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Data presented here provide the first demonstration that circulating amylin regulates metabolism in vivo, and support an endocrine hormonal role that is distinct from its autocrine action at pancreatic islets. When rats were pre-treated with the potent amylin antagonist AC187 (n = 18), and then administered a 2 mm01 glucose load, the rise in plasma lactate was less than in rats administered glucose only (n = 27; P < 0.02). When rats were treated so that plasma glucose and insulin profiles were similar (n = 8), the increase in plasma lactate in the presence of AC187 was only 50.3% as high as the increase when AC187 was absent (P < 0.001). These experimental results fit with the view that some of the lactate appearing in plasma after a glucose load comes from insulin-sensitive tissues. The experiments also support the view that an important fraction of the increase in lactate depends on processes inhibited by a selective amylin antagonist, most likely amylin action in muscle.

The pentapeptide Ser-Asn-Val-Phe-Ala-OBzl has been identified as the smallest inhibitory peptide of myosin light chain kinase (MLCK) derived from the primary sequence of the light chain phosphorylation site. The specific contributions of individual amino acid side chains and backbone elements of this pentapeptide toward the stabilization of the enzyme-inhibitor (E-I) complex have been evaluated. The potency of these peptides as inhibitors of MLCK has been enhanced by the incorporation of synthetic nonnatural amino acids into the sequence. Finally, it has been demonstrated that these peptide sequences could be converted into pseudopeptides with synthetic nonpeptide subunits designed to mimic peptide bonds, and that certain pseudopeptides retained the high-affinity inhibition of the parent pentapeptides.

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