Lack of evidence for adrenergic innervation of the external urethral sphincter

Catecholamine histofluorescence studies of the external urethral sphincter in 11 normal dogs, 4 dogs treated with tranylcypromine and 4 humans have demonstrated that this striated muscle does not possess adrenergic innervation. This finding suggests that the sympathetic nervous system affects outlet resistance only through its influence on the smooth musculature of the bladder neck and urethra.     

Adrenergic innervation of the striated muscle of the intrinsic external urethral sphincter from patients with lower motor spinal cord lesion

The adrenergic innervation of smooth and striated muscle components of the intrinsic external urethral sphincter from patients with suprasacral lesions and detrusor-sphincter dyssynergia has been described previously, when no adrenergic nerves were found associated with striated muscle fibers. In our study the intrinsic external urethral sphincter from patients with lower motor neuron lesions and detrusor areflexia was studied histochemically using the glyoxylic acid method to visualize catecholamines. Varicose adrenergic nerves were demonstrated in the smooth muscle. Adrenergic nerve fibers also were found along the edge of individual striated muscle fibers as well as around striated muscle bundles. Blood vessels in both regions of the urethral sphincter were innervated by adrenergic nerves. We conclude that in patients with lower motor neuron lesions and detrusor areflexia there is a substantial invasion by adrenergic nerve fibers in relation to smooth and striated muscle in the urethra, although the function of the nerve fibers is not known.     

Mechanical properties and innervation of the smooth muscle layers of the urethra of greyhounds

OBJECTIVE: To investigate the properties of the smooth muscle layers in the urethral wall of male and female greyhounds, and to consider their roles in continence and micturition. MATERIALS AND METHODS: The distribution and innervation of the smooth muscle layers of the prostate capsule and membranous urethra of male greyhounds were assessed. Strips of smooth muscle from these regions were used to determine the neuropharmacological properties by assessing the excitatory and inhibitory responses to nerve stimulation, and the effects of blocking agents. These were compared with strips from the proximal urethra and from the female urethra. RESULTS: The smooth muscle of the membranous urethra comprised 9% of the wall and received its innervation exclusively in branches from the pelvic plexus. The cholinergic innervation in the male produced 80% of the total contractile response in the longitudinal membranous urethra, 50% in the prostate capsule and 13% in the circular muscle of the proximal urethra. In the female all areas had poor contractile responses. Inhibitory fibres produced relaxation in all parts of male and female urethrae with the major effect caused by nitric oxide. Adrenergic nerves contributed to both residual excitation (alpha receptors) and inhibition (beta receptors). CONCLUSIONS: The longitudinal smooth muscle of the male membranous urethra probably shortens the urethra during micturition, through the activity of cholinergic nerves, whereas the circular smooth muscle of the proximal urethra, under adrenergic control, may be contracted during continence and ejaculation. In the female, the smooth muscle plays a minor role.     

Vesicourethral smooth muscle: Function and relation to structure

The effects of acetylcholine and norepinephrine on the longitudinal and circular smooth muscle strips from the rabbit bladder body, bladder base, and proximal urethra have been studied and compared. Based on the functional responses that were obtained, it was concluded that the vesicourethral structure can consist of three muscular systems. One system consists o the acetyl-choline sensitive detrusor, the deep bladder base, and the longitudinal smooth muscle layer of the urethra. The second muscle system comprises the norepinephrine-sensitive detrusor muscle, the superficial bladder base, the bladder neck, and part of the longitudinal urethral smooth muscle. The third muscle system is the circular urethral musculature, unrelated to the detrusor circular muscle.     

Spinal cord lesions at different levels affect either the adrenergic or vasoactive intestinal polypeptide-immunoreactive nerves in the human urethra

The urethras from 1 patient with cervical (C1-2) and 2 patients with thoracic (T10) spinal cord lesions were studied histochemically and immunohistochemically for adrenergic and vasoactive intestinal polypeptide-immunoreactive nerves. Dense vasoactive intestinal polypeptide-immunoreactive but not adrenergic nerves were found in the urethral smooth muscle, around the blood vessels and at the base of the mucosa in the patients with thoracic lesions. In contrast, adrenergic but not vasoactive intestinal polypeptide-immunoreactive nerves were found associated with the smooth muscle of the urethra and around the blood vessels in the patient with a cervical lesion. In patients with cervical or thoracic lesions neither adrenergic nor vasoactive intestinal polypeptide-immunoreactive nerves were found around striated muscle fibers of the intrinsic external urethral sphincter. The results are discussed in relation to the possible function of these nerves in the urethra of patients with autonomic dysreflexia and detrusor-sphincter dyssynergia.     

Contractant and relaxant properties of the female rabbit urethral submucosa

Isolated submucosal (lamina propria) preparations from the female rabbit urethra exhibited both contractant and relaxant properties. The nerve-mediated contraction to electrical field stimulation was adrenergic in nature, and both this response and the contraction induced by exogenous application of noradrenaline were blocked to a greater extent by alpha 2 than by alpha 1-adrenoceptor blocking agents. Vasoactive intestinal polypeptide was found to be a potent inhibitor of the noradrenaline-mediated contraction. Neuropeptide Y induced contraction of the preparation, but also inhibited the nerve-mediated contractant response. In noradrenaline-contracted preparations, electrical field stimulation induced a non-adrenergic, non-cholinergic relaxation. The maximum relaxant response was significantly greater when the preparations were contracted by clonidine than by noradrenaline. Abundant smooth muscle cells with no obvious connection to vessel walls were found in the submucosa, but to what extent the contractant and relaxant responses can be ascribed to vascular or non-vascular smooth muscle is not settled. The results indicate a non-uniform distribution of the peripheral nervous control within the wall of the female rabbit urethra. The demonstrated contractant and relaxant properties of the submucosal tissue might be of importance for urethral function.     

Direct effect of amezinium on rabbit urethra: Effect of estrogen and progesterone treatment

The effect of amezinium, a new antihypotensive agent, and hormonal treatment on the female rabbit urethra was investigated. Cumulative dose responses were obtained for amezinium and norepinephrine on strips of muscle from the urethras of ovariectomized female rabbits by means of the tissuebath system. Amezinium enhanced the response to electrical field stimulation and showed a direct contractile response on the urethra. These responses were only about 20% of the maximum norepinephrine response. The contractile response to amezinium was completely blocked by prazosin. When rabbits were pretreated with estrogen, with or without progesterone, for 4 weeks, the response to amezinium increased to 40% of the maximum norepinephrine response. Although amezinium enhances muscle contractile responses to electrical stimulation, this effect is strong when amezinium is used alone; concurrent estrogen treatment improves the effects of amezinium.EDITORIAL COMMENT The authors present their initial investigation on the effect of amezinium on the tone of female rabbit urethral muscle. The study is well designed, using classical experimental methodology. The investigators show that amezinium has a moderate contractile effect on female rabbit urethral muscle strips. This effect is blocked by the addition of prazosin, a direct adrenergic antagonist, resulting in urethral muscular relaxation. The effect of amezinium is enhanced by pretreatment with estrogen, either alone or in combination with progesterone. Pretreatment with progesterone has no significant impact on the urethral muscular contraction caused by amezinium. Amezinium has been used in human studies for the treatment of hypotension, and appears to be well tolerated. Only further extensive investigation will show whether this interesting compound has clinical use in the treatment of female genuine stress urinary incontinence.     

Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence

This review discusses the control of the urethra by the central nervous system, emphasizing the importance of nervous system control and the role of serotonin and noradrenaline in storage, micturition and sphincter reflexes. The concept of pharmacological neuromodulation and the use of pharmacological therapy as first-line therapy for stress urinary incontinence (SUI) is presented. Coordination between the urinary bladder and urethra is mediated by many reflex pathways organized in the brain and spinal cord. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes depend on interneuronal circuitry in the spinal cord and are modulated by descending pathways. It would therefore seem that neurotransmission in the central nervous system and periphery may be important in SUI, and moreover that pharmacological agents affecting these neurotransmitter pathways may be used to treat SUI. The central and peripheral mechanisms of action of duloxetine affect serotonin and noradrenaline neurotransmission in ways that may ameliorate the symptoms of SUI.     

Effects of vasoactive intestinal polypeptide on isolated urethral and urinary bladder smooth muscle from rabbit and man

Vasoactive intestinal polypeptide concentration-dependently inhibited the contractant responses of isolated preparations of the female rabbit bladder and urethra induced by electrical field stimulation and exogenous application of acetylcholine (bladder) and noradrenaline (urethra). The inhibition of alpha-adrenoceptor and muscarinic cholinoceptor-mediated activity in the urethra and bladder amounted to 50 to 90 per cent of induced contractions. The nonadrenergic noncholinergic contraction induced by electrical field stimulation in the urethra was reduced slightly, whereas corresponding response in the bladder was more sensitive. The maximum inhibition of both the electrically induced responses and contractions induced by exogenous noradrenaline and acetylcholine was of comparable size in the urethra and the bladder. The effects of vasoactive intestinal polypeptide seemed to be exerted postjunctionally since no significant influence of the peptide was seen on the release of 3H-noradrenaline from adrenergic nerve endings in the urethra. The effects of vasoactive intestinal polypeptide in human urethral and bladder preparations were less consistent. The noradrenaline-induced contraction in urethral preparations was inhibited by 29 +/- 9 per cent (no. = 22). The effects on electrically induced contractions in the urethra, and on responses to acetylcholine and electrical field stimulation in the bladder, were small and inconsistent. It is concluded that vasoactive intestinal polypeptide may be of importance for regulation of lower urinary tract smooth muscle activity in the rabbit. It cannot be excluded that the peptide has a modulatory role in neurotransmission in human urethral muscle. However, the present results do not support the view of vasoactive intestinal polypeptide as an inhibitor of contraction in human detrusor.     

Effect of the Bowman-Birk inhibitor (a soy protein) on in vitro bladder neck/urethral and penile corporal smooth muscle activity

AIMS: The Bowman-Birk inhibitor (BBI), is a serine protease inhibitor derived from soy beans, which is presently being evaluated in clinical trials for its ability to serve as a cancer preventive or anti-inflammatory agent. The form of BBI currently in clinical trials is known as Bowman-Birk inhibitor concentrate (BBIC). There have been anecdotal reports from patients of improved voiding and sexual functions in the ongoing BBIC trials. The objective of this study was to quantify the effect of BBI and BBIC on urethral and corporal smooth muscle activity. METHODS: In vitro muscle strip studies of New Zealand White rabbit urethra/bladder neck and penile corpora in the presence or absence of BBI or BBIC incubation (5 mg/mL) were performed. RESULTS: In dose-response curves to alpha stimulation, BBI mediated a shift to the right (decreased receptor sensitivity in bladder/urethra as well as corpora with no change in the maximal response). Bladder base/ urethra contraction by field stimulation was significantly inhibited by BBI at higher frequencies (1-32 Hz) (12.2 + 0.8 g vs. 6.3 + 0.75 g, P < 0.05). BBI inhibited field stimulated relaxation of corporal muscle at lower frequencies. Muscarinic contraction of the bladder neck/urethra in alpha prestimulated tissue was significantly inhibited by BBI (5.3 + 0.2 g vs. 2.7 + 0.1 g, P < 0.05). BBI has an inhibitory effect on alpha adrenergic dose-response curves in bladder neck/urethral and corpora smooth muscle. BBI also significantly inhibited neurohumoral cholinergic release and in vitro muscarinic contraction of the urethra. The effects on corpora relaxation were less pronounced. CONCLUSIONS: The data suggest that the phytochemical BBI may promote physiologic effects of urethral relaxation and improved voiding by unique mechanisms and deserves further study as a pharmacologic agent for lower urinary tract symptoms.     

Roles of prostaglandin on rabbit vesicourethral smooth muscle contraction]

The effects of prostaglandin (PG) E1, E2 and F2 alpha on isolated smooth muscles of rabbit bladder and urethra were studied by in vitro techniques for recording contractile activities. To examine the mechanism of PGs' effect, intracellular cyclic AMP content was also measured by radioimmunoassay. Spontaneous contractile force of muscle strips isolated from rabbit urinary bladder dome and base was increased dose-dependently by administration of PGE1, E2 or F2 alpha. Isolated muscle strips from bladder dome responded to PG more markedly than those from bladder base. The rank order of potency to induce contractile responses was PGF2 alpha greater than PGE2 greater than PGE1 in both dome and base muscles. Spontaneous contractile force of muscle strips isolated from rabbit urethra was increased dose-dependently by administration of PGF2 alpha, and, in contrast, was decreased dose-dependently by PGE1 or E2. These effects were not affected by pretreatment with atropine, phentolamine, propranolol and tetrodotoxin, but were significantly inhibited by pretreatment with verapamil, a Ca-antagonist. Cyclic AMP accumulation in urethral muscle strips significantly increased after administration of PGE1. These results demonstrated that contractile response of rabbit bladder smooth muscle to PG was mainly induced by Ca2+ influx and that cyclic AMP was related to the relaxation of rabbit urethral smooth muscle by PGE1.     

Response of urethral smooth muscles to pharmacological agents. II. Noncholinergic, nonadrenergic agonists and antagonists

We studied the effects of a variety of noncholinergic, nonadrenergic agents on the smooth muscles of the cat urethra. Prostaglandin F2 alpha contracted both urethral muscle layers to a similar extent. Prostaglandin E2 contracted the longitudinal and relaxed the circular muscle layers. The effects of the prostaglandins seem to be directly myogenic since cholinergic and adrenergic blockers and tetrodotoxin did not affect them. Bradykinin and substance P contracted both urethral muscle layers. Other tested agonists (neurotensin, vasoactive intestinal peptide, cyclic 3,5 adenosine monophosphate, adenosine diphosphate sodium, cyclic 3,5 guanosine monophosphate sodium, bombesin) had no effect on the cat urethral smooth muscles.     

Alterations in the nitric oxide synthase binding sites and non-adrenergic, non-cholinergic mediated smooth muscle relaxation in the diabetic rabbit bladder outlet: possible relevance to the pathogenesis of diabetic cystopathy.

PURPOSE: To investigate the effect of diabetes mellitus (DM) on the density and distribution of nitric oxide synthase (NOS) and the smooth muscle responses to non-adrenergic, non-cholinergic (NANC) nerve stimulation and exogenous nitric oxide (NO) in the rabbit lower urinary tract. MATERIALS AND METHODS: Transverse sections of detrusor, bladder neck and urethra, from control and six months alloxan-induced DM New Zealand White rabbits were incubated with a radioligand for NOS ([3H]-L-N(G)-nitroarginine). Densitometric analysis was performed on the autoradiographs. NADPH diaphorase histochemistry was also used as a marker for NOS activity. Responses to NANC nerve stimulation (5 to 20 Hz) and to NO (10(-6) to 3x10(-4) M.) on smooth muscle strips from detrusor, bladder neck and urethra were measured in organ baths. RESULTS: NOS binding sites were significantly (p<0.03) more dense in the bladder neck than in the detrusor in both DM and control groups. In DM bladder neck, NOS binding sites were significantly (p<0.04) increased compared with the controls. NADPH diaphorase activity appeared markedly increased in the detrusor, bladder neck and urethra of DM animals compared with controls. The mean IC50 for exogenous NO in control versus DM were not statistically different in the bladder neck (1.03x10(-4) M versus 9.8x10(-5) M) and urethra (8.1x10(-5) M versus 8.8x10(-5) M), but the relaxations to 5x10(-6) M of NO were significantly impaired (p<0.04) in the DM urethral smooth muscle. NANC nerve-mediated relaxations were significantly impaired (p<0.001) in the DM urethral smooth muscle. CONCLUSIONS: Alterations of both the NOS binding sites and functional responses to NANC nerve stimulation suggest that NO may have a pathophysiological role in the urinary bladder dysfunction associated with DM.     

The effect of alpha-adrenergic stimulation in stress incontinence.

The urethra is innervated by adrenergic fibres and its smooth muscle is equipped mainly with alpha-adrenoreceptors. Norephedrine chloride, which is an alpha-stimulating agent, has been proposed as therapy for stress incontinence, since it was shown to increase the maximum urethral pressure at rest. For further study of the effect of norephedrine chloride on the urethal closure pressure at rest and in a dynamic situation, we examined ten severely stress-incontinent women before and after three weeks of treatment with this agent (100 mg by mouth twice daily). The urethral closure pressure at rest, between coughs of varied strength and at the precise moment of stress were recorded. The margin to leakage, the tone of the urethral wall and the transmission of pressure from abdomen to urethra were also among the estimated factors. No improvement was found in any of these respects. Alpha stimulation in this form therefore seems ineffective in severe stress incontinence and is not an alternative to surgical treatment.     

Histochemical and contractile properties of striated muscles of urethra and levator ani of dogs and sheep

AIMS: To understand their possible importance in long- and short-term control of continence, some properties of the striated muscles of the urethra and pelvic floor (levator ani) of dogs and sheep were investigated, especially fiber types and contractile characteristics. MATERIALS AND METHODS: Striated muscles of urethra and levator ani of 29 male and 6 female dogs and 11 male and 6 female sheep were removed and cut into strips. Some strips were frozen and stained for ATPase at pH 9.4 and 4.3 for fiber typing; others were set up in an organ bath to study contractile responses to nerve stimulation. RESULTS: All muscles contained both type I (slow) and type II fibers, ranging from 97% type II in female greyhound urethra to 60% in female sheep levator ani. For each muscle, there were fewer type II muscles in sheep than in dog. The diameters of the urethral fibers were about 60% of the levator ani in dogs and 34% in sheep. Contraction of the urethral muscle was faster than for levator ani and declined to about 80% of the peak, 500 msec after the beginning of stimulation at 20 Hz. The levator ani contraction rose to a steady level as long as stimulation continued. CONCLUSIONS: Both the levator ani and urethral striated muscles contain slow and fast fiber types. The levator ani muscles are capable of sustained contraction with rapid onset which will produce long-term closure of the urethra. The circular urethral muscle contraction was faster but less well maintained.     

Carbon monoxide relaxes the female pig urethra as effectively as nitric oxide in the presence of YC-1

PURPOSE: Nitric oxide (NO) and carbon monoxide (CO) have been suggested to relax smooth muscle by activating soluble guanylate cyclase (sGC), binding to the same site of the enzyme. 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) (Cayman Co., Malm?, Sweden) increases the catalytic rate of sGC by binding to an allosteric site. We investigated whether YC-1 can modulate the relaxant responses of isolated urethral smooth muscle to exogenous CO, (NO) and electrical field stimulation. MATERIALS AND METHODS: In spontaneously active and noradrenaline (Sigma-Aldrich Chemie GmbH, Steinheim, Germany) pre-contracted preparations of circular urethral smooth muscle from female pigs relaxant responses were evoked by electrical field stimulation before and after incubation with 10(-5) M. YC-1. The concentration-response curves for CO and NO were investigated in noradrenaline pre-contracted strips before and after incubation with YC-1. The tissue contents of cyclic 3',5'-guanosine monophosphate (cGMP) and cyclic adenosine monophosphate after electrical field stimulation, and the administration of CO or NO was investigated in the absence and presence of YC-1. RESULTS: YC-1 significantly increased the amplitude of the relaxations evoked by electrical field stimulation, CO and NO, and simultaneously caused significant increases in the cGMP content in all preparations. The effect on CO induced relaxant responses was conspicuous. In the presence of YC-1 the potency and maximal relaxant effect of CO were similar to those of NO in the absence of YC-1. CONCLUSIONS: YC-1 enhances cGMP dependent relaxant responses of the female pig urethra in vitro. The finding that the response to CO was greatly increased after sensitizing sGC suggests a potential for CO as a relaxant mediator in urethral smooth muscle.     

Nerve-mediated functions in the circular and longitudinal muscle layers of the proximal female rabbit urethra

In the present study, nerve mediated functions in the circular and longitudinal muscle layers of the female rabbit urethra were characterized. Based on light microscopic findings, the interest was focused on the proximal third of the organ. A microsurgical dissection technique was developed, allowing separation of the two muscle layers. The following studies were carried out: functional in vitro investigations including exogenous application of drugs and electrical field stimulation, investigations of the release of 3H-noradrenaline (NA), and autoradiography for visualization of muscarinic receptors. The results can be summarized as follows: the adrenergic nervous influence, which was mediated mainly via alpha 1-adrenoceptors, dominated the contractile response of the circular layer and contributed significantly to the contraction of the longitudinal layer. A previously described fast, non-adrenergic, non-cholinergic response was found in the circular muscle layer. This response should probably be ascribed to striated muscle with a different innervation and/or structure than skeletal muscle in general. Muscarinic cholinoceptors were abundant in the outer parts of the urethral wall and decreased in density in luminal direction. A significant cholinergic contractile component was demonstrated in the longitudinal muscle. A non-adrenergic, non-cholinergic nerve-mediated relaxant response was found in both layers, although more pronounced in the circular one. Vasoactive intestinal polypeptide completely relaxed both circular and longitudinal preparations contracted by noradrenaline. A possible basis for an interaction between adrenergic and cholinergic nerve endings was demonstrated in the circular muscle layer. Stimulation of muscarinic receptors on the adrenergic nerve endings markedly reduced the release of 3H-NA. The present results support the findings in previous studies on circularly and longitudinally oriented full-thickness preparations of the female urethra and further underline the differences in structure, innervation and receptor functions between the different muscle layers of the urethral wall.     

Urethral responses to autonomic nerve stimulation.

Urethral contraction in response to cholinergic stimulation has been repeatedly proved and is a universally accepted fact. The adrenergic response is still disputed: (1) Is it a contraction or a relaxation, or a combination of both? (2) Where are the adrenergic receptors? Are they on the intrinsic urethral smooth muscles (with a biphasic response); in two different structures of the same organ (urethral and vascular smooth muscles); or on two anatomically different urethral smooth muscular units? Sympathomimetic and hypogastric nerve stimulation alone, as well as with pharmacologic blockade, showed that the contraction response to adrenergics is independent of the pelvic nerve and does persist even after urethral smooth muscle blockade by atropine, but is abolished after alpha blockade by phentolamine. The same contraction response, manifested in rise in intraurethral pressure, can be induced by pure vasoconstrictors. The relaxation response is reduced by beta blockade. Whether it is the direct response of a specific urethral group of musculature to sympathetic stimulation or an indirect urethral response to trigonal activity in answer to the same stimulus is discussed.     

Excitatory effect of propiverine hydrochloride on urethral activity in rats

Objectives: To investigate the effects of the antimuscarinic agent, propiverine, on the bladder and urethra in rats. Methods: A total of 54 female rats were given propiverine, imidafenacin (an antimuscarinic agent), or distilled water by gavage once or twice daily. After 2 weeks, bladder and urethral activity were recorded under urethane anesthesia. In the propiverine group, the changes of bladder and urethral activity before and after intravenous injection of α₁‐adrenergic antagonists (prazosin, silodosin and naftopidil) were also recorded. Furthermore, the leak point pressure after electrical stimulation of abdominal wall muscles was measured in rats with vaginal distension from the control and propiverine groups. Results: Intravesical baseline pressure was significantly lower in the propiverine and imidafenacin groups compared with the control group, whereas the urethral baseline pressure was significantly higher in the propiverine group compared with the control or imidafenacin groups. Intravenous injection of prazosin (an α₁‐receptor antagonist) significantly decreased the urethral baseline pressure in both of the propiverine and control groups. Intravenous injection of silodosin and naftopidil (α_1A‐ and α_1D‐receptor antagonists, respectively) significantly decreased the maximum contraction pressure and the urethral baseline pressure in the propiverine group. The leak point pressure of the propiverine group was significantly higher than that of the control group. Conclusions: An increase of catecholamines after propiverine administration might activate smooth muscle of the proximal urethra via α_1A‐ and α_1D‐adrenergic receptors, as well as activating urethral and pelvic floor striated muscle via the spinal motoneurons.     

Adrenergic and non-adrenergic contraction of isolated urethral muscle from rabbit and man

Isolated urethral muscle from rabbit and man was subjected to electrical field stimulation and the components of the resulting contraction were analyzed. Contraction usually consisted of 2 main components. One was rapidly developing, non-adrenergic and atropine-resistant. The other developed more slowly and was sensitive to alpha-adrenoceptor blockade and to chemical sympathectomy with 6-hydroxydopamine. By lowering the temperature from 37C to 20C, these contraction components could be separated from each other. Both could be blocked by tetrodotoxin but the effects of this drug were not consistent in human tissue. Characteristic for the initial contraction component was its dependence on the tension of the preparation; it increased with increasing tension. The adrenergic part of the contraction could be effectively blocked by phentolamine and prazosin, whereas rauwolscine was less effective. Atropine and scopolamine also inhibited the adrenergic part of the contraction, whereas acetylcholine caused a transient increase. The non-adrenergic contraction component was less sensitive to deprivation of extracellular Ca2+ than the adrenergic; almost 40 per cent remained after exposure to Ca2+ free solution for 40 min., whereas the adrenergic component disappeared after 20 min. exposure. Light and electron microscopic investigation revealed 3 distinct layers of the rabbit urethral wall, 1 outer consisting of smooth and striated muscle, 1 middle consisting of smooth muscle only, and a submucosal layer where vessels and smooth muscle cells were found. Removal of the longitudinal muscle layer did not change the responses to electrical stimulation. The results suggest that the electrically induced adrenergic activation of urethral muscle of both rabbit and man was mediated mainly via alpha-adrenoceptors and that this muscle is innervated not only by sympathetic, adrenergic nerves but also by a type of nerve able to release a non-cholinergic, contraction-mediating transmitter.