A pharmacological and histochemical study of hamster urethra and the role of urothelium

Abstract

1 Electrical field stimulation (EFS) of circular strips of hamster proximal urethra caused frequency-dependent relaxations at raised tone. Phentolamine (10-6 M), propranolol (10-6 M) and atropine (10-6 M) were present throughout the experiment. Neurogenic relaxation was attenuated by L-NG_ nitroarginine methyl ester (L-NAME) (10-' M), was restored by L-arginine (3 x l0-3 M) but not by D-arginine (3 x 10-3 M) and completely blocked by tetrodotoxin (10-6 M). Neurogenic relaxation was also reduced by suramin (l0-' M) and totally blocked by suramin together with L-NAME. Strips of hamster urethra devoid of urothelium showed little, if any, relaxant response to EFS. 2 An immunohistochemical study showed nitric oxide synthase-immunoreactive nerves in the smooth muscle layers and in the lamina propria, just beneath the urothelium, but no nitric oxide synthase (NOS) staining in the urothelial layer. 3 Noradrenaline elicited a significantly greater contraction in strips without urothelium than in control strips. L-NAME (10-' M) did not affect noradrenaline-induced contraction in both control and urothelium-free strips. The contractile response to acetylcholine was not dependent on the presence or absence of urothelium. Nevertheless the response induced by exogenous acetylcholine (10-3 M) was increased by L-NAME (10-' M), both in intact and in urothelium-free strips. 4 Prostaglandin E2 (10-8 5 x 10-6 M) and 2-methyl-thio-ATP (10-9-I0-5 M) relaxed proximal urethra. Suramin (10-4 M) significantly inhibited the relaxation induced by 2-methyl-thio-ATP. The amplitude of these responses was not significantly different between intact and urothelium-free strips and was not blocked by L-NAME (10-4 M). 5 These results suggest that nitric oxide (NO) is the principal transmitter involved in the non-adrenergic, non-cholinergic (NANC) relaxation of hamster proximal urethra possibly together with another inhibitory transmitter released from nerves. NO can be released from nerves located in the circular smooth muscle layer and in the lamina propria rather than in the urothelium. The reduced neurogenic relaxation in urothelium-free preparations suggests that a NO-dependent inhibitory factor is released from the urothelium. In addition, ATP and prostaglandin E2 may be involved, together with NO, in the urethra during micturition.

The Nitric Oxide Synthase/ Nitric Oxide and Heme Oxygenase/ Carbon Monoxide Pathways in the Human Ureter

“…Possibly, NO release may be initiated by stretching of the ureter, produced by boluses of urine. Such a mechanism would be in agreement with observations by Pinna et al [27], who showed that NO-dependent relaxation of hamster urethral muscle strips was dependent upon an intact urothelium.…”

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

“…PGE 1 , PGE 2 , and PGF 2␣ all contract detrusor muscle, but in the urethra, PGE 1 and PGE 2 cause relaxation, whereas PGF 2␣ produces contraction (Andersson, 1993). This pattern of effects has been demonstrated in animal (Persson and Andersson, 1976;Khanna et al, 1978;Gotoh et al, 1986;Morita et al, 1994;Pinna et al, 1996), as well as human urethral smooth muscle (Andersson et al, 1978a). In women receiving PGE 2 intravesically or intraurethrally, a decrease in the maximum urethral pressure and a reduction of the closure pressure were found (Andersson et al, 1978a;Schussler, 1990).…”

Purinergic signalling in the urinary tract in health and disease

“…The principal NANC inhibitory transmitter is now clearly established, namely, NO [26,214,258,283,414,563,655,674]. However, a small component of purinergic neurotransmission may also be involved [24,561,563]. ATP has been shown to cause urethral relaxation, perhaps via P2Y 1 receptors, in pigs [719], guinea-pigs [124], rabbits [533] and hamsters [559].…”

“…Amongst compounds which cause relaxation, the putative transmitter was claimed not to be VIP, ATP, 5-HT or adenosine, because blockade of these responses by pharmacological manipulation did not produce a parallel effect on the neurogenic response [282,295,377,720]. The principal NANC inhibitory transmitter is now clearly established, namely, NO [26,214,258,283,414,563,655,674]. However, a small component of purinergic neurotransmission may also be involved [24,561,563].…”