Effects of inhibition of the l-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro
On leave from Shinshu University School of Medicine, Matsumoto, Japan.
Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden
- 1The 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 conscious rats and in vitro, in isolated muscle preparations from the rat detrusor and urethra.
- 2l-NG-nitro arginine methyl ester (l-NAME), 10 and 20 mg kg−1, administered intra-arterially, decreased micturition volume and bladder capacity, and increased spontaneous bladder contractions. d-NAME (20 mg kg−1) had no effect. No changes in the urodynamic parameters were recorded if l-NAME (20 mg kg−1) was administered in combination with l-arginine (200 mg kg−1).
- 3Cystometries performed after intra-arterial administration of sodium nitroprusside (SNP) (3 mg kg−1) and 3-morpholino-sydnonimin hydrochloride (SIN-1, 2 mg kg−1) showed a decrease in bladder capacity, micturition volume and threshold pressure. SIN-1, but not SNP, induced spontaneous bladder contractions.
- 4Isolated precontracted urethral preparations responded to electrical stimulation with a frequency-dependent tetrodotoxin-sensitive relaxation. l-NAME (10−4 m), but not d-NAME, reduced the maximal relaxation to 31 ± 8% (n = 8) of the response prior to drug administration. The inhibition induced by l-NAME was completely reversed by l-arginine (10−3 m). SNP (10−8−10−4 m), SIN-1 (10−6−3 × 10−4 m) and NO (10−5−10−3 m; present in acidified solution of NaNO2), caused relaxation (93–100%) of urethral preparations. l-NAME did not affect these relaxations.
- 5Detrusor strips contracted by carbachol or K+ showed contractions in response to electrical stimulation, even when pretreated with α,β-methylene ATP and/or atropine. Small relaxations (14–41%) of detrusor strips were evoked by SNP (10−6−10−4 m), SIN-1 (10−5−3 × 10−4 m) and NO (10−5−10−3 m). Electrically (20 Hz) induced contractions of the detrusor muscle were unaffected by addition of l-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 the bladder outlet region, but that its role in the detrusor is questionable. They also suggest that the site of action of l-NAME for inducing bladder hyperactivity in the rat is the outlet region rather than the detrusor muscle.