| 1. |
- Ekelund, Ulf, et al.
(författare)
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Effects of selective ETB-receptor stimulation on arterial, venous and capillary functions in cat skeletal muscle
- 1994
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Ingår i: British Journal of Pharmacology. - 1476-5381. ; 112:3, s. 887-894
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Tidskriftsartikel (refereegranskat)abstract
- 1. This paper describes, in quantitative terms, the in vivo effects of two selective ETB-receptor agonists (IRL 1620 and BQ 3020) on vascular resistance (tone) in the following consecutive sections of the vascular bed of sympathectomized cat skeletal muscle: large-bore arterial resistance vessels (> 25 microns), small arterioles (< 25 microns) and the veins. The effects on capillary pressure transcapillary fluid exchange were also recorded. 2. Both IRL 1620 and BQ 3020, infused i.a. to the muscle preparation, evoked an initial transient dilator response followed by a moderate dose-dependent constrictor response, both being preferentially confined to the small arterioles. The dilator response was associated with a transient increase, and the constrictor response with a sustained decrease, in capillary pressure, the latter causing net transcapillary fluid absorption. The capillary filtration coefficient decreased during the constrictor response, indicating constriction of terminal arterioles/precapillary sphincters. 3. The vascular responses to the ETB-receptor agonists were unaffected by blockade of endothelium-derived nitric oxide (NG-nitro-L-arginine methyl ester) and by selective ETA-receptor blockade (FR139317). However, blockade of prostacyclin production with indomethacin decreased the amplitude of the dilator response, and decreased the time required to reach a steady-state vasoconstrictor response to the ETB-receptor agonists. 4. The effect of ETB-receptor stimulation on vascular tone was also evaluated in vitro on the cat femoral artery and vein. IRL 1620 had no effect on the femoral artery but caused a weak dose-dependent relaxation in the femoral vein. This large vein relaxation response seemed to be mediated by endothelium-derived nitric oxide and not by prostacyclin.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Szabo, Csaba, et al.
(författare)
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An amplifying effect of exogenous and neurally stored 5-hydroxytryptamine on the neurogenic contraction in rat tail artery
- 1991
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Ingår i: British Journal of Pharmacology. - 1476-5381. ; 102:2, s. 401-407
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Tidskriftsartikel (refereegranskat)abstract
- 1. The interactions between sympathetic neuroeffector transmission and 5-hydroxytryptamine (5-HT) were investigated in segments of rat isolated tail artery. 2. Contractile responses to field stimulation of the artery segments were abolished by tetrodotoxin (3 x 10(-7) M). A subthreshold concentration of acutely applied exogenous 5-HT (10(-8) M) markedly enhanced the contractions induced by sympathetic nerve stimulation, through an action on postjunctional 5-HT2-receptors. 3. The amplifying effect of 5-HT involved an enhanced influx of extracellular calcium into the smooth muscle cells. In contrast, the neurogenic contractions in vessels not exposed to 5-HT were not dependent on extracellular calcium. 4. The adrenergic component of the amplified response involved postjunctional alpha 1- but not alpha 2- adrenoceptor activation. 5. Exposure of the vessels to 5-HT (5 x 10(-7) M) for 30 min resulted in uptake of the amine into the perivascular sympathetic nerves, as demonstrated by immunohistochemistry. After chemical sympathectomy with 6-hydroxydopamine in vitro or in vivo, or surgical sympathectomy, there was little or no uptake. 6. Exposure to 5-HT followed by repeated washing resulted in an enhancement of the neurogenic contraction, which was still fully tetrodotoxin-sensitive. The enhanced response was blocked by ketanserin (10(-8) M) and prevented by the presence of the 5-HT uptake blocker, paroxetine (3 x 10(-8) M), during the period of exposure to 5-HT.
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| 5. |
- Thesleff, S, et al.
(författare)
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Tetrahydroaminoacridine (tacrine) stimulates neurosecretion at mammalian motor endplates
- 1990
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Ingår i: British Journal of Pharmacology. - 0007-1188 .- 1476-5381. ; 100:3, s. 487-490
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Tidskriftsartikel (refereegranskat)abstract
- 1. Tacrine (20 microM) induced, like 4-aminoquinoline (4-AQ, 200 microM), the appearance of a population of miniature endplate potentials (m.e.p.ps) with more than twice the normal amplitude or time-to-peak. The times-to-peak of nerve impulse-evoked endplate potentials were not similarly affected. 2. Cholinesterase inhibition by edrophonium (25 microM) did not prevent tacrine or 4-AQ from inducing this population of m.e.p.ps. 3. Nerve-muscle preparations in which the normal calcium-sensitive quantal release of acetylcholine had been blocked by botulinum neurotoxin type A also responded to tacrine by an increase in the frequency of giant or slow m.e.p.ps. 4. Reduction of the temperature from 30 degrees to 14 degrees C reduced the frequency of giant or slow m.e.p.ps induced either by tacrine or by 4-AQ. A similar effect was obtained by colchicine (5 mM). This supports the idea that proximo-distal axonal transport is required for the secretory activity. 5. The neurosecretion evoked by tacrine could explain the therapeutic effects of the drug claimed in the treatment of Alzheimer's type of dementia.
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