Electrophysiological and proarrhythmic parameters in transmural canine left-ventricular needle biopsies.

This study was designed to validate the use of small, transmural, left-ventricular biopsies in the dog for investigations of electrophysiological and proarrhythmic properties of the heart. This technique could facilitate pharmacological in vitro testing in remodelled hearts of both man and animal. Small, transmural, semi-cylindrical, left-ventricular biopsies from dogs with normal sinus rhythm (SR) were characterized electrophysiologically and compared with biopsies from electrically remodelled hearts from dogs with chronic, complete AV-block (CAVB). In at least five biopsy segments recordings were made to determine the action potential duration (APD), the transmural gradient of repolarization, the maximal transmural dispersion (deltatM(max)) and presence of early after-depolarizations (EADs) at different pacing cycle lengths (PCLs) in the absence and presence of a class-III agent, ibutilide (10(-6) M). The biopsies showed stable and normal AP characteristics, a conduction velocity of 0.22 +/- 0.05 m/s and normal frequency dependence of the APD. The location of the longest APD varied, thus creating transmural repolarization gradients with differing morphology. Ibutilide prolonged the APD, accentuated repolarization gradients and induced EADs. CAVB biopsies had significantly longer APDs, a larger dispersion of repolarization and showed more EADs in the presence of ibutilide than SR biopsies. We conclude that this biopsy technique provides coherent and valid transmural electrophysiological data in dogs under various conditions.

2-Iminohomopiperidinium salts as selective inhibitors of inducible nitric oxide synthase (iNOS).

An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.