Effects of carvedilol on structural and functional outcomes and plasma biomarkers in the mouse transverse aortic constriction heart failure model.

Introduction: Despite the widespread use of the mouse transverse aortic constriction heart failure model, there are no reports on the characterization of the standard-of-care agent carvedilol in this model.

Methods: Left ventricular pressure overload was produced in mice by transverse aortic constriction between the innominate and left common carotid arteries. Carvedilol was administered at multiple dose levels (3, 10 and 30 mg/kg/day ; yielding end-study mean plasma concentrations of 0.

Early echocardiographic predictors of outcomes in the mouse transverse aortic constriction heart failure model.

Introduction: Mouse transverse aortic constriction (TAC) is a widely-used model of pressure overload-induced heart failure. An intrinsic limitation of the model is variability in the response to pressure overload even when employing a standard severity of stenosis. Few literature studies have explicitly reported the use of entry criteria or early predictors to mitigate variability and enrich outcomes in this model.

Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.

The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species.

Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective β3 adrenergic receptor agonists for the treatment of overactive bladder.

A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity.

Transurethral bladder catheterization of male rhesus macaques: a refinement of approach.

Background: Successful transurethral bladder catheterization in male non-human primates can be challenging. An optimized approach for consistent and reproducible catheterization using a refined technique is described.

Methods: Under sedated and non-sedated conditions, transurethral bladder catheterization was performed on 25 male rhesus macaques of varying ages and body weights over time.

Comparative analysis of the effects of antimuscarinic agents on bladder functions in both nonhuman primates and rodents.

Both the physiological role of muscarinic receptors for bladder function and the therapeutic efficacy of antimuscarinic agents for overactive bladder syndrome are well documented. We investigated the effect of antimuscarinic agents with different subtype selectivity on urodynamic parameters in nonhuman primates and rodents and compared plasma levels of these agents between species. Anesthetized rhesus monkeys were transurethrally catheterized, and the bladder was infused with saline.

Correlation between pharmacologically-induced changes in cystometric parameters and spinal c-Fos expression in rats.

The inhibition of bladder sensory transmission is critical for the pharmacotherapy of urine storage symptoms. The purpose of this study is to examine the correlation between pharmacologically-induced changes in cystometric parameters and spinal c-Fos expression in anesthetized rats with bladder hyperactivity induced by the intravesical infusion of acetic acid. Animals were intravenously infused with either oxybutynin (OXY), a muscarinic receptor antagonist, tamsulosin (TAM), an alpha1-adrenoceptor antagonist, CL316243 (CL), a beta3-adrenoceptor agonist, or saline.

Inter-strain tissue-infiltrating T cell responses to minor histocompatibility antigens involved in graft-versus-host disease as determined by Vbeta spectratype analysis.

Lethal graft-vs-host disease (GVHD) can be induced between MHC-matched murine strains expressing multiple minor histocompatibility Ag differences. In the B6->BALB.B model, both CD4(+) and CD8(+) donor T cells can mediate lethal GVHD, whereas in the B6->CXB-2 model, only CD8(+) T cells are lethal.