C. Sjögren

Cystometrical Evaluation of Bladder Instability in Rats with Infravesical Outflow Obstruction

Cystometries were performed in normal rats and in rats with bladder hypertrophy due to infravesical outflow obstruction. Investigations were performed in the presence and absence of anesthesia. pentobarbital anesthesia depressed spontaneous contractile activity in the bladder and the micturition reflex, thereby making measurements of other variables, such as bladder capacity and residual volume, impossible. In conscious animals infravesical outflow obstruction led to development of increased bladder capacity, marked residual volume, and unstable detrusor contractions. The model seems to be well suited for further evaluation of the mechanisms involved in the development of detrusor instability and the responses to pharmacological treatment.

Effects of Pinacidil and Cromakalim (BRL 34915) On Bladder Function in Rats with Detrusor Instability

Normal rats as well as rats with bladder hypertrophy secondary to outflow obstruction were investigated cystometrically before and after administration of the potassium channel openers pinacidil or cromakalim one mg./kg. orally. In normal rats cromakalim decreased micturition pressure by 15 +/- 6%. A diminished micturition pressure was also seen after pinacidil (by 18 +/- 8%) but this did not achieve statistical significance. Further, no clear-cut effects on bladder capacity, residual volume, basal bladder pressure, threshold pressure, bladder compliance or on bladder wall tension were seen in this group of rats neither in the presence of pinacidil nor cromakalim. Rats with bladder hypertrophy exhibited a significant bladder instability during cystometrical investigations. The mean amplitude of the spontaneous bladder contraction exceeded 20 cm. H2O prior to micturition. Administration of pinacidil and cromakalin decreased the spontaneous contractions to 26 +/- 12% and 22 +/- 7%, respectively, of that seen in the absence of the drugs. Furthermore, pinacidil decreased micturition pressure by 61 +/- 12%. Also cromakalim decreased micturition pressure (by 27 +/- 13%) but this effect did not achieve statistical significance. After both pinacidil and cromakalim these rats tended to develop residual urine. In accordance with the results in normal rats pinacidil and cromakalim showed no effects on bladder capacity, basal bladder pressure, threshold pressure, bladder compliance or on bladder wall tension in rats with bladder hypertrophy. The findings of an almost complete disappearance of spontaneous bladder contractions in rats with bladder instability and a remaining voiding ability after administration of pinacidil or cromakalim suggest that potassium channel openers may be a therapeutic alternative in the treatment of bladder instability associated with outflow obstruction.

Contents and Effects of Substance P and Vasoactive Intestinal Polypeptide in the Bladder of Rats with and without Infravesical Outflow Obstruction

The concentrations of substance P and vasoactive intestinal polypeptide (VIP) were determined in the upper, middle, and lower part of the bladder of rats with and without infravesical outflow obstruction. In the obstructed animals there was a significant increase in bladder weight and the total amounts of substance P and VIP were increased. However, the concentrations of substance P were significantly lower than in the control bladders. The concentrations of VIP, on the other hand, were significantly higher in the middle and lower parts of obstructed bladders than in the controls. In isolated strips of the normal and obstructed bladders VIP had neither contractile nor relaxant effects. The peptide had no effect on electrically induced contractions. Substance P produced concentration-dependent contractions in both normal and obstructed bladders. However, obstructed bladders were significantly less sensitive than controls. It is concluded that the bladder instability seen in rats with infravesical outflow obstruction cannot be explained only in terms of changes in the bladder content of substance P or VIP.

Contribution of prostaglandins to the adenosine triphosphate-induced contraction of rabbit urinary bladder.

1 Adenosine 5′‐triphosphate (ATP) produced an inital rapid, phasic contraction and a later, slowly developing tonic contraction in the isolated detrusor of the rabbit but mainly a rapid, phasic response in the guinea‐pig bladder. 2 Electrical field stimulation elicited only a rapid, phasic contraction in both rabbit and guinea‐pig bladders. 3 Prostaglandin synthesis inhibition by means of indomethacin and suprofen abolished the tonic response to ATP in the rabbit detrusor, leaving the phasic part of the contraction almost unaffected. The ATP‐induced contraction in guinea‐pig bladder was not influenced by indomethacin. 4 The contractile response of rabbit urinary bladder to prostaglandins F2α and E2 and to carbachol were not significantly influenced by indomethacin. The contractions induced by the prostaglandins were similar to the tonic response to ATP. 5 Tetrodotoxin, atropine, phentolamine, and theophylline did not alter the ATP‐induced contraction. However, the calcium antagonists, nifedipine and nimodipine, abolished the phasic ATP response and greatly reduced the tonic part of the contraction. 6 Tachyphylaxis occurred on repeated addition of ATP; the response to field stimulation was progressively reduced only after indomethacin pretreatment. 7 ATP and prostaglandins may contribute to the non‐adrenergic, non‐cholinergic component of the excitation of rabbit and guinea‐pig bladder.

Effects of Cromakalim (BRL 34915) and Pinacidil on Normal and Hypertrophied Rat Detrusor in Vitro

Normal and hypertrophied rat detrusor were investigated in vitro with regard to effects of the K(+)-channel openers pinacidil and cromakalim. Both drugs abolished spontaneous contractile activity and induced a relaxation of normal and hypertrophied detrusor preparations. In both types of preparation, contractions elicited by K+, carbachol or electrical field stimulation were depressed in the presence of the K(+)-channel openers. Responses induced by K+ or electrical stimulation were more reduced in the hypertrophied than in the normal detrusor. Both K(+)-channel openers increased the efflux of 86Rb+ in a concentration-dependent way and this increase was similar in normal and hypertrophied detrusor. If applicable to man, this data suggest that K(+)-channel openers may be effective in the treatment of bladder instability secondary to outflow obstruction.

Increases in Blood Flow of the Female Rabbit Urethra Following Low Dose Estrogens

The effects of low doses (0.05 to 20 micrograms./kg.) of estradiol-17 beta (E2) and estriol (E3) on blood perfusion in the genitourinary tissues were examined two and 24 hours after an intra-arterial injection into rabbits. Whereas 0.05 microgram./kg. E2 or E3 caused no detectable change, 0.5 microgram./kg. of either E2 or E3 markedly increased blood flow measured after two hours in urethra, vagina and uterus. No significant increase in the blood flow in the urinary bladder or the ureters was observed. With 20 micrograms./kg. E2 or E3 a much greater increase (10 to 25-fold) in the blood flow in the urethra, vagina and uterus was observed after two hours. At this time a small increase (about two-fold) could also be measured in urinary bladder and ureters. Twenty-four hours after this treatment (20 micrograms./kg. E2 or E3), the blood flow in the urinary organs was not significantly different from the pretreatment values but it was still significantly elevated in uterus and vagina. These data show that the blood flow in the female urethra is just as sensitive to low doses of estrogens as uterus and vagina. Both E2 and E3 seem to be equally effective in increasing blood perfusion in the urogenital tissues.

Supersensitivity to carbachol in the parasympathetically decentralized feline urinary bladder.

We investigated the concentration-response relations for carbachol, the morphological characteristics and the mechanical properties of feline detrusor strips from 1) normal cats, cats subjected to 2) parasympathetic sacral decentralization, 3) urinary diversion followed by parasympathetic sacral decentralization and 4) urinary diversion only. Hypertrophy of the detrusor and supersensitivity to carbachol (a decrease of EC50) were found only after parasympathetic decentralization. No hypertrophy developed and no change in the EC50-value for carbachol was found if urinary diversion preceded the parasympathetic decentralization. A decreased ability of force production per unit cross sectional smooth muscle area was found in the decentralized bladders compared to the controls. However, the total ability of force production and hence also pressure production of the decentralized bladders would be expected to be enhanced due to a 4 to 5-fold increase of bladder weight (mainly muscle mass). No differences in the active length-tension relations were found in the 4 groups. It is suggested that parasympathetic decentralization per se does not give rise to detrusor hypertrophy or increased sensitivity to carbachol. Provided that the situation in man is comparable to that in the cat, it might be that the supersensitivity test a.m. Lapides-Glahn reflects the presence of detrusor hypertrophy rather than the presence of a neurogenic lesion.

Effects of pinacidil on bladder muscle.

SummaryInfravesical outflow obstruction and bladder hypertrophy are often associated with bladder hyperactivity causing frequency, urge and urinary incontinence. This hyperactivity may be due to a supersensitivity to depolarising stimuli. Drugs that inhibit smooth muscle activity by opening K+channels, resulting in hyperpolarisation, would therefore seem to be an attractive therapeutic principle. Pinacidil is an effective vasodilator classified as a K+channel opener. The drug has been shown to effectively depress spontaneous contractile activity, the contractions induced by low (< 40 mmol/L) concentrations of K+, carbachol and by electrical stimulation of nerves in isolated normal human bladder tissue and also in normal and hypertrophied rat bladder. The effect was more pronounced in hypertrophied detrusor. Pinacidil in concentrations inhibiting muscle activity also increased the efflux of86Rb in bladder tissue. In vivo pinacidil suppressed spontaneous contractile activity in rats with infravesical bladder obstruction and detrusor hypertrophy. The findings make K+channel openers an interesting, potentially useful therapeutic principle in hyperactivity associated with bladder hypertrophy.

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.