Christer Sjögren

Atropine Resistance of Transmurally Stimulated Isolated Human Bladder Muscle

Human detrusor strips were obtained from patients undergoing reimplantation of ureters because of reflux, transvesical prostatectomy, or cysto-urethrectomy en bloc because of bladder malignancy. The strips were electrically stimulated. A frequency-dependent contractant response was obtained that was potentiated by physostigmine and abolished by tetrodotoxin. The maximum response approximately equaled that of acetylcholine in a maximum concentration. In most bladder preparations from patients without known functional bladder disturbances, atropine (0.01 to 0.1 microM) had a marked inhibitory effect, and at concentrations exceeding 1 microM the blockade was complete. In strips obtained from patients undergoing transvesical prostatectomy, and who also had a cystometrically verified unstable bladder, there was a varying degree of atropine resistance, with some preparations showing a 50 per cent resistance to atropine. Prazosin, phentolamine, yohimbine, guanethidine, clonidine, and noradrenaline had no consistent effects on the electrically induced bladder contraction. Nifedipine and nimodipine caused a maximum of 65 per cent inhibition of the response. Addition of nimodipine to atropine-resistant strips when maximum atropine inhibition had been reached abolished the contractions. Omitting calcium from the bath solution rapidly abolished the electrically induced contraction. It is suggested that in the normal human bladder the contraction induced by electrical stimulation is mainly atropine sensitive. However, in the functionally disturbed bladder, part of the bladder contraction is atropine resistant, a finding that may have clinical implications.

Direct effects of adenosine and adenine nucleotides on isolated human urinary bladder and their influence on electrically induced contractions.

Adenosine triphosphate concentration-dependent contracted strips of isolated human urinary bladder. Three types of responses were recognized. One consisted of an initial, transient, phasic contraction followed by a sustained tonic response, another lacked the tonic part and the 3rd had intermediate-type characteristics. Adenosine diphosphate produced an intermediate type of contraction, while adenosine monophosphate, adenosine and 2-chloroadenosine had no effect. Preparations obtained from hypertrophic bladders were more sensitive to adenosine triphosphate than macroscopically normal preparations. Indomethacin abolished tonic responses and reduced phasic adenosine triphosphate and adenosine diphosphate induced responses by about 30 per cent; addition of PGE2 and PGF2 alpha reestablished the phasic responses. Atropine, physostigmine, hexamethonium and phentolamine had no effect on the adenosine triphosphate induced contractions. These contractions were reduced by 33 to 48 per cent after nifedipine pretreatment and abolished within 10 minutes in a calcium-free medium. The response to transmural nerve stimulation was initially stimulated and then reduced by 30 to 80 per cent by purines in the order of potency ATP greater than APPCP = ADP greater than AMP greater than adenosine = 2-chloroadenosine. Acetylcholine induced contractions were reduced by 10 to 30 per cent. Indomethacin inhibited the response to transmural nerve stimulation by about 30 per cent but did not influence inhibition produced by adenosine triphosphate. Atropine-resistant responses to transmural nerve stimulation were significantly reduced by both adenosine triphosphate and indomethacin; nifedipine abolished the responses. The results suggest that adenosine triphosphate has a calcium-dependent direct contractive effect on isolated human urinary bladder and also that it may release prostaglandins. Muscular hypertrophy seems to increase the sensitivity to adenosine triphosphate. The response to transmural nerve stimulation was influenced by adenosine triphosphate probably both by prejunctional and postjunctional effects.

Characterization of the α‐adrenoceptors in the female rabbit urethra

1 A radioligand binding technique was used to evaluate the proportions of α1‐ and α2‐adrenoceptors in crude membrane preparations obtained from the female rabbit bladder base and urethra. In addition, urethral rings were studied in vitro in an attempt to determine if α1‐ and/or α2‐adrenoceptors are located postjunctionally in the urethral smooth muscle. 2 Studies of the inhibition of [3H]‐dihydroergocryptine binding by the selective α1‐adrenoceptor antagonist prazosin or the selective α2‐adrenoceptor antagonist rauwolscine revealed the α‐adrenoceptor population to consist of approximately 25% α1‐adrenoceptors and 75% α2‐adrenoceptors. These proportions were confirmed in saturation studies with [3H]‐prazosin and [3H]‐rauwolscine. The sum of α1‐ and α2‐adrenoceptors labelled by these selective α1‐ and α2‐adrenoceptor antagonists was about equal to the number labelled by the non‐selective α‐adrenoceptor antagonist [3H]‐dihydroergocryptine. 3 Noradrenaline, as well as the selective α1‐adrenoceptor agonist phenylephrine and the selective α2‐adrenoceptor agonist clonidine, induced contractions of urethral ring preparations. Prazosin blocked contractions induced by phenylephrine to a greater extent than contractions induced by clonidine. The opposite was true for the inhibitory effect of rauwolscine. 4 In addition to showing that both α1‐ and α2‐adrenoceptor binding sites exist in membrane preparations of the rabbit bladder base and urethra, the results reveal the presence of both adrenoceptor subtypes postjunctionally in the rabbit urethra; and both mediate contraction of the smooth muscle.

Adrenoceptors and Cholinoceptors Controlling Noradrenaline Release from Adrenergic Nerves in the Urethra of Rabbit and Man

The possible influence of adreno- and cholinoceptors on noradrenaline release from adrenergic nerve endings in urethral smooth muscle of rabbit and man was investigated in preparations preincubated with 3H-noradrenaline. The preparations were continuously perfused in a temperature controlled ( 37C ) chamber and the amount of electrically induced efflux of 3H calculated as a fraction of the total amount of 3H in the preparation at the time of stimulation. In preparations from both rabbit and man, the fractional release of 3H induced by electrical field stimulation was reproducible, and significantly increased in the presence of the alpha 2-receptor antagonist rauwolscine and the muscarinic cholinoceptor antagonists scopolamine and atropine. There was a significant decrease of 3H-release in the presence of the alpha 2-receptor agonist clonidine and the cholinoceptor agonist carbachol. No evidence for the presence of prejunctionally located alpha 1 or nicotinic receptors was found. The results suggest the possibilities of 1) a negative feed-back regulation of the release of noradrenaline from adrenergic nerve endings in the urethra, mediated via prejunctionally located alpha 2-adrenoceptors, 2) an interaction at the nerve terminal level between adrenergic and cholinergic nerves mediated via muscarinic cholinoceptors on the adrenergic nerve terminals.

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.

Dose-Response Relationship of a Topical Nasal Decongestant: Phenylpropanolamine

By means of anterior rhinomanometry, the decongestant effect of topically applied phenylpropanolamine (PPA) was evaluated in 40 patients with nasal obstruction. A dose-response relation was obtained for 0.5, 2.5 and 5.0% PPA solution, with the maximum effect (40% decongestion) found with the 2.5% solution. The decongestant effect was comparable to that induced by physical exercise (50% decongestion). It is concluded that PPA nose-drops are effective and offer an attractive alternative to some of the commonly used nasal decongestants.

A Pharmacological in Vitro Study of the Mouse Urinary Bladder at the Time of Acute Change in Bladder Reservoir Function after Irradiation

Mouse urinary bladder strips were investigated as to whether the acute change in bladder reservoir function seen after irradiation might be due to major changes in basic nerve and smooth muscle functions. The release mechanism of acetylcholine, cholinergic and non-cholinergic nerve activation explored by indomethacin and potassium channel activation were investigated. It was concluded that the normal mouse bladder is partly cholinergically and partly non-cholinergically innervated. The role of acetylcholine is of the same importance as in other rodents. However, it was not possible to distinguish any difference between normal and irradiated mouse bladders in respect to nerve and smooth muscle function.

Occurrence of Nasal Congestion during Pregnancy

After symptom registration of 39 pregnant women and 23 nonpregnant women during several months, it was possible to conclude that nasal congestion during pregnancy occurs during the last 3 months before delivery. This symptom of pregnancy might be an underestimated problem not dependent on previous pregnancies. Nasal congestion during pregnancy does not seem to be correlated to other common inconveniences such as nausea and gastrointestinal reflux.

An Experimental Model for Long-Term Examinations of Urethral and Uterine Pressures in Conscious Dogs: Effect of a Highly Selective Compound Contracting Urethral Smooth Muscles

An experiment model was designed for studies of urethral and uterine pressures in a conscious animal, thereby avoiding the interference of anesthesia on these responses. Dogs were trained to stand in cradles for an experimental period of 3 hours, during which urethral and uterine pressures and ECG were recorded. Substances were administered either orally or intravenously. Intravenously given phenylpropanolamine (PPA; 0.3 mg./kg.) and a newly synthetized compound S113 (0.5 mg./kg. intravenously) increased the urethral pressure by about 30 and 100%, respectively. Oral administration of PPA (3.5 mg./kg.) and S113 (6 mg./kg.) increased it by about 60 and 85%, respectively. In contrast to PPA, S113 evoked no cardiac effects. Whereas PPA had pronounced effects on uterine contractility, S113 had only minor effects. Furthermore, the responses in the experiments were stable and reproducible. This dog model seems to be useful for long-term recordings of urethral and uterine pressures.

Nasal mucosal congestion after treatment with bromocriptine

Nine women were given bromocriptine a few days after delivery in order to inhibit lactation. Nasal airway resistance to airflow (NAR) was recorded and blood samples were taken before treatment with bromocriptine, 2 to 3 hours after the first dose of this drug, and after 3 to 5 days on this treatment. All the women had increased nasal congestion after bromocriptine and NAR rose significantly. The prolactin, estradiol, and progesterone hormone levels decreased significantly, but no significant difference was found in the levels of thyroid‐stimulating hormone (TSH) and vasoactive intestinal polypeptide (VIP). The bromocriptine effect may be caused by different mechanisms.