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- Gomez-Pinilla, Pedro J, et al.
(författare)
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Melatonin restores impaired contractility in aged guinea pig urinary bladder
- 2008
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Ingår i: Journal of Pineal Research. - : Blackwell Publishing Ltd. - 1600-079X .- 0742-3098. ; 44:4, s. 416-425
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Tidskriftsartikel (refereegranskat)abstract
- Urinary bladder disturbances are frequent in the elderly population but the responsible mechanisms are poorly understood. This study evaluates the effects of aging on detrusor myogenic contractile responses and the impact of melatonin treatment. The contractility of bladder strips from adult, aged and melatonin-treated guinea pigs was evaluated by isometric tension recordings. Cytoplasmatic calcium concentration ([Ca2+](i)) was estimated by epifluorescence microscopy of fura-2-loaded isolated detrusor smooth muscle cells, and the levels of protein expression and phosphorylation were quantitated by Western blotting. Aging impairs the contractile response of detrusor strips to cholinergic and purinergic agonists and to membrane depolarization. The impaired contractility correlates with increased [Ca2+](i) in response to the stimuli, suggesting a reduced Ca(2+)sensitivity. Indeed, the agonist-induced contractions in adult strips were sensitive to blockade with Y27362, an inhibitor of Rho kinase (ROCK) and GF109203X, an inhibitor of protein kinase C (PKC), but these inhibitors had negligible effects in aged strips. The reduced Ca2+ sensitivity in aged tissues correlated with lower levels of RhoA, ROCK, PKC and the two effectors CPI-17 and MYPT1, and with the absence of CPI-17 and MYPT1 phosphorylation in response to agonists. Interestingly, melatonin treatment restored impaired contractility via normalization of Ca2+ handling and Ca2+ sensitizations pathways. Moreover, the indoleamine restored age-induced changes in oxidative stress and mitochondrial polarity. These results suggest that melatonin might be a novel therapeutic tool to palliate aging-related urinary bladder contractile impairment.
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| 2. |
- Brioni, JD, et al.
(författare)
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Activation of dopamine D-4 receptors by ABT-724 induces penile erection in rats
- 2004
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences; 1999. - 0027-8424 .- 1091-6490. ; 101:17, s. 6758-6763
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Tidskriftsartikel (refereegranskat)abstract
- Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D(4) receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D(4) receptor agonist that activates human dopamine D(4) receptors with an EC(50) of 12.4 nM and 61% efficacy, with no effect on dopamine D(1), D(2), D(3), or D(5) receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction.
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| 7. |
- Hedlund, Petter
(författare)
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Genes and erectile function
- 2003
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Ingår i: Current Opinion in Urology. - 0963-0643. ; 13:5, s. 397-403
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review Few human studies have been performed with specific genetic endpoints coupled with erectile function or dysfunction. Most knowledge of gene expression and the function thereof on penile erection has been aqcuired in experimental models. The purpose of the present review is to give an overview of the available information obtained in studies of genes or genetic products versus erectile function or dysfunction. Recent findings The association of, for example, systemic vascular disease with diminished erectile function has brought attention to investigations of the distribution, in men with erectile dysfunction, of some genotype variants proposed to be involved in cardiovascular disease. Altered expression or activities of some smooth muscle regulatory components of the ischaemic, diabetic, or ageing penis have been reported. Summary Although penile erection can be considered a polygenic trait, some key effectors for normal erectile function within, for example, the nitric oxide/cyclic guanosine monophosphate pathway may be identified. Findings in future population-based studies may disclose the presence of a particular mutation of a gene or gene variants that may predispose to the development of erectile dysfunction. The exact molecular pathogenesis of erectile dysfunction is not known, and may vary between different forms of erectile dysfunction. With integrated approaches in genetic, molecular, and functional investigations, we can learn more of the impact of a particular genotype on erectile function, and also identify targets for preventive, pharmacological, or molecular measures.
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| 8. |
- Hedlund, Petter
(författare)
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PT-141 Palatin
- 2004
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Ingår i: Current Opinion in Investigational Drugs. - 2040-3429. ; 5:4, s. 62-456
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Tidskriftsartikel (refereegranskat)
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