ABSTRACT1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time-and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silverstained degenerating nigral neurons. The resistance of 7-NIinjected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTPinduced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.

The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.

A wide variety of 2-substituted aminoadenosines were prepared for comparison with the moderately A2 receptor selective adenosine agonist 2-anilinoadenosine (CV-1808). High selectivity combined with significant affinity at the A2 receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A2 selective compound, was modified by introduction of a variety of substituents in the benzene ring and the side chain. Some of these changes led to improved A2 affinity and increased selectivity. Replacement of the phenyl moiety by cyclohexenyl produced a 210-fold selective agonist 3ag (CGS 22989) whereas the cyclohexanyl analogue 3af (CGS 22492) was 530-fold selective at the A2 site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists.

Aims Functional decline due to skeletal muscle abnormalities leads to poor outcomes in patients with acute heart failure (AHF). The 6-minute walking test (6MWT) reliably evaluates functional capacity, but its technical difficulty for the elderly often limits its benefits. Although the Short Physical Performance Battery (SPPB) is a comprehensive measure of physical performance, its role in AHF remains unclear. This study aimed to examine the prognostic significance of SPPB compared to the 6MWT in elderly patients hospitalized for AHF. Methods and Results We retrospectively analyzed 1,192 elderly patients with AHF whose SPPB and 6MWT were measured during the hospitalization. The primary outcome measure was defined as a composite of all-cause death and heart failure readmission until 1 year after discharge. Patients with lower SPPB scores (0 − 6, n = 373) had significantly poorer outcomes than those with higher SPPB scores (7 − 12, n = 819) even after multivariable adjustment (adjusted hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 1.01 − 1.61, p = 0.049), similar to those with shorter 6MWT (<median) than those with longer 6MWT (adjusted HR:1.61, 95% CI:1.27 − 2.04, p < 0.001). Although both SPPB and 6MWT (net reclassification index [NRI]: 0.139, p = 0.036 and NRI: 0.350, p < 0.001, respectively) exhibited incremental prognostic value over conventional risk factors of HF, the additive prognostic effect of 6MWT was superior to that of SPPB (NRI: 0.300, p < 0.001). Conclusions Reduced functional capacity assessed by either the SPPB or 6MWT was associated with worse outcomes in hospitalized elderly patients with AHF. The incremental prognostic value over the conventional risk factors was higher in 6MWT than in SPPB. Trial Registration UMIN000023929

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