Phasic Contractions Research Articles

Rift-enhanced foredeep and contractional tectonics interplay in the outer Albanides

The Albanides thrust belt is associated with the ENE-ward subduction of the Adriatic lithosphere facing the Peri-Adriatic Basin, a foredeep filled with a Neogene-Quaternary sedimentary sequence more than 6 km thick. This basin segment is anomalously deep, compared to the adjacent foredeeps, and dominated by Neogene strata deposited at a rate of circa 0.3–0.4 mm/yr. Moreover, the Upper Miocene deposits of the Peri-Adriatic Basin lie on deeply eroded anticlines composed of Meso-Cenozoic carbonate units. This observation is in contrast with the expected constant steady-state fold uplift trend generally observed in orogens related to E-NE directed subductions. These observations suggest that following a Late Oligocene to Early-Middle Miocene contractional tectonic phase associated with subaerial erosion, the northern portion of the frontal zone of the outer Albanides accretionary prism was affected by strong subsidence during the Late Miocene. Evidence from field mapping combined with the integration of exploration wells and seismic reflection profiles indicate that this unexpected subsidence may be related to a Miocene extensional/transtensional tectonic phase. The actual anomalously high heat flow (>80 mW/m2) in the offshore depocenter of the Peri-Adriatic Basin also supports this interpretation.This extensional tectonic phase was unrelated to the subduction process, suggested by the obliquely orientation of the new basin with respect to the strike of the Albanides thrust belt, also partially superimposed on it. This Miocene event and the associated thermal pulse could have played a crucial role for the generation of hydrocarbons in the Outer Albanides. The tectonic interplay between this rifting episode and the usual foredeep flexural evolution may explain the peculiar evolution of the Outer Albanides and the associated anomalous foredeep. This basin can be defined as a rift-enhanced foredeep generated by two spatially co-existing, but independent tectonic processes, i.e., by the flexural loading exerted by the orogenic fold-and-thrust system and the rifting in the foreland itself.

Proteinase-activated receptors regulate intestinal functions in a segment-dependent manner in rats

Proteinases released e.g. during inflammatory or allergic responses affect gastrointestinal functions via proteinase-activated receptors such as PAR1 and PAR2. As the gastrointestinal tract exerts pronounced gradients along its longitudinal axis, the present study focuses on the effect of PAR1 and PAR2 agonists on electrogenic ion transport (measured as short-circuit current; Isc), tissue conductance (Gt) and contractility of the longitudinal muscle layer of rats. In Ussing chamber experiments, the PAR1 agonist TFLLR-NH2, which mimics the tethered ligand liberated after cleavage of the receptor, evoked only a modest increase in Isc (<0.5 μEq·h−1·cm−2) in small intestine, but a strong increase (3–4 μEq·h−1·cm−2) in colon. Pretreatment with tetrodotoxin reduced the response of the colonic segments to the level of the small intestine. Thrombin, the natural activator of PAR1, was much less effective suggesting biased activation by this peptidase. A similar gradient along the longitudinal axis of the intestine was observed with trypsin, the endogenous activator of PAR2. Divergent actions of PAR1 activation by enzymatic cleavage or a mimetic peptide were also observed when recording isometric contractions of longitudinal muscle. For example, in the jejunum TFLLR-NH2 concentration-dependently induced a contractile response, whereas thrombin showed only inconsistent effects. The PAR2 activator AC264613 induced a concentration-dependent decrease in muscle tone combined with an inhibition of phasic spontaneous contractions. PCR experiments and immunohistochemical stainings confirmed the expression of PAR1 and PAR2. The data implies that PAR1 and PAR2 functions vary depending on the intestinal segment.

The formation and evolution of Ni2Cr precipitates in Ni–Cr model alloys as a function of stoichiometry characterized by synchrotron x-ray diffraction

Ni-based alloys containing significant amounts of Cr, may precipitate new phases during long-term service at elevated temperatures. In Ni–Cr model alloys, the formation of Ni2Cr has been found to impact the material properties, including the strength and ductility after isothermal aging below the critical temperature of 590 °C. In this work, we quantify the formation and evolution of long-range ordering in four Ni–Cr binary model alloys (Ni/Cr = 1.8, 2.0, 2.2, 2.4) after isothermal aging up to 10,000 h at temperatures between 373 and 475 °C. The alloys were characterized by hardness testing and synchrotron-based x-ray diffraction to quantify the impact of Ni2Cr phase fraction and precipitate size on mechanical properties. After 500 h of isothermal aging, the formation of Ni2Cr was detected in all four alloys at 475 °C. In the stochiometric alloy samples (Ni/Cr = 2.0), the formation of Ni2Cr was found after 500 and 3000 h aging at 418 and 373 °C, respectively. We found that the matrix lattice contraction and Ni2Cr phase fraction both saturate after early aging times. This is in stark contrast to the hardness and Ni2Cr precipitate size that both continue to increase with increasing aging time. Our results highlight that changes in hardness correlate linearly with Ni2Cr precipitate size rather than phase fraction. This important structure-property relationship can potentially help define Ni–Cr-based component lifetimes directly through an understanding of how Ni2Cr formation impacts strength and ductility. We find that a precipitation hardening model for critical resolved shear stress with weakly coupled dislocations shows good agreement with the material property changes quantified from experimental measurements.

Regional Synchronization during Economic Contraction: The Case of the U.S. and Japan

ABSTRACT Two decades of studies have found significant regional differences in the timing of transitions in national business cycles and their durations. Earlier studies partly detect regional synchronization during business cycle expansions and contractions in Europe, the United States, and Japan. We examine this possibility by applying a sophisticated method for identifying the time-varying degree of synchronization to regional business cycle data in the U.S. and Japan. The method is prominent in nonlinear sciences but has been infrequently applied in business cycle studies. We find that the degree of synchronization in regional business cycles increased during contractions and decreased during expansions throughout the period under study. Such asymmetry between the contraction and expansion phases of a business cycle will contribute to our better understanding of the phenomenon of business cycles.

Convergence rate bounds for iterative random functions using one-shot coupling

One-shot coupling is a method of bounding the convergence rate between two copies of a Markov chain in total variation distance, which was first introduced in Roberts and Rosenthal (Process Appl 99:195–208, 2002) and generalized in Madras and Sezer (Bernoulli 16:882–908, 2010). The method is divided into two parts: the contraction phase, when the chains converge in expected distance and the coalescing phase, which occurs at the last iteration, when there is an attempt to couple. One-shot coupling does not require the use of any exogenous variables like a drift function or a minorization constant. In this paper, we summarize the one-shot coupling method into the One-Shot Coupling Theorem. We then apply the theorem to two families of Markov chains: the random functional autoregressive process and the autoregressive conditional heteroscedastic process. We provide multiple examples of how the theorem can be used on various models including ones in high dimensions. These examples illustrate how the theorem’s conditions can be verified in a straightforward way. The one-shot coupling method appears to generate tight geometric convergence rate bounds.

Can f(R) gravity isotropise a pre-bounce contracting universe?

We address the important issue of isotropisation of a pre-bounce contracting phase in f(R) gravity, which would be relevant to constructing any viable nonsingular bouncing scenario in f(R) gravity. The main motivation behind this work is to investigate whether the f(R) gravity, by itself, can isotropise a contracting universe starting initially with small anisotropy without incorporating a super-stiff or non-ideal fluid, impossible in general relativity. Considering Bianchi I cosmology and employing a dynamical system analysis, we see that this is not possible for R n (n > 1) and R + αR 2 (α > 0) theory, but possible for 1/α eαR (α > 0) theory. On the other hand, if one does not specify an f(R) theory a priori but demands a cosmology smoothly connecting an ekpyrotic contraction phase to a nonsingular bounce, the ekpyrotic phase may not fulfil the condition for isotropisation and physically viability simultaneously.

Evolution of black holes through a nonsingular cosmological bounce

We study the classical dynamics of black holes during a nonsingular cosmological bounce. Taking a simple model of a nonsingular bouncing cosmology driven by the combination of a ghost and ordinary scalar field, we use nonlinear evolutions of the Einstein equations to follow rotating and non-rotating black holes of different sizes through the bounce. The violation of the null energy condition allows for a shrinking black hole event horizon and we find that for sufficiently large black holes (relative to the minimum Hubble radius) the black hole apparent horizon can disappear during the contraction phase. Despite this, we show that most of the local cosmological evolution remains largely unaffected by the presence of the black hole. We find that, independently of the black hole's initial mass, the black hole's event horizon persists throughout the bounce, and the late time dynamics consists of an expanding universe with a black hole of mass comparable to its initial value.

The Transcription Factor Zfp335 Promotes Differentiation and Persistence of Memory CD8+ T Cells by Regulating TCF-1.

Memory CD8+ T cells play an essential role in providing effective and lifelong protection against pathogens. Comprehensive transcriptional and epigenetic networks are involved in modulating memory T cell development, but the molecular regulations of CD8+ memory T cell formation and long-term persistence remain largely unknown. In this study, we show that zinc finger protein 335 (Zfp335) is indispensable for CD8+ T cell memory establishment and maintenance during acute infections. Mice with Zfp335 deletion in CD8+ T cells exhibit a significant reduction of memory T cells and memory precursor cells in the contraction phase. Zfp335 deficiency in CD8+ T cells resulted in decreased expression of memory featured genes Eomes and IL-2Rβ, leading to a loss of memory identity and an increase of apoptosis in response to IL-7 and IL-15. Mechanistically, Zfp335 directly binds to and regulates TCF-1, known to be critical for memory T cell development. Importantly, overexpression TCF-1 could rescue the defects in the survival of both CD8+ memory precursors and memory T cells caused by Zfp335 deficiency. Collectively, our findings reveal that Zfp335 serves as a novel transcriptional factor upstream of TCF-1 in regulating CD8+ T cell memory.

Model to Inhibit Contraction in Third-Degree Burns Employing Split-Thickness Skin Graft and Administered Bone Marrow-Derived Stem Cells.

Third-degree burns typically result in pronounced scarring and contraction in superficial and deep tissues. Established techniques such as debridement and grafting provide benefit in the acute phase of burn therapy, nevertheless, scar and contraction remain a challenge in deep burns management. Our ambition is to evaluate the effectiveness of novel cell-based therapies, which can be implemented into the standard of care debridement and grafting procedures. Twenty-seven third-degree burn wounds were created on the dorsal area of Red Duroc pig. After 72 h, burns are surgically debrided using a Weck knife. Split-thickness skin grafts (STSGs) were then taken after debridement and placed on burn scars combined with bone marrow stem cells (BM-MSCs). Biopsy samples were taken on days 17, 21, and 45 posttreatment for evaluation. Histological analysis revealed that untreated control scars at 17 days are more raised than burns treated with STSGs alone and/or STSGs with BM-MSCs. Wounds treated with skin grafts plus BM-MSCs appeared thinner and longer, indicative of reduced contraction. qPCR revealed some elevation of α-SMA expression at day 21 and Collagen Iα2 in cells derived from wounds treated with skin grafts alone compared to wounds treated with STSGs + BM-MSCs. We observed a reduction level of TGFβ-1 expression at days 17, 21, and 45 in cells derived from wounds treated compared to controls. These results, where the combined use of stem cells and skin grafts stimulate healing and reduce contraction following third-degree burn injury, have a potential as a novel therapy in the clinic.

Age-Related Decline in Vascular Responses to Phenylephrine Is Associated with Reduced Levels of HSP70.

Aging impairs the expression of HSP70, an emergent player in vascular biology. However, it is unknown if age-related alterations in HSP70 are linked to a decline in arterial function. In this study, we test the hypothesis that the contributions of HSP70 to vascular contraction are diminished in middle-aged animals. We determined the basal levels of HSP70 in the aorta of young and middle-aged Sprague Dawley male rats using Western blotting. Functional studies were performed in a wire myograph system. Force development in response to phenylephrine was assessed in the presence or absence of extracellular calcium (Ca2+), and in aortic rings treated or non-treated with an HSP70 inhibitor. Fluorescent probes were used to evaluate vascular oxidative stress and nitric oxide levels. We report that middle-aged rats have significantly lower levels of HSP70. Blockade of HSP70 attenuated vascular phasic and tonic contraction in isolated aortas. It appears that a functional HSP70 is required for proper Ca2+ handling as inhibition of this protein led to reduced force–displacement in response to Ca2+ dynamics. Furthermore, middle-aged aortic rings exposed to the HSP70 inhibitor display higher reactive oxygen species levels without changes in nitric oxide. In summary, we show that middle-aged animals have lower levels of HSP70 in aortas, which associates with an age-related decline in vascular responses to α-1 adrenergic stimulation.

Bio-impedance method to monitor colon motility response to direct distal colon stimulation in anesthetized pigs

Electrical stimulation has been demonstrated as an alternative approach to alleviate intractable colonic motor disorders, whose effectiveness can be evaluated through colonic motility assessment. Various methods have been proposed to monitor the colonic motility and while each has contributed towards better understanding of colon motility, a significant limitation has been the spatial and temporal low-resolution colon motility data acquisition and analysis. This paper presents the study of employing bio-impedance characterization to monitor colonic motor activity. Direct distal colon stimulation was undertaken in anesthetized pigs to validate the bio-impedance scheme simultaneous with luminal manometry monitoring. The results indicated that the significant decreases of bio-impedance corresponded to strong colonic contraction in response to the electrical stimulation in the distal colon. The magnitude/power of the dominant frequencies of phasic colonic contractions identified at baseline (in the range 2–3 cycles per minute (cpm)) were increased after the stimulation. In addition, positive correlations have been found between bio-impedance and manometry. The proposed bio-impedance-based method can be a viable candidate for monitoring colonic motor pattern with high spatial and temporal resolution. The presented technique can be integrated into a closed-loop therapeutic device in order to optimize its stimulation protocol in real-time.

Measurement of Heart Contractility in Isolated Adult Human Primary Cardiomyocytes.

The evaluation of changes in heart contractility is essential during preclinical development for new cardiac- and non-cardiac-targeted compounds. This paper describes a protocol for assessing changes in contractility in adult human primary ventricular cardiomyocytes utilizing the MyoBLAZER, a non-invasive optical method that preserves the normal physiology and pharmacology of the cells. This optical recording method continuously measures contractility transients from multiple cells in parallel, providing both medium-throughput and valuable information for each individual cell in the field of view, enabling the real-time tracking of drug effects. The cardiomyocyte contractions are induced by paced electrical field stimulation, and the acquired bright field images are fed to an image-processing software that measures the sarcomere shortening across multiple cardiomyocytes. This method rapidly generates different endpoints related to the kinetics of contraction and relaxation phases, and the resulting data can then be interpreted in relation to different concentrations of a test article. This method is also employed in the late stages of preclinical development to perform follow-up mechanistic studies to support ongoing clinical studies. Thus, the adult human primary cardiomyocyte-based model combined with the optical system for continuous contractility monitoring has the potential to contribute to a new era of in vitro cardiac data translatability in preclinical medical therapy development.

COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation

Immunization with two mRNA vaccine doses elicits robust spike-specific CD8+ T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction of booster vaccination campaigns. However, the effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains unclear. Here we show that spike-specific CD8+ T cells are activated and expanded in all analyzed individuals receiving the 3rd and 4th mRNA vaccine shots. This CD8+ T cell boost response is followed by a contraction phase and lasts only for about 30-60 days. The spike-specific CD8+ T memory stem cell pool is not affected by the 3rd vaccination. Both 4th vaccination and breakthrough infections with Delta and Omicron rapidly reactivate CD8+ T memory cells. In contrast, neutralizing antibody responses display little boost effect towards Omicron. Thus, COVID-19 mRNA booster vaccination elicits a transient T effector cell response while long-term spike-specific CD8+ T cell immunity is conserved to mount robust memory recall targeting emerging variants of concern.

Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors

Imatinib has been reported to induce heart failure and/or QTc prolongation. To better understand their underlying mechanisms, we assessed its effects on cardiohemodynamic, electrocardiographic and echocardiographic variables along with biomarkers of myocardial damage. Imatinib mesylate in doses of 1 and 10 mg/kg was intravenously administered to the halothane-anesthetized beagle dogs (n = 4). Effects of imatinib on each phase of isovolumetric contraction, ejection, isovolumetric relaxation and filling were studied, whereas its electrophysiological effects on early and late repolarization were analyzed by measuring J-Tpeak and Tpeak-Tend, respectively. The low and high doses of imatinib provided peak plasma concentrations of 3.23 and 17.39 μg/mL, reflecting clinically-relevant and supratherapeutic concentrations, respectively. Neither lethal ventricular tachyarrhythmia nor cardiohemodynamic collapse was observed. Imatinib decreased amplitude of peak −dP/dt, indicating suppression of isovolumetric relaxation, whereas no significant change was detected in the other phases. Imatinib prolonged QTc and J-Tpeakc without altering Tpeak-Tend, indicating increase of net inward current, which leads to intracellular Ca2+ overload. Thus, imatinib suppressed ventricular active relaxation and early repolarization, which may suggest the association of mitochondrial dysfunction-associated inhibition of ATP production. Since those findings were also reported for dasatinib, sunitinib and lapatinib, they could be common cardiac phenotype of tyrosine kinase inhibitors in vivo.

The robustness of slow contraction and the shape of the scalar field potential

We use numerical relativity simulations to explore the conditions for a canonical scalar field ϕ minimally coupled to Einstein gravity to generate an extended phase of slow contraction that robustly smooths the universe for a wide range of initial conditions and then sets the conditions for a graceful exit stage. We show that to achieve robustness it suffices that the potential V(ϕ) is negative and M Pl|V, ϕ /V|≳5 during the smoothing phase. We also show that, to exit slow contraction, the potential must have a minimum. Beyond the minimum, we find no constraint on the uphill slope including the possibility of ending on a positive potential plateau or a local minimum with V min > 0.Our study establishes ultralocality, i.e., all spatial gradients quickly becoming negligible, for a wide range of potentials as a key both to robust smoothing and to graceful exit.

Role of PTHrP in attenuating transient pressure rises and associated afferent nerve activity of the rat bladder.

Parathyroid hormone-related protein (PTHrP) released from detrusor smooth muscle (DSM) as the bladder fills acts as an endogenous DSM relaxant to facilitate bladder storage function. Here, the effects of exogenous PTHrP on transient pressure rises (TPRs) in the bladder and associated afferent nerve activity during bladder filling were investigated. In anaesthetized rats, changes in the intravesical pressure were measured while the bladder was gradually filled with saline. Afferent nerve activity was simultaneously recorded from their centrally disconnected left pelvic nerves. In DSM strips, spontaneous and nerve-evoked contractions were isometrically recorded. The distribution of PTHrP receptors (PTHrPRs) in the bladder wall was also examined by fluorescence immunostaining. The bladders in which the contralateral pelvic nerve was also centrally disconnected developed nifedipine, an L-type voltage-dependent Ca2+ channel blocker-sensitive TPRs (< 3mmHg). Intravenous administration of PTHrP suppressed these TPRs and associated bursts of afferent nerve activity. In the bladders with centrally connected contralateral pelvic nerves, atropine, a muscarinic receptor antagonist-sensitive large TPRs (> 3mmHg) developed in the late filling phase. PTHrP diminished the large TPRs and corresponding surges of afferent nerve activity. In DSM strips, bath-applied PTHrP (10nM) suppressed spontaneous phasic contractions, while less affecting nerve-evoked contractions. PTHrPRs were expressed in DSM cells but not in intramural nerve fibers. Thus, PTHrP appears to suppress bladder TPRs and associated afferent nerve activity even under the influence of low degree of parasympathetic neural input during storage phases. Endogenous PTHrP may indirectly attenuate afferent nerve activity by suppressing TPRs to facilitate urinary accommodation.

Right ventricular and atrial strain in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy.

While immune checkpoint inhibitor (ICI) therapy significantly improves survival rates in advanced melanoma, ICI can evoke severe immune-related cardiovascular adverse events. Right ventricular (RV) dysfunction negatively impacts the outcomes in cardiovascular diseases and may be an early sign for overall cardiotoxicity. We aimed to assess RV function in melanoma patients undergoing ICI therapy using conventional echocardiographic and strain imaging techniques. We retrospectively examined 30 patients (40% women, age 59±13years) with advanced melanoma (stage III/IV) before and 4weeks after the start of ICI therapy (follow-up at 39±15days); n=15 of the patients received nivolumab, and n=15 received the combination therapy nivolumab/ipilimumab. Two-dimensional echocardiography with assessment of RV longitudinal strain of the free wall (RV-LSFW) and assessment of right atrial (RA) strain from speckle tracking was performed at baseline and after the start of ICI therapy. Short-term ICI therapy caused a reduction of RV-LSFW (-25.5±6.4% vs. -22.4±4.3%, P=0.002) and of RA strain during contraction phase (-10.6±3.5% vs. -7.7±3.1%, P=0.001). Conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and pulmonary artery systolic pressure were not different between the two time points (TAPSE 26±5 vs. 25±5mm, P=0.125; FAC 38±13% vs. 38±14%, P=0.750; and pulmonary artery systolic pressure 27±10 vs. 25±8mmHg, P=0.268). Analysis of RV and RA strain shows alterations even in a short-term follow-up, while changes in RV function are not visible by conventional RV parameters. Alterations in RV and RA strain could be early signs of cardiotoxicity and therefore should be assessed in patients undergoing ICI therapy.

Functional expression of NaV1.7 channels in freshly dispersed mouse bronchial smooth muscle cells.

Isolated smooth muscle cells (SMCs) from mouse bronchus were studied using the whole cell patch-clamp technique at ∼21°C. Stepping from -100 mV to -20 mV evoked inward currents of mean amplitude -275 pA. These inactivated (tau = 1.1 ms) and were abolished when external Na+ was substituted with N-Methyl-d-glucamine. In current-voltage protocols, current peaked at -10 mV and reversed between +20 and +30 mV. The V1/2s of activation and inactivation were -25 and -86 mV, respectively. The current was highly sensitive to tetrodotoxin (IC50 = 1.5 nM) and the NaV1.7 subtype-selective blocker, PF-05089771 (IC50 = 8.6 nM), consistent with NaV1.7 as the underlying pore-forming α subunit. Two NaV1.7-selective antibodies caused membrane-delineated staining of isolated SMC, as did a nonselective pan-NaV antibody. RT-PCR, performed on groups of ∼15 isolated SMCs, revealed transcripts for NaV1.7 in 7/8 samples. Veratridine (30 µM), a nonselective NaV channel activator, reduced peak current evoked by depolarization but induced a sustained current of 40 pA. Both effects were reversed by tetrodotoxin (100 nM). In tension experiments, veratridine (10 µM) induced contractions that were entirely blocked by atropine (1 µM). However, in the presence of atropine, veratridine was able to modulate the pattern of activity induced by a combination of U-46619 (a thromboxane A2 mimetic) and PGE2 (prostaglandin E2), by eliminating bursts in favor of sustained phasic contractions. These effects were readily reversed to control-like activity by tetrodotoxin (100 nM). In conclusion, mouse bronchial SMCs functionally express NaV1.7 channels that are capable of modulating contractile activity, at least under experimental conditions.

MiR-24-3p down-regulates the expression of the apoptotic factors FasL and BIM in human natural killer cells

MicroRNAs are involved in the regulation of different functions in immune and non-immune cells. Here we show that miR-24-3p functionally interacts with FASLG mRNA and down-regulates its expression. This interaction occurs in human natural killer cells (NK), leading to the modulation of FasL surface expression. Moreover, miR-24-3p also modulates the mRNA and protein expression of BIM in NK cells. Thus, it likely contributes to the control of both the extrinsic and intrinsic apoptotic pathways. In line with this hypothesis, inhibition of miR-24-3p improves both initiator caspase-8 and effector caspase-3 and -7 activities, increases cell apoptosis, and reduces cell viability. Our data suggest that miR-24-3p can act as a survival factor in NK cells, affecting the FasL-mediated killing of Fas expressing cells and the BIM-dependent cell death. More generally, miR-24-3p may condition the level of cell apoptosis, which increases at the contraction phase of the immune response when the clearance of various expanded effector cells is needed.

Mirabegron and solifenacin are effective for the management of the increased urinary frequency induced by psychological stress in female mice

Evidence to support the effectiveness of β3-adrenoceptor agonist mirabegron and anti-muscarinic solifenacin in the management of bladder dysfunction caused by psychological stress is lacking. This study investigates whether mirabegron or solifenacin reduces the bladder overactivity caused by water avoidance stress (WAS) in mice. Female mice were exposed to WAS for 1 h/day for 10 days and received either placebo, solifenacin or mirabegron in drinking water. Controls were age-matched without stress exposure. Voiding behaviour and functional isolated whole bladder responses during distension and in response to pharmacological agents and electrical field stimulation was investigated. Urinary frequency was significantly increased following stress. Mice treated with mirabegron or solifenacin displayed significantly fewer voiding events compared to the stressed mice, and voiding frequency in drug-treated animals was comparable to unstressed controls. The maximal contractile responses of bladders to carbachol were significantly enhanced by stress and reduced by mirabegron but not solifenacin. The frequency of phasic bladder contractions following stimulation with carbachol was significantly enhanced following stress and remained elevated in the mirabegron treated group. However, treatment with solifenacin significantly reduced the frequency of phasic contractions to unstressed control levels. Solifenacin and mirabegron are beneficial in reducing the overall voiding dysfunction caused by WAS in mice.