Low concentrations of the stable prostaglandin endoperoxide U44069 stimulate shape change in quin2-loaded platelets without a measurable increase in [Ca2+]i

AbstractDose-response relationships for raised cytoplasmic free calcium concentration, [Ca2+]i, and shape change were measured simultaneously in quin2-loaded human platelets. With the calcium ionophore ionomycin the threshold [Ca2+]i for shape change was 300 nM with a maximal response at 800 nM. With 1 mM external Ca2+ the U44069 concentrations required to stimulate half-maximal shape change and an increase in [Ca2+]i were 2 and 41 nM, respectively. For PAF these values were 8.7 and 164 pgml, respectively. Low concentrations of U44069 and PAF evoked substantial shape change without any rise in [Ca2+]i. In the absence of external Ca2+, U44069 stimulated half-maximal shape change at 2 nM, and half-maximal elevation of [Ca2+]i at 69 nM: here, increased [Ca2+i never reached the threshold [Ca2+i for shape change derived with ionomycin. These results suggest that some transduction mechanism other than elevated [Ca2+]i, as yet unidentified, can cause shape change.U44069Ionomycin Ca2+Shape changePlateletPlatelet-activating facto

Selective amylin antagonist suppresses rise in plasma lactate after intravenous glucose in the rat Evidence for a metabolic role of endogenous amylin

AbstractData 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 mmol 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

Flexibility versus rigidity for orally bioavailable cyclic hexapeptides

Cyclic peptides and macrocycles have the potential to be membrane permeable and orally bioavailable, despite often not complying with the “rule of five” used in medicinal chemistry to guide the discovery of oral drugs. Here we compare solvent-dependent three-dimensional structures of three cyclic hexapeptides containing d-amino acids, prolines, and intramolecular hydrogen bonds. Conformational rigidity rather than flexibility resulted in higher membrane permeability, metabolic stability and oral bioavailability, consistent with less polar surface exposure to solvent and a reduced entropy penalty for transition between polar and nonpolar environments

Amylin and epinephrine have no direct effect on glucose transport in isolated rat soleus muscle

AbstractAmylin and epinephrine did not significantly affect insulin stimulated, or basal, 3-O-methylglucose transport in isolated rat soleus muscle, as measured by the release of 3-O-methylglucose from pre-loaded tissue. Both amylin and epinephrine inhibited insulin-stimulated 2-deoxyglucose uptake (by 25% and 38%, respectively) in soleus muscle from fed rats but not from fasted rats. The latter results are consistent with amylin and epinephrine stimulating glycogenolysis and inhibiting hexokinase activity by intracellular accumulation of glucose 6-phosphate. We conclude that amylin, like epinephrine, does not specifically inhibit glucose transporters in skeletal muscle