| 1. |
- 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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| 2. |
- 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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| 3. |
- Vagianos, C, et al.
(författare)
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Effects of alpha-adrenoceptor active drugs, prostaglandin F2 alpha and vasopressin on cystic and hepatic arteries of pig and man
- 1990
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Ingår i: Pharmacology and Toxicology. - 1600-0773. ; 66:2, s. 77-82
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Tidskriftsartikel (refereegranskat)abstract
- Human and pig cystic and pig hepatic arteries were suspended in tissue baths and the effect of alpha-adrenoceptor selective drugs, prostaglandin F2 alpha (PGF2 alpha) and vasopressin were investigated. Prazosin fulfilled the criteria for competitive antagonism in concentrations 10(-9)-10(-7) M. The pA2-values were 9.53 in human cystic, 9.74 in pig cystic, and 9.57 in pig hepatic artery. Rauwolscine had no significant effect in the different arteries. In human cystic artery noradrenaline had significantly (P less than 0.05) higher Emax and pEC50-values (135% of the preceding K(+)-induced contraction and 6.4, respectively) compared with pig cystic (106% and 5.7, respectively) and pig hepatic artery (116% and 5.9, respectively). Vasopressin had no effect in the cystic arteries, whereas it had a high potency (pEC50 was 8.5) but low intrinsic activity (Emax was 14%) in pig hepatic artery. Prostaglandin F2 alpha had a significantly higher Emax in human than in pig arteries. No differences were found in pEC50-values. This study indicates a similarity in pharmacological characteristics of some vasoactive drugs especially between pig cystic and hepatic arteries. If this is also true in man, the easily obtainable cystic artery can be used for screening the effect of drugs on the hepatic artery.
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| 4. |
- Werkström, Viktoria, et al.
(författare)
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Inhibitory innervation of the guinea-pig urethra; roles of CO, NO and VIP
- 1998
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Ingår i: Journal of the Autonomic Nervous System. - 0165-1838. ; 74:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The inhibitory innervation of guinea-pig urethral smooth muscle was investigated histochemically and functionally. The distribution of immunoreactivities to haem oxygenases (HO), neuronal NO synthase (nNOS), and vasoactive intestinal polypeptide (VIP) was studied, and the functional effects of the corresponding putative transmitters, CO, NO, and VIP, were assessed. HO-2 immunoreactivity was found in all nerve cell bodies of intramural ganglia, localized between smooth muscle bundles in the detrusor, bladder base and proximal urethra. About 70% of the ganglionic cell bodies were also NOS-immunoreactive (IR), whereas a minor part was VIP-IR. Some ganglion cells exhibiting tyrosine hydroxylase (TH) activity were demonstrated. Rich numbers of NOS-IR varicose nerve terminals could be found innervating the smooth muscle of the urethra, whereas VIP-IR terminals were less numerous. A rich number of TH-IR terminals were observed. The bladder showed a similar distribution of nerves, although only a few number of TH-IR nerves could be found. In bladder preparations exposed to sodium nitroprusside, cGMP-IR cells could be seen, forming an interconnecting network with long spindle-shaped processes. The cGMP-IR cells were especially abundant in the outer smooth muscle layers of the bladder, but less numerous in the urethra. In urethral strip preparations, electrical field stimulation evoked long-lasting frequency-dependent relaxations. The relaxations were not inhibited by the NO-synthesis inhibitor, L-NOARG, or enhanced by the NO-precursor, L-arginine. The haem precursor, 5-aminolevulinic acid (5-ALA), or the inhibitor of guanylate cyclase, ODQ, did not affect the urethral relaxations. Exogenously applied NO, SIN-1, and VIP relaxed the preparations by approximately 50%, whereas the relaxation evoked by exogenous CO was minor. These results suggest that CO probably is not involved in non-adrenergic, non-cholinergic inhibitory control of the guinea-pig urethra, where a non-NO/cGMP mediated relaxation seems to be predominant.
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| 5. |
- Wide-Swensson, Dag, et al.
(författare)
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Effects of isradipine, a new calcium antagonist, on maternal cardiovascular system and uterine activity in labour
- 1990
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Ingår i: British Journal of Obstetrics and Gynaecology. - : Wiley. - 1365-215X .- 1470-0328 .- 1471-0528. ; 97:10, s. 945-949
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Tidskriftsartikel (refereegranskat)abstract
- The effects of isradipine (a new calcium antagonist of the dihydropyridine type) on maternal blood pressure and heart rate, fetal heart rate, and uterine activity in labour were measured. Uterine activity was recorded by an intrauterine microtip transducer catheter connected to a fetal monitor. Isradipine was given as a slow injection in doses of 0.5 mg (10 women), 1 mg (11 women), and 1.5 mg (6 women). A reduction of systolic (6-16%) and diastolic (19-22%) blood pressure was seen, and concomitantly there was an increase in maternal (29-34%) and fetal (3-10%) heart rates. Reduction in uterine activity was not dose-related (maximum reduction 17%). Side effects (headache, palpitations) were minor and well tolerated. One women in the high-dose group had a shortlasting episode of hypotension. The results suggest that isradipine given as a bolus dose decreases blood pressure in pregnant women with little effects on uterine activity and fetal heart rate.
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| 6. |
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| 7. |
- Andersson, Karl-Erik
(författare)
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Detrusor contraction - Focus on muscarinic receptors
- 2004
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 38:Suppl 215, s. 54-57
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Forskningsöversikt (refereegranskat)abstract
- Stimulation of muscarinic receptors is a main mechanism for contractile activation of the detrusor from both animals and humans. Muscarinic receptors are coupled to G-proteins, but the signal transduction systems may vary. In general, M-1 , M-3 and M-5 receptors are considered to couple preferentially to G(q/11) , activating phosphoinositide hydrolysis, in turn leading to mobilization of intracellular calcium through inositol trisphosphate generation. M-2 and M-4 receptors couple to pertussis toxin-sensitive G(i/o) , resulting in inhibition of adenylyl cyclase activity. However, in the detrusor smooth muscle, other signalling pathways may be involved. Recent investigations revealed that a main pathway for muscarinic receptor activation of the detrusor may be calcium influx via L-type calcium channels, and increased sensitivity to calcium of the contractile machinery via inhibition of myosin light chain phosphatase through activation of Rho-kinase. The importance of these findings for treatment of voiding dysfunction remains to be established.
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| 8. |
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| 9. |
- Andersson, Karl-Erik
(författare)
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Overactive bladder--pharmacological aspects.
- 2002
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Ingår i: Scandinavian Journal of Urology and Nephrology, Supplementum. - : Informa UK Limited. - 0300-8886 .- 0036-5599 .- 1651-2065. ; Suppl 210:Supp 210, s. 72-81
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Tidskriftsartikel (refereegranskat)abstract
- The micturition reflex can be initiated by contraction or distension of detrusor smooth muscle cells, or by signals from the urothelium. It has been shown that bladder distension causes release of ATP from the urothelium and that ATP can activate P2X(3) receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably the activation of afferent fibres during bladder filling involves not only ATP, but a cascade of inhibitory and stimulatory transmitters/mediators. These mechanisms may be targets for future drugs. Both in the normal and functionally disturbed bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, interstitial cystitis, and also in the ageing bladder, a non-cholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions. Drugs blocking different P2X receptor subtypes, or counteracting bladder contraction via other mechanisms. e.g. beta(3)-adrenoceptor stimulation, may be developed for treatment of the overactive bladder.
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| 10. |
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