These results suggest that beta3-AR agonists may be effective in the treatment of urinary frequency.

These results suggest that beta3-AR agonists may be effective in the treatment of urinary frequency.

1 Electrical stimulation evoked release of 3 H-noradrenaline (NA) and 14 C-acetylcholine (ACh), as well as neurally evoked contractions were measured at various (1 ± 40 Hz, 100 shocks) stimulation frequencies in bladder strips from neurally intact (NI) and spinal cord transected (SCT) rats. 2 The frequency response curves for ACh and NA release were shifted to the left in SCT bladder strips as compared to NI bladder strips. 3 Atropine (1 mM) depressed ACh release in NI bladder strips at high frequency stimulation (10 and 40 Hz) but not at low frequency stimulation (2 ± 5 Hz). However, in SCT bladders, atropine depressed ACh release both at low and high frequencies of stimulation, indicating that muscarinic facilitation occurs at lower frequencies. 4 Atropine depressed the release of NA in NI bladders at only 40 Hz stimulation, but depressed release at all frequencies in SCT bladders. 5 The amplitude of neurally evoked contractions of bladder strips from NI rats was enhanced as the frequency of stimulation was increased from 1 to 40 Hz (80 shocks). The frequency response curve was shifted to the left in SCT bladders. Atropine blocked the neurally evoked contractions in SCT bladder strips to a greater extent than the contractions in NI strips indicating a cholinergic dominance in the SCT bladders. 6 Maximal contractile force of SCT bladder strips evoked by neural stimulation at 20 Hz 10 shocks and 80 shocks was signi®cantly lower than that of NI bladder strips, whereas the release of ACh was signi®cantly higher in SCT than NI bladders indicating a postjunctional defect in the SCT preparations. 7 It is suggested that presynaptic muscarinic facilitatory mechanisms are upregulated in the cholinergic and adrenergic nerve terminals in SCT bladders leading to a larger relative contractile response at lower frequencies of stimulation (2 ± 5 Hz). Thus the hyperre¯exic bladder occurring after spinal cord injury may be due in part to an enhancement of transmitter release at bladder postganglionic nerve terminals.

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A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.

1 Neurally evoked contractions and release of 3 H-acetylcholine (ACh) during electrical ®eld stimulation were measured in rat urinary bladder strips. 2 The a 1 agonist phenylephrine (PE, 2 ± 8 mM) increased the amplitude of neurally evoked contractions, facilitated the release of ACh and increased the baseline tone of the bladder strips. 3 The PE-induced facilitation of the contractions did not signi®cantly change during a prolonged exposure to PE (120 min), whereas the PE-induced rise in baseline tone gradually decreased to 65% of the initial value. 4 Low concentrations of speci®c a 1A antagonists, 5-methyl urapidil (5-MU), REC15/2739 and WB-4101 competitively inhibited the facilitation of the neurally-evoked contractions (pA 2: 8.77; 9.59 and 9.62, respectively), whereas higher concentrations of 5-MU (IC 50 : 48 nM) were required to suppress the PE-rise in baseline. WB-4101 (100 mM) inhibited the PE-induced facilitation of ACh release. 5 The irreversible a 1B antagonist chloroethyl-clonidine (CEC, 10 ± 50 mM) inhibited the PE-evoked rise in base line tone, but did not aect the PE-induced facilitation of the neurally evoked contractions nor the facilitation of ACh release. However, CEC increased the area and amplitude of the neurally-evoked contractions by 261+33 and 47.2+8.4%, respectively. Atropine signi®cantly inhibited the CEC evoked increase in area and amplitude of the electrically evoked contractions (76.5+4.8 and 40.8+3%, respectively) indicating that CEC facilitated the cholinergic responses of the electrically stimulated bladder strips. 6 It is concluded that a 1A and CEC sensitive a 1B and/or a 1D adrenoceptors are expressed in the rat bladder in dierent locations. On the cholinergic nerve terminals a 1A adrenoceptors mediate prejunctional facilitation, whereas postjunctional a 1B /a 1D adrenoceptors mediate smooth muscle contraction.

Doxorubicin (DX)-treated mice represent an animal model for studying new drugs for heart disease. Coincidentally, in the collection of damaged myocardial tissue, thrombosis was detected in the atrium. The incidence reached 75% in mice given 4 mg/kg DX iv 10 times. They were white thrombi consisting of the fibrin, platelets, and neutrophils. Cardiac muscle damage was more prominent in the atria than in the ventricles. Light microscopically, vacuolization and degeneration of atrial myocytes and interstitial inflammatory cell infiltration were observed. Electron microscopy revealed dilatation of the sarcoplasmic reticulum and an increase in number of normal and/or degenerate mitochondria. Inflammation extended from the cardiac muscle to the endocardium. The cause of atrial thrombosis in DX-treated mice is unknown but may relate to endocardial damage and changes of blood flow in the atrium secondary to cardiac muscle damage. DX-treated mice could serve as an experimental animal model for the evaluation of efficacy and toxicity of antithrombotic or antiplatelet drugs.

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