Protein composition of endurance trained human skeletal muscle.

Evidence suggests that myofibers from endurance trained skeletal muscle display unique contractile parameters. However, the underlying mechanisms remain unclear. To further elucidate the influence of endurance training on myofiber contractile function, we examined factors that may impact myofilament interactions (i. e., water content, concentration of specific protein fractions, actin and myosin content) or directly modulate myosin heavy chain (MHC) function (i. e., myosin light chain (MLC) composition) in muscle biopsy samples from highly-trained competitive (RUN) and recreational (REC) runners. Muscle water content was lower (P<0.05) in RUN (73±1%) compared to REC (75±1%) and total muscle and myofibrillar protein concentration was higher (P<0.05) in RUN, which may indicate differences in myofilament spacing. Content of the primary contractile proteins, myosin (0.99±0.08 and 1.01±0.07 AU) and actin (1.33±0.09 and 1.27±0.09 AU) in addition to the myosin to actin ratio (0.75±0.04 and 0.80±0.06 AU) was not different between REC and RUN, respectively, when expressed relative to the amount of myofibrillar protein. At the single-fiber level, slow-twitch MHC I myofibers from RUN contained less (P<0.05) MLC 1 and greater (P<0.05) amounts of MLC 3 than REC, while MLC composition was similar in fast-twitch MHC IIa myofibers between REC and RUN. These data suggest that the distinctive myofiber contractile profile in highly-trained runners may be partially explained by differences in the content of the primary contractile proteins and provides unique insight into the modulation of contractile function with extreme loading -patterns.

Synthesis and antiarrhythmic activity of cis-2,6-dimethyl-alpha,alpha-diaryl-1-piperidinebutanols.

A series of alpha,alpha-diaryl-1-piperidinebutanols was evaluated for antiarrhythmic activity in the coronary ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group yielded compounds with the best antiarrhythmic profiles in this series. The length of the methylene chain separating the diarylcarbinol and the amino group was not crucial. Substitution of a hydrogen or a number of functional groups for the hydroxyl group had little effect on efficacy or duration but yielded compounds that produced severe tachycardias. Replacement of one of the aryl groups by hydrogen or a pyridinyl or cyclohexyl group had little effect on efficacy but decreased the duration of action. Compound 18 (pirmenol) was ultimately chosen for further studies and is now being investigated in man.

Synthesis and antiarrhythmic activity of alpha-[(diarylmethoxy)methyl]-1-piperidineethanols.

A series of alpha-[(diarylmethoxy)methyl]-1-piperidineethanols was evaluated for antiarrhythmic activity in the coronary artery ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group afforded the best antiarrhythmic agents in this series and was essential for long duration of action. This investigation indicated that quaternary ammonium salts were not essential for a long duration of action. It was also shown that the antiarrhythmic activity could be separated from the tachycardia frequently caused by this type of agent.

Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types.

The synthesis and angiotensin converting enzyme (ACE) inhibiting activities of quinapril (CI-906, 22), its active diacid (CI-928, 33), and its dimethoxy analogue (CI-925, 25) are reported. These tetrahydro-3-isoquinolinecarboxylic acid derivatives possess equivalent in vitro potency and in vivo efficacy to enalapril. Sulfhydryl analogues with the same structural variation are also highly potent. In contrast, tetrahydro-1-isoquinolinecarboxylic acid and homologous isoindoline-1-carboxylic acid analogues show a striking divergence in potency between the two types, sulfhydryl analogues being essentially inactive, while non-sulfhydryl analogues are equipotent with the proline prototype. This is the first evidence suggesting that alternate binding modes may exist for the two major structural classes of small molecule ACE inhibitors.