The release of Gd from all linear Gd3+ complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd3+ from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd3+ from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.

OBJECTIVE To evaluate the potential of sildenafil, vardenafil and tadalafil, all phosphodiesterase‐5 (PDE‐5) inhibitors used for treating erectile dysfunction, for treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). MATERIALS AND METHODS The mRNA expression of the PDE‐5 was determined in rat LUT tissues. The PDE‐5 inhibitors were also tested in organ‐bath experiments and in a partial bladder outlet obstruction (BOO) rat model in vivo. RESULTS The highest PDE‐5 mRNA expression was in the bladder, followed by the urethra and prostate. PDE‐5 inhibitors dose‐dependently reduced the contraction of the isolated bladder, urethral and prostate strips. The rank order of potency was vardenafil > sildenafil > tadalafil. In human prostate stromal cells vardenafil inhibited cell proliferation and was more effective than tadalafil and sildenafil. In the BOO model, there was a reduction in the non‐voiding contractions after bolus intravenous administration of 3 mg/kg sildenafil and vardenafil. CONCLUSION These results show that PDE‐5 is expressed in LUT tissues. PDE‐5 inhibitors induced significant relaxation of these tissues, inhibited the proliferation of human prostate stromal cells and reduced the irritative symptoms of BPH/LUTS in vivo. Therefore, PDE‐5 inhibitors could be used as an effective treatment for BPH/LUTS.

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Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.

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Background and purpose: Cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory and cardiovascular disorders. Their actions are mediated by CysLT1 and CysLT2 receptors. Here we report the discovery of 3-({[(1S,3S)-3-carboxycyclohexyl]amino}carbonyl)-4-(3-{4-[4-(cyclo-hexyloxy)butoxy]phenyl}propoxy) benzoic acid (HAMI3379), the first potent and selective CysLT2 receptor antagonist. Experimental approach: Pharmacological characterization of HAMI3379 was performed using stably transfected CysLT1 and CysLT2 receptor cell lines, and isolated, Langendorff-perfused, guinea pig hearts. Key results: In a CysLT2 receptor reporter cell line, HAMI3379 antagonized leukotriene D4-(LTD4-) and leukotriene C4-(LTC4-) induced intracellular calcium mobilization with IC50 values of 3.8 nM and 4.4 nM respectively. In contrast, HAMI3379 exhibited very low potency on a recombinant CysLT1 receptor cell line (IC50 > 10 000 nM). In addition, HAMI3379 did not exhibit any agonistic activity on both CysLT receptor cell lines. In binding studies using membranes from the CysLT2 and CysLT1 receptor cell lines, HAMI3379 inhibited [ 3 H]-LTD4 binding with IC50 values of 38 nM and >10 000 nM respectively. In isolated Langendorff-perfused guinea pig hearts HAMI3379 concentration-dependently inhibited and reversed the LTC4-induced perfusion pressure increase and contractility decrease. The selective CysLT1 receptor antagonist zafirlukast was found to be inactive in this experimental setting. Conclusions and implications: HAMI3379 was identified as a potent and selective CysLT2 receptor antagonist, which was devoid of CysLT receptor agonism. Using this compound, we showed that the cardiac effects of CysLTs are predominantly mediated by the CysLT2 receptor.

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The results of this preclinical study support the use of 5/6-nephrectomized rats as a model for prolonged circulation time of GBCAs as seen in patients with severe renal impairment. Surgically induced severe renal impairment resulted in delayed clearance of the administered GBCAs in the study animals. The highest amount of Gd was observed in the skin after treatment with the nonionic linear GBCAs, whereas the lowest Gd values were observed after treatment with the macrocyclic agent. This suggests that the difference in the Gd values observed in rat skin tissue after treatment with the different GBCAs is caused of a different propensity of the different GBCAs to release Gd in vivo. However, the analytical method used does not distinguish between chelated and unchelated Gd.