Animals were randomly divided into a control group (Ctrl), which received saline (0.9% NaCl), and the Asth group, subjected to in vivo sensitization with ovalbumin (OVA) nebulization. Morphological analysis was performed by hematoxylin-eosin staining. Bronchial hyperresponsiveness was evaluated by nebulization time in the fifth, sixth, and seventh inhalations (NT5-7) and tracheal isometric contractions were assessed by force transducer. Total antioxidant capacity was measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and protein expression by Western blot. Histologically, the Asth group developed peribronchial cellular infiltrate, epithelial hyperplasia and smooth muscle thickening. After the fourth nebulization, the Asth group developed bronchial hyperreactivity. The trachea from the Asth group contracted after in vitro stimulation with OVA, differing from the Ctrl group, which showed no response. Additionally, airway smooth muscle hyperreactivity to carbachol and histamine was observed in the Asth group only in intact epithelium preparations, but not to KCl, and this effect was associated with an augmented production of reactive oxygen species. Moreover, lung inflammation impaired the relaxant potency of isoproterenol only in intact epithelium preparations, without interfering with nifedipine, and it was found to be produced by transforming growth factor-ß negative modulation of ß adrenergic receptors and, furthermore, big-conductance Ca2+-sensitive K+ channels. These effects were also associated with increased levels of phosphatidylinositol 3-kinases but not extracellular signal-regulated kinases 1/2 or phosphorylation, and augmented α-actin content as well, explaining the increased smooth muscle mass. Furthermore, pulmonary antioxidant capacity was impaired in the Asth group. Therefore, we developed a standardized and easy-to-use, reproducible guinea pig model of lung inflammation that mimics airway smooth muscle hypercontractility, facilitating the investigation of the mechanisms of bronchial hyperresponsiveness in asthma and new therapeutic alternatives.

Chronic aerobic swimming exercise promotes functional and morphological changes in rat ileum.

Several studies have reported the gastrointestinal (GI) effects promoted by the physical exercise. Thus, we aimed to evaluate the influence of swimming exercise on the contractile reactivity, lipid peroxidation and morphology of rat ileum. Wistar rats were divided into sedentary (SED) and groups exercised for two (EX2), four (EX4), six (EX6) or eight (EX8) weeks, 5 days/week. Animals were killed; the ileum was removed and suspended in organ baths where the isotonic contractions were recorded. Lipid peroxidation was evaluated by MDA (malondialdehyde) measurement with TBARS (thiobarbituric acid reactive substances) assay and morphology by histological staining. Cumulative concentration-response curves to KCl were attenuated, as the Emax values were changed from 100% (SED) to 63.1±3.9 (EX2), 48.8±3.8 (EX4), 19.4±1.8 (EX6) and 59.4±2.8% (EX8). Similarly, cumulative concentration-response curves to carbamylcholine hydrochloride (CCh) were attenuated, as the Emax values were changed from 100% (SED) to 74.1±5.4 (EX2), 75.9±5.2 (EX4) and 62.9±4.6 (EX6), but not in the EX8 (89.7±3.4%). However, CCh potency was increased in this latter, as the EC50 was altered from 1.0±0.1×10(-6) (SED) to 2.1±0.4×10(-7) (EX8). MDA concentration was altered only in EX4 (44.3±4.4) compared with SED (20.6±3.6 µmol/l). Circular layer was reduced in SED when compared with the exercised groups. Conversely, longitudinal layer was increased. In conclusion, chronic swimming exercise reduces the ileum contraction, equilibrates the oxidative damage and promotes changes in tissue size to establish an adaptation to the exercise.