Rapid effects of estrogen and progesterone on tone and spontaneous rhythmic contractions of the rabbit bladder

Previous studies indicate that bladder instability in man may be associated with increased spontaneous rhythmic contractile activity. Ca²⁺ influx plays a central role in smooth muscle contractions, and recent evidence suggests that steroid hormones rapidly affect Ca²⁺ influx. Therefore we tested the hypothesis that estrogen and progesterone modulates spontaneous rhythmic detrusor contractions. Tissues were secured to isometric force (F) transducers in tissue baths and length-adjusted until K⁺-depolarization produced maximum contractions (F_o). Spontaneous rhythmic contractions (SRC) were sampled before and immediately after addition of estradiol or progesterone (10⁻⁵ M) to tissue baths. The average frequency and amplitude of SRC were, respectively, 0.156 Hz and 0.053 F/F_o (n = 24). Estradiol caused an immediate reduction in SRC, such that by 10 min, tone, frequency and amplitude were each reduced by, respectively, 36%, 46% and 47% (n = 7, P < 0.05). However, progesterone caused an immediate weak contraction, and at steady state (10 min), progesterone increased frequency of SRC by 152% but decreased SRC amplitude by 50% (n = 10, P < 0.05). Novel therapies using unique steroids that do not interact with genomic receptors may potentially reduce bladder smooth muscle activity, thereby reducing detrusor instability. Received: 3 December 1998 / Accepted: 4 March 1999     

Time-dependent up-regulation of neuronal 5-hydroxytryptamine binding sites in the detrusor of a rabbit model of partial bladder outlet obstruction

Serotonin (5-hydroxytryptamine; 5-HT), a vasoactive bioamine with potent contractile activity, is thought to act indirectly in the urinary bladder by the stimulation of its presynaptic receptors. This results in the release of acetylcholine (ACh), which then acts on muscarinic receptors to produce bladder contractility. Bladder outlet obstruction (BOO) can lead to detrusor instability associated with denervation supersensitivity to ACh. Using a rabbit model of partial BOO, we investigated whether there were any associated changes in the neuronal 5-HT binding sites. Partial BOO was induced in adult male New Zealand White rabbits. Sham-operated age-matched rabbits acted as controls. After 1, 3 and 6 weeks the urinary bladders were excised. Detrusor sections were incubated with [³H]-5-HT. Autoradiographs were generated and analysed densitometrically. The presence of nerves was detected using immunohistochemistry with NF200. Autoradiography demonstrated a time-dependent, significant (P < 0.0001) up-regulation of [³H]-5-HT binding sites in the detrusor smooth muscle after the induction of BOO. Immunohistochemistry confirmed that the [³H]-5-HT binding sites were neuronal. In the rabbit model of partial BOO there was a significant time-dependent up-regulation of neuronal [³H]-5-HT binding sites in the detrusor. This change may influence 5-HT-mediated ACh release, resulting in increased bladder contractility. This, in turn, may play a role in detrusor instability associated with denervation post-junctional supersensitivity. These results provide a possible rationale for further investigation into the use of 5-HT antagonists in the treatment of detrusor instability associated with BOO.     

Piboserod (SB 207266), a selective 5-HT4 receptor antagonist, reduces serotonin potentiation of neurally-mediated contractile responses of human detrusor muscle

The aim of this study is to evaluate the potency of piboserod (SB 207266), a selective 5-HT₄ receptor antagonist, at inhibiting the 5-HT₄-mediated potentiating effect of serotonin (5-HT) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations (EFS). Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500 mg and EFS (20 Hz, 1 ms duration at 300 mA for 5 s) was applied continuously at 1 min intervals. After stabilization of the EFS-induced contractions, concentration-response curves to 5-HT (0.1 nM–100 M) were constructed in the absence or presence of 1 or 100 nM of piboserod. The experiments were performed in the presence of methysergide (1 M) and ondansetron (3 M) to block 5HT₁/5HT₂ and 5-HT₃ receptors, respectively. 5-HT potentiated the contractile responses to EFS of human bladder strips in a concentration-dependent manner, with a maximum mean of 60.0±19.9% of the basal EFS-evoked contractions. Piboserod did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to EFS. In presence of 1 and 100 nM of piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0±7.9 and 38.7±8.7%, respectively. A mean apparent antagonist dissociation constant value (K_B) of 0.56±0.09 nM was determined. These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips. Therefore, the 5-HT₄ receptor might represent an attractive pharmacological target for the treatment of overactive bladder.     

Inhibition of diabetic bladder smooth muscle cell proliferation by endothelin receptor antagonists

Urinary bladder hypertrophy and hyperplasia are well recognised in diabetic cystopathy. The urinary bladder is known to synthesise endothelin-1 (ET-1), a potent vasoconstrictor peptide with mitogenic properties. Using diabetic New Zealand White (NZW) rabbits, we investigated the potential role of ET receptor subtypes (ET_A and ET_B) on the proliferation of bladder smooth muscle cells (SMC). Diabetes mellitus was induced in adult male NZW rabbits. After 6 months, control (n=6) and diabetic (n=6) bladders were removed and SMC from the dome and bladder neck were grown using standard explant methodology. At passage two, the cells were made quiescent and then further incubated in foetal calf serum (FCS), control age-matched rabbit serum (CRS) or diabetic rabbit serum (DRS) in the presence or absence of ET_A-antagonist (BQ123) or ET_B-antagonist (BQ788). SMC proliferation was then measured with 5-bromo-2′deoxy-uracil 24 h later and by cell counting (using a haemocytometer) at 48 h. Neither BQ123 nor BQ788 influenced detrusor or bladder neck SMC proliferation in FCS or CRS. However, in the presence of DRS, BQ123 and BQ788 significantly inhibited diabetic detrusor and bladder neck SMC proliferation at 30 and 100 nmol/l (P < 0.03 and P < 0.01, respectively). Cell counts were also significantly reduced from the diabetic detrusor and bladder neck (P < 0.01 and P < 0.03 with BQ123 and BQ788, respectively). These results suggest that ET may play a pathophysiological role in the bladder SMC hyperplasia associated with diabetes mellitus. Received: 24 November 1999 / Accepted: 21 March 2000     

Acute effects of serotonin on rat bladder contractility.

INTRODUCTION: The purpose of this study is to investigate in vitro the effects of serotonin on the rat detrusor. In particular, it examines which drugs inhibit the serotonin-induced detrusor contractions. MATERIALS AND METHODS: Isometric tension changes of isolated rat bladder muscle strips were recorded in an organ bath using a force transducer. Acute effects of serotonin (0.0001-0.01 mM) on resting tension were assessed. Electrical field stimulation (EFS); bethanechol (0.0001-0.01 mM); ATP (1-3 mM)- or KCl (63.5-254 mM)-induced contractions using an application in an organ bath were compared with serotonin-induced contractions. In order to examine the action mechanism of serotonin-induced stimulation, EFS-, bethanechol-, ATP- or KCl-induced contraction on serotonin treatment (0.001 mM) was assessed and serotonin (0.001-0.1 mM) was cumulatively added to the organ bath following preincubation with propranolol, ketanserin, tropisetron, propiverine, sodium nitroprusside or doxazosin. RESULTS: The serotonin-induced response has two phases: an initial transient contraction and a prolonged tonic phase. Serotonin produced a reversible and dose-dependent contraction of the detrusor strips. Responses to bethanechol significantly increased with a concentration of 0.001 mM serotonin (p < 0.05). There was no effect on the responses to ATP, KCl, or EFS on 0.001 mM serotonin. The 5-HT(2) receptor is mainly responsible for serotonin-induced contractions of the detrusor (p < 0.05), while the 5-HT(1) receptor is partially responsible. Doxazosin and propiverine each significantly suppressed the response to serotonin, while sodium nitroprusside and tropisetron each had no effect (p < 0.05). CONCLUSIONS: Because the 5-HT(2) antagonist blocked the effect of serotonin-induced bladder contractions and the stimulation of the adrenoreceptors, the 5-HT(2) antagonist seems to improve lower urinary tract symptoms.     

Doxazosin and serotonin (5-HT) receptor (1A, 2A, and 4) antagonists inhibit 5-HT-mediated human cavernosal contraction

Penile erection results from the balance between relaxation and contractile mechanisms of the corpus cavernosum. Only a few studies suggest a role for endogenous contractile agents such as 5-hydroxytryptamine (5-HT). Our aim was to confirm the possible role of 5-HT in human erection. The effect of 5-HT on human cavernosal tissues, as well as those of doxazosin (shown previously to have 5-HT inhibitory action), ketanserin (5-HT (2A) receptor antagonist), NAN-190 (5-HT (1A) receptor antagonist), and SB 203186 (5-HT (4) receptor antagonist) on 5-HT-mediated effects, were assessed using the organ bath technique, including electrical field stimulation study (EFS). Results are presented as median (mg/mg = mg contraction/mg of tissue). Consistent 5-HT-mediated (10(-3) M) contractions were demonstrated (n = 18; 63 mg/mg). These contractions were inhibited with ketanserin by 90% (n = 8), NAN-190 by 68% (n = 12), and SB 203186 by 55% (n = 12). Doxazosin showed a similar 5-HT inhibitory action in a concentration-dependent manner (10(-4) M; 94% reduction; n = 8, 10(-6) M; 68.3% reduction; n = 8). Our EFS studies indicated the presence of neuronally derived 5-HT and that a majority of the nonnoradrenogenic contraction (54%) was mediated via 5-HT(2A) receptors. These findings suggest that 5-HT may play a role in the human detumescence process via 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors. Neuronally released 5-HT is probably an important contractile neurotransmitter in the erectile process. Doxazosin, ketanserin, and 5-HT(1A) and 5-HT(4) receptor antagonists may be useful as part of combination therapy used to treat erectile dysfunction.     

Muscarinic receptor subtypes in porcine detrusor: comparison with humans and regulation by bladder augmentation

The properties of muscarinic acetylcholine␣receptors of porcine and human bladder detrusor were␣compared in radioligand binding studies using [³H]quinuclidinylbenzylate as the radioligand. The receptor affinity for the radioligand and the density of␣muscarinic receptors was similar in male and female pigs and in humans (K _d = 35 ± 8 pM, B _max = 153 ± 30 fmol/mg protein). Atropine and subtype-selective antagonists had steep and monophasic competition curves in porcine and human detrusor with a rank order of potency of atropine ≫ hexahydro-sila-difenidol ≥ AF-DX 116 ≥ pirenzepine, indicating the presence of a␣homogeneous population of M₂ muscarinic receptors. In female pigs bladder outflow obstruction generated by partial urethral ligation or its surgical treatment by ileum augmentation or autoaugmentation did not significantly alter expression of muscarinic receptors or of α_2A-adrenoceptors, but the power was insufficient to exclude alterations of less than 60%. We conclude that porcine and human detrusor express muscarinic receptors of the M₂ subtype; despite these qualitative similarities the use of the porcine model may be limited by large biological variance with regard to quantitative receptor expression. Received: 9 June 1997 / Accepted: 27 October 1997     

Positive bladder cooling reflex in patients with bladder outlet obstruction due to benign prostatic hyperplasia

The bladder cooling reflex was evaluated in patients with bladder outlet obstruction to study the effect of obstruction on the afferent neural function of the bladder, especially on the C-afferents. The bladder cooling test was performed by infusion of 0 °C saline into the bladder with simultaneous detrusor pressure measurement in 104 patients with bladder outlet obstruction due to benign prostatic hyperplasia. In 49 patients (47%) a positive cooling reflex was observed. This was defined as a rise in the detrusor pressure following cold saline instillation exceeding 15 cmH₂O (range 15–130 cmH₂O, mean 60.6 cmH₂O; positive group). In the remainder of cases the pressure rise ranged from 0 to 12 cmH₂O (mean 6.1 cmH₂O; negative group). Bladder outlet obstruction may cause some alteration in the afferent neural function of the bladder, in particular of the C-afferent fibers.     

Combination of Alfuzosin and Tadalafil Exerts an Additive Relaxant Effect on Human Detrusor and Prostatic Tissues In Vitro

Background

Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are highly prevalent in aging men and are strongly linked. Alpha₁-blockers such as alfuzosin are effective monotherapies for LUTS. Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil are the first-line treatment for ED. Both drugs act by two different mechanisms of action on common urogenital target organs and, thus, may have additive effects.

Objectives

We evaluated in vitro the effects of alfuzosin, tadalafil, and the combination of both on human detrusor and prostatic smooth muscle.

Design, setting, and participants

Prostatic and bladder tissue were obtained from patients (n = 20 and n = 17, respectively) undergoing cystoprostatectomy for bladder cancer.

Measurements

In organ baths, isolated prostatic strips and isolated bladder strips were incubated with vehicle, tadalafil (10⁻⁶ M and 10⁻⁵ M), alfuzosin (3 × 10⁻⁸ M or 10⁻⁶ M and 10⁻⁵ M) or a combination. Concentration-response curves (CRCs) to norepinephrine were generated on prostatic strips and detrusor strips precontracted with carbachol. Strips were also submitted to electrical field stimulation (EFS).

Results and limitations

When alfuzosin and tadalafil were combined, the maximal relaxation to norepinephrine on carbachol-precontracted detrusor strips was significantly increased compared with tadalafil alone, and EFS-induced detrusor contractions were better inhibited compared with each compound alone. Tadalafil significantly inhibited norepinephrine-induced prostatic strip contractions by reducing the maximal effect, whereas alfuzosin shifted the CRC of norepinephrine to the right. Combining both tadalafil and alfuzosin resulted in a greater relaxant effect. Likewise, the combination was more effective at reducing EFS-induced contractions compared with each compound alone.

Conclusions

The combination of alfuzosin and tadalafil exerts an additive effect of inhibiting adrenergic smooth muscle tone of prostatic tissue and EFS-induced detrusor contractions and conversely, of enhancing adrenergic relaxation of detrusor precontracted with carbachol. These experiments provide experimental support for the clinical investigation of the combination of α1-blockers and PDE5 inhibitors in the treatment of LUTS.     

Relaxant effects of some benzothiazolinone derivatives on isolated rabbit corpus cavernosum

 In the present study, two 6-(fluorobenzoyl)-3-piperazinomethyl-2-benzothiazolinone derivatives were synthesized and their relaxant effects on isolated rabbit corpus cavernosum investigated. Compounds Y-16 and Y-21 can alter the ability of corpus cavernosum smooth muscle to contract. Strips of rabbit corpus cavernosum smooth muscle were mounted in isolated tissue baths for measurement of isometric contractile force. Compounds (10⁻⁶–10⁻³ M) did not cause contraction but induced relaxation in precontracted corpus cavernosum smooth muscle. Neither N-nitro-l-arginine methylester (L-NAME) nor indomethacin affected the relaxant effect of these compounds. Glibenclamide and tetraethylammonium chloride (TEA) also did not influence the relaxation induced by the compounds. In conclusion, in isolated rabbit corpus cavenosum, Y16 and Y21 have a relaxant potency equal or superior to known vasoactive agents. Further investigations are needed to show the importance of these effects for the diagnosis and treatment of erectile dysfunction. Received: 5 December 2000 / Accepted: 5 March 2001     

Altered neural control of micturition in the aged F344 rat

The purpose of this study was to determine whether micturition reflexes are altered in aged rats. Voiding frequencies and awake cystometrograms (CMGs) were measured in young (3–5 months old) and aged (24 months) F344 male rats. Bladder contractions induced by subcutaneous apomorphine and intravesical capsaicin stimulation were measured using awake CMGs. Urodynamic parameters were compared. Aged rats voided less frequently (4.1 vs 6.9 times/18 h, P=0.006), with a higher volume per void (1.1 vs 0.7 ml, P=0.02) and had a higher micturitional threshold pressure (8.7 vs 4.6 mmHg, P=0.0001) than the young rats. Apomorphine induced a higher frequency of bladder contractions in aged animals compared to young animals (5.5 vs 3.1 contractions/min, P=0.03). Intravesical capsaicin caused a lower pressure bladder response in the aged rats (38.5 vs 70.6 mmHg, P=0.01) compared to the young rats. Bladder afferents and central micturition pathways may be altered in aged rats. Impaired bladder contractility in the elderly may be exacerbated by reduced sensory input, whereas the propensity for detrusor instability could result from altered central processing. This study demonstrated the utility of the F344 animal model to study micturitional changes resulting from aging. Received: 14 April 2000 / Accepted: 4 July 2000     

Functional response of cavernosal tissue to distension

We studied rabbit isolated erectile tissue responses to changes in preload and to active tension development with norepinephrine. The effects of antagonists of endothelin-1, prostaglandins E₂ and F_2αand of nitric oxide were also tested on normal and de-endothelialized preparations. Tissue distension was found to elicit spontaneous rhythmic contractions. Increase in preload diminished the latency of the spontaneous activity and augmented the developed force. Active tension development and the inhibitor of the Na⁺,K⁺ pump, ouabain, opposed the spontaneous activity. A marked reduction in the resting tension with abolition of the spontaneous activity was observed on normal, but not on de-endothelialized tissues, following the addition of the specific prostaglandin E₂ and F_2α receptor antagonist, SC-19220. At 3 × 10⁻⁴ M, the highest concentration used, the endothelin-A receptor antagonist BQ-123 failed to change the pattern of the spontaneous activity and the resting tension of normal tissues. The nitric oxide synthesis inhibitor, l-NAME, did not produce reliable effects. These findings point to a causal relation between cavernosal tissue distension and phasic and tonic contractions. Phasic contractions appear to be elicited by smooth muscle cells through the enzyme Na⁺,K⁺-ATPase. Increase in the resting tone could be mediated, at least in part, by the endothelium, through the release of prostaglandins E₂ and/or F_2αbut not of endothelins. We discuss the hypothesis that, in cavernosal tissue, mechanotransduction of distension to contractile responses is an important determinant of detumescence. Received: 5 November 1996 / Accepted: 27 May 1997     

Risk factors for renal scarring in children and adolescents with lower urinary tract dysfunction

Risk factors for renal scarring in children with lower urinary tract dysfunction (LUTD) were evaluated. The medical records of 120 patients were assessed concerning gender, presence of vesicoureteric reflux (VUR), bladder capacity, detrusor overactivity, residual urine, febrile urinary tract infection (UTI), bacteriuria, constipation, detrusor sphincter incoordination (DSI), high detrusor pressure at maximal cystometric capacity (PMCC), low compliance, and thickness and trabeculation of the bladder wall. Renal scarring was diagnosed by ^99mtechnetium-dimercaptosuccinic acid renal scan (DMSA). Renal scarring was detected in 38 patients (31%). VUR, UTI, decreased bladder capacity, urinary residue, and trabeculated and thick bladder wall were associated with scarring at univariate analysis. Multivariate analysis showed VUR (P < 0.0001) as the independent risk factor for renal scarring. Thickness of the bladder wall was a marginal risk factor (P  = 0.07). Although UTI was not a risk factor, it was associated with VUR (P  = 0.03). In our analysis, VUR was the main risk factor; however, renal scarring was probably due to multifactorial causes, as VUR was associated with UTI.     

Effect of peak inspiratory flow on gas exchange, pulmonary mechanics, and lung histology in rabbits with injured lungs

Purpose The aim of this study was to evaluate, using a rabbit model, the little-known effect of different levels of peak inspiratory flow on acutely injured lungs. Methods Fourteen male rabbits (body weight, 2711 ± 146 g) were anesthetized and their lungs were injured by alveolar overstretch with mechanical ventilation until Pa_O2 was reduced below 300 mmHg. Injured animals were randomly assigned to: the P group—to receive pressure-regulated volume-control ventilation (PRVCV; n = 7); and the V group—to receive volume-control ventilation (VCV; n = 7). Other ventilator settings were: fraction of inspired oxygen (FI_O2), 1.0; tidal volume, 20 ml·kg⁻¹; positive end-expiratory pressure (PEEP) 5 cmH₂O; and respiratory rate, 20 min⁻¹. The animals were thus ventilated for 4 h. Throughout the protocol, ventilatory parameters and blood gas were measured every 30 min. After the protocol, the lung wet-to-dry ratio and histological lung injury score were evaluated in the excised lungs. Results Throughout the protocol, peak inspiratory flow and mean inspiratory flow values in the P group were significantly higher than those in the V group (26.7 ± 5.0 l·min⁻¹ vs 1.2 ± 0.2 l·min⁻¹, and 4.3 ± 0.3 l·min⁻¹ vs 1.1 ± 0.1 l·min⁻¹; P < 0.05). The wet-to-dry ratio in the P group was also significantly higher than that in the V group (7.7 ± 0.9 vs 6.3 ± 0.5; P < 0.05). More animals in the P group than in the V group had end-of-protocol Pa_O2/FI_O2 ratios below 200 mmHg (43% vs 0%; P = 0.06). Conclusion In rabbits with injured lungs, high peak inspiratory flow with high tidal volume (V_T) reduces the Pa_O2/FI_O2 ratio and increases the lung wet-to-dry ratio.     

Effects of ovarian hormones on β-adrenergic receptor-mediated relaxation in the female rabbit bladder

The effects of ovarian hormones on β-adrenergic receptor-mediated responses in female rabbit detrusor smooth muscles were investigated. Ovariectomized mature female New Zealand white rabbits were untreated or treated with estrogen and/or progesterone for 2 weeks. The contractile responses to carbachol and KCl in the detrusor strips were not significantly different in all groups. As compared with dobutamine and GS-332, isoproterenol and procaterol significantly relaxed the detrusor strips derived from all groups on KCl-induced tonic contractions. Combined with estrogen treatment, isoproterenol, procaterol and GS-332 caused a significant increase in this muscle relaxation. Furthermore, estrogen treatment caused a significant increase in relaxation as a result of forskolin and the cyclic AMP (cAMP) production that was induced by isoproterenol, procaterol and GS-332. However, estrogen treatment did not affect the relaxant response to dibutyryl cyclic AMP. Progesterone treatment did not affect β-adrenergic receptor-mediated responses. These results suggest that estrogen treatment causes the increased relaxant responses mediated by β₂- and β₃-adrenergic receptor subtypes, which may be related to the increased cAMP content in female rabbit detrusor smooth muscles. Received: 26 February 1999 / Accepted: 1 July 1999     

The latissimus dorsi bladder myoplasty to assist detrusor function

The objective of this study was to evaluate whether an innervated skeletal muscle might augment detrusor function. In four dogs we performed the latissimus dorsi myoplasty, a transfer of the latissimus muscle as an innervated free flap wrapped around the bladder. Stimulation of the latissimus dorsi free flap initially achieved an average bladder pressure of 45.8 ± 8.41 cm H₂O, sufficient for partial evacuation. After 4 months the muscle generated a maximal pressure of 82 cm H₂O, resulting in an evacuation of 27.7%. For selected patients, the latissimus dorsi bladder myoplasty may provide an alternative to intermittent catheterization in the future. Received: 14 March 1997 / Accepted: 12 January 1998     

Contractility Changes of the Deep Dorsal Penile Vein Due to Serotonin

Purpose

Penile erection is a complex neurovascular phenomenon that takes place with the active contribution of arterial and sinusoidal structures. However, some authors claim that larger veins including the deep dorsal veins that produce contractions, might be involved in the physiology of erection. This study was designed to clarify the contractile properties of deep dorsal penile veins (DDPV).

Materials and Methods

The effect of serotonin (5-HT), noradrenaline (NA), adenosine triphosphate (ATP) and acethylcholine (Ach) on the isolated DDPVs of 16 impotent men, 9 with veno-occlusive dysfunction and 7 without venous leakage, and 5 potent men (controls) who underwent radical prostatectomy, were examined in vitro.

Results

Although NA, ATP and Ach had no effect, 5-HT produced concentration-dependent contractions. E_max and pEC₅₀ of 5-HT were 411 +/− 10 mg., 5.92 +/− 0.25; 1020 +/− 260 mg., 5.83 +/− 0.24 and 160 +/− 40 mg., 6.4 +/− 0.22 in controls and patients who had venous leakage and no venous leakage, respectively. Samples of controls were contracted only with 5-HT₂ agonist, DOI (pEC₅₀ = 5.63 +/− 0.02), and these contractions were antagonized with 5-HT₂ antagonist ketanserin. On the other hand, both DOI (pEC₅₀ = 6.30 +/− 0.77) and 5-HT₁ agonist, 5-CT (pEC₅₀ = 6.23 +/− 0.21) produced venoconstriction in patients with veno-occlusive dysfunction.

Conclusions

The present findings suggest that 5-HT receptor functions in the DDPVs are of 5-HT₂ subtype in potent men and the altered response to 5-HT in patients with veno-occlusive disease may play a role in the pathophysiology of impotence.     

Effect-compartment equilibrium rate constant (k eo) for propofol during induction of anesthesia with a target-controlled infusion device

The effect-compartment concentration (C_e) of a drug at a specific pharmacodynamic endpoint should be independent of the rate of drug injection. We used this assumption to derive an effect-compartment equilibrium rate constant (k_eo) for propofol during induction of anesthesia, using a target controlled infusion device (Diprifusor). Eighteen unpremedicated patients were induced with a target blood propofol concentration of 5 μg · ml⁻¹ (group 1), while another 18 were induced with a target concentration of 6 μg · ml⁻¹ (group 2). The time at loss of the eyelash reflex was recorded. Computer simulation was used to derive the rate constant (k_eo) that resulted in the mean C_e at loss of the eyelash reflex in group 1 being equal to that in group 2. Using this population technique, we found the k_eo to be 0.57 min⁻¹. The mean (SD) effect compartment concentration at loss of the eyelash reflex was 2.39 (0.70) μg · ml⁻¹. This means that to achieve a desired C_e within 3 min of induction, the initial target blood concentration should be set at 1.67 times that of the desired C_e for 1 min, after which it should revert to the desired concentration.     

Intestinal Afferent Nerve Sensitivity is Increased During the Initial Development of Postoperative Ileus in Mice

Introduction  Neuronal reflex inhibition of gastrointestinal motility is a key mechanism in the development of postoperative ileus (POI). The aim of our study was to determine whether intestinal afferent nerve fibers are sensitized during the first hours after surgery contributing to this mechanism. Methods  Under enflurane anesthesia, C57BL/6 mice underwent laparotomy followed by sham treatment or standardized small bowel manipulation to induce POI. After 1, 3, or 9 h, extracellular multi-unit mesenteric afferent nerve recordings were performed in vitro from 2 cm segments of jejunum (subgroups n = 6) superfused with Kreb’s buffer (32°C, gassed with O₂/CO₂ mixture). Segments were cannulated to monitor luminal pressure and intestinal motility. Afferent impulses as response to bradykinin (0.5 μM) and to mechanical ramp distension of the intestinal lumen from 0 to 80 cmH₂O were recorded. Results  At 1 h, amplitudes of intestinal contractions were 0.8 ± 0.2 cmH₂O after induction of POI and 5.0 ± 0.8 cmH₂O in sham controls (mean ± SEM; p < 0.01). A similar difference was observed for segments harvested at 3 and 9 h. Afferent firing to serosal bradykinin was increased at 1, 3, and 9 h in POI segments compared to sham controls (p < 0.05 at 1 h, p < 0.01 at 3 and 9 h). During distension with high pressures, afferent firing rate was increased at 1 and 3 h in segments after induction of POI compared to sham controls. Nine hours postoperatively, contracted and dilated segments were observed during POI that were investigated separately. While afferent firing in dilated segments was increased to 176 ± 16 imp s⁻¹ at 80 cmH₂O luminal distension (p < 0.01), it was 46 ± 5 imp s⁻¹ in contracted segments (p < 0.001) compared to 77 ± 4 imp s⁻¹ in sham controls. Conclusions  Afferent firing to bradykinin and high threshold distension is augmented in the early phase of POI. As these stimuli are known to sensitize predominantly spinal afferents, this mechanism may contribute to reflex inhibition of intestinal motility during POI.     

Recovery from Fontan circulation failure by application of continuous negative extrathoracic pressure

A 2-year-old girl developed lethal circulatory failure, general edema, and hepatic dysfunction in an acute phase after total cavopulmonary connection, a Fontan-type operation. Application of continuous negative extrathoracic pressure (CNEP) with a cuirass ventilator at −4 cmH₂O under spontaneous respiration dramatically improved hemodynamics, with systolic arterial pressure increasing from 82 mmHg to 90 mmHg, and central venous pressure decreasing from 15 mmHg to 13 mmHg; also, urine output increased, from 1.6 ml·kg⁻¹·h⁻¹ to 6.4 ml·kg⁻¹·h⁻¹. Improvements in hepatic function and fluid retention (reduction of pleural fluid and ascites) were also observed. The patient was successfully weaned from CNEP after 5 days. CNEP is an easily applicable, noninvasive tool to reduce pulmonary impedance, and is specifically useful to improve hemodynamics in patients after a Fontan-type operation. Our result suggests that CNEP may represent a first-line option to save patients from critical circulatory failure after a Fontan-type operation.