| 11. |
- Hedlund, Petter, et al.
(författare)
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Effects of nicorandil on human isolated corpus cavernosum and cavernous artery
- 1994
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Ingår i: Journal of Urology. - : Elsevier. - 0022-5347 .- 1527-3792. ; 151:4, s. 1107-1113
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Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO) released from nonadrenergic-noncholinergic (NANC) nerves seems to be a principal mediator of the relaxation of penile erectile tissue necessary for erection, and drugs acting by release of NO have been shown to produce erection when injected intracorporeally into impotent patients. By producing hyperpolarization, K+ channel openers are effective in relaxing isolated penile erectile tissue from rabbit and man, and can produce tumescence and erection when injected intracorporeally into animals. Nicorandil is classified as a K+ channel opener, but it also acts as a donor of NO. In the present study, the effects of nicorandil on isolated preparations from human corpus cavernosum (CC) and deep cavernous artery (Acc) were compared with those of cromakalim (K+ channel opener) and SIN-1 (NO donor). Nicorandil produced a concentration-dependent relaxation of CC and Acc preparations. The relaxations obtained at the highest nicorandil concentration used (10(-4) M.) were 75 +/- 3% and 66 +/- 4% in CC preparations contracted by noradrenaline and endothelin-1, respectively. The corresponding effects in Acc preparations were 70 +/- 14% and 73 +/- 5%. Glibenclamide (blocking ATP-dependent K+ channels) significantly reduced the nicorandil-induced relaxation in CC, but not in Acc. Methylene blue (believed to block soluble guanylate cyclase) reduced nicorandil's relaxant effect in CC, although statistical significance was not obtained. NG-nitro-L-arginine 10(-4) M. (NO synthase inhibitor) did not significantly influence the effect of nicorandil on precontracted preparations in either tissue. In CC preparations contracted by electrical field stimulation, nicorandil and cromakalim concentration dependently inhibited the responses. This effect was significantly counteracted by glibenclamide. It is concluded that nicorandil is effective in relaxing human CC chiefly by its K+ channel opening action, and to some extent by its ability to release NO. For nicorandil's relaxing effect on Acc, ATP dependent K+ channels seem to be of limited importance. If effective in impotent patients, the drug may represent a new, interesting approach to the treatment of erectile dysfunction.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Persson, Katarina, et al.
(författare)
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Difference in the actions of calcitonin gene-related peptide on pig detrusor and vesical arterial smooth muscle
- 1991
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 143:1, s. 45-53
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Tidskriftsartikel (refereegranskat)abstract
- Calcitonin gene-related peptide has been demonstrated in urinary bladder nerves, and suggested to play a role in local control of bladder motility. In isolated strips of pig detrusor muscle, calcitonin gene-related peptide did not affect spontaneous contractile activity, or contractions induced by high K+, carbachol, substance P, and electrical field stimulation. In contrast, calcitonin gene-related peptide elicited a concentration-dependent and pronounced (78–99%) relaxation of vesical arteries precontracted with endothelin-1, noradrenaline or prostaglandin F2x. As a vasodilator, CGRP was approximately 50 times more potent than acetylcholine. Removal of the endothelium abolished acetylcholine-induced relaxation, but did not affect the relaxation produced by calcitonin gene-related peptide. Pretreatment with methylene blue, glibenclamide or indomethacin had no influence on CGRP's ability to relax the vessels. The inhibitor of NO-synthesis, NG-nitro-L-arginine, had no effect on the maximum vascular relaxation induced by calcitonin gene-relate peptide. It is concluded that in the pig, calcitonin gene-related peptide has no functionally important mechanical effects on isolated detrusor muscle strips, but is a potent dilator of vesical arteries. The vascular effects of the peptide are endothelium-independent, and seem to be exerted directly on the vascular smooth muscle.
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| 16. |
- Persson, Katarina, et al.
(författare)
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Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro
- 1992
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Ingår i: British Journal of Pharmacology. - 0007-1188 .- 1476-5381. ; 107, s. 178-184
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Tidskriftsartikel (refereegranskat)abstract
- 1 The present study was performed to investigate how blockade of the L-arginine/nitric oxide (NO)pathway influences the function of the lower urinary tract in vivo, as studied by cystometry in consciousrats and in vitro, in isolated muscle preparations from the rat detrusor and urethra.2 L-N0-nitro arginine methyl ester (L-NAME), 10 and 20 mg kg-, administered intra-arterially,decreased micturition volume and bladder capacity, and increased spontaneous bladder contractions.D-NAME (20mgkg-') had no effect. No changes in the urodynamic parameters were recorded ifL-NAME (20mgkg-') was administered in combination with L-arginine (200mgkg-').3 Cystometries performed after intra-arterial administration of sodium nitroprusside (SNP) (3mgkg-') and 3-morpholino-sydnonimin hydrochloride (SIN-1, 2mgkg-') showed a decrease in bladdercapacity, micturition volume and threshold pressure. SIN-1, but not SNP, induced spontaneous bladdercontractions.4 Isolated precontracted urethral preparations responded to electrical stimulation with a frequencydependenttetrodotoxin-sensitive relaxation. L-NAME (10-4 M), but not D-NAME, reduced the maximalrelaxation to 31 ± 8% (n = 8) of the response prior to drug administration. The inhibition induced byL-NAME was completely reversed by L-arginine (10-3 M). SNP (10-1 10-4 M), SIN-1 (10-6-3 x l0-4M) and NO (10-5-10-3M; present in acidified solution of NaNO2), caused relaxation (93-100%) ofurethral preparations. L-NAME did not affect these relaxations.5 Detrusor strips contracted by carbachol or K' showed contractions in response to electricalstimulation, even when pretreated with a,p-methylene ATP and/or atropine. Small relaxations (14-41%)of detrusor strips were evoked by SNP (10-6-10-4M), SIN-1 (10-5-3 x 10-4M) and NO (10-5-10-3M). Electrically (20 Hz) induced contractions of the detrusor muscle were unaffected by addition ofL-NAME (10-6_10-4 M) or L-arginine (10-3 M).6 The present results suggest that the L-arginine/NO pathway is of functional importance for thebladder outlet region, but that its role in the detrusor is questionable. They also suggest that the site ofaction of L-NAME for inducing bladder hyperactivity in the rat is the outlet region rather than thedetrusor muscle.
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| 17. |
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| 18. |
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| 19. |
- Persson, Katarina, et al.
(författare)
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Nitric oxide and relaxation of pig lower urinary tract
- 1992
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Ingår i: British Journal of Pharmacology. - 0007-1188 .- 1476-5381. ; 106:2, s. 416-422
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Tidskriftsartikel (refereegranskat)abstract
- 1 We studied the non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation induced by electrical stimulation in pig isolated lower urinary tract smooth muscle, and the possible involvement of the L-arginine (L-ARG)/nitric oxide (NO) pathway in this response. 2 Trigonal strips, precontracted by noradrenaline (NA), carbachol or endothelin-1 (ET-1), relaxed frequency-dependently in response to electrical stimulation. Maximum relaxation was obtained at 6-8 Hz, and amounted to 56 +/- 2%, 77 +/- 3% and 62 +/- 6% of the agonist-induced tension in preparations contracted by NA, carbachol, or ET-1, respectively. Exposure to N(G)-nitro-L-arginine (L-NOARG; 10(-7) - 10(-5) M) concentration-dependently reduced the relaxant response in preparations contracted by NA. L-NOARG (10(-6) M) reduced the maximal response to 51 +/- 8% of control. L-NOARG (10(-5) M) abolished all relaxation, and unmasked a contractile component; D-NOARG had no effect. Also in trigonal preparations. where the tension had been raised by carbachol or ET-1, L-NOARG (10(-5) M) markedly reduced relaxations evoked by electrical stimulation. 3 In trigonal preparations contracted by NA, maximal relaxation was increased after pretreatment with L-ARG (10(-3) M), and the inhibitory effect of L-NOARG (10(-6) M) was prevented. Incubation of the trigonal strips with methylene blue had no effect on relaxations elicited at frequencies <6Hz, but a small inhibition was observed at higher frequencies. 4 Administration of NO (present in acidified solution of NaNO2) induced concentration-dependent relaxations in trigonal preparations contracted by NA, carbachol, or ET-1. L-NOARG (10(-5) M) and L-ARG (10(-3) M) had no effect on these relaxations. However, methylene blue (10(-5) M) significantly shifted the concentration-response curve for NO to the right. NANC-relaxation and NO-induced relaxation of trigonal preparations were both inhibited by oxyhaemoglobin (10(-5) M) and pyrogallol (10(-4) M). 5 In urethral preparations precontracted by NA, electrical stimulation caused frequency-dependent relaxations. A maximum relaxation of 73 +/- 4% was obtained at 10 Hz. Also in the urethra, NANC-relaxation was blocked by L-NOARG (10(-5) M), and a contractile response generally appeared. 6 Detrusor strips treated with alpha-beta-methylene ATP (10(-5) M) and atropine (10(-6) M), and then contracted by ET-1, showed relaxations (19 +/- 3% of the induced tension) in response to electrical field stimulation (2-20 Hz) only when the tension was high. No response at all, or small contractions, were found in response to electrical stimulation in K+ (35 mM)-contracted detrusor strips. Detrusor preparations contracted by carbachol were concentration-dependently relaxed by exogenously administered NO, SIN-1 (NO-donor), and isoprenaline, whereas vasoactive intestinal polypeptide had minor effects. NO and SIN-1 induced maximal relaxations of 63 +/- 3% and 70 +/- 4%, respectively, of the tension induced by carbachol. Isoprenaline produced an almost complete relaxation (96 +/- 4%). 7 The results suggest that NANC-nerve mediated relaxation, involving the L-ARG/NO pathway, can be demonstrated consistently in the pig trigonal and urethral, but not in detrusor smooth muscle. The importance of this pathway for lower urinary tract physiology and pathophysiology remains to be established.
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| 20. |
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