G protein-coupled octopamine receptors of insects and other invertebrates represent counterparts of adrenoceptors in vertebrate animals. The ␣ 2 -adrenoceptor agonist medetomidine, which is in clinical use as a veterinary sedative agent, was discovered to inhibit the settling process of barnacles, an important step in the ontogeny of this crustacean species. Settling of barnacles onto ship hulls leads to biofouling that has many harmful practical consequences, and medetomidine is currently under development as a novel type of antifouling agent. We now report that medetomidine induces hyperactivity in the barnacle larvae to disrupt the settling process. To identify the molecular targets of medetomidine, we cloned five octopamine receptors from the barnacle Balanus improvisus. We show by phylogenetic analyses that one receptor (BiOct␣) belongs to the ␣-adrenoceptor-like subfamily, and the other four (BiOct␤-R1, BiOct␤-R2, BiOct␤-R3, and BiOct␤-R4) belong to the ␤-adrenoceptor-like octopamine receptor subfamily. Phylogenetic analyses also indicated that B. improvisus has a different repertoire of ␤-adrenoceptor-like octopamine receptors than insects. When expressed in CHO cells, the cloned receptors were activated by both octopamine and medetomidine, resulting in increased intracellular cAMP or calcium levels. Tyramine activated the receptors but with much lesser potency than octopamine. A hypothesis for receptor discrimination between tyramine and octopamine was generated from a homology three-dimensional model. The characterization of B. improvisus octopamine receptors is important for a better functional understanding of these receptors in crustaceans as well as for practical applications in development of environmentally sustainable antifouling agents.

The interrelationships between biliary bile acid, lecithin and cholesterol secretion rates were studied druing depletion of the bile acid pool and during duodenal administration of cholic or chenodeoxycholic acid in thirteen patients 7-12 days after operation for uncomplicated gallstone disease. The mean lecithin secretion rate was signigicantly higher during cholic acid than during chenodeoxycholic acid infusion. The relationship between bile acid and cholesterol secretion rates was curvilinear, y = x/(a + bx) during bile acid pool depletion and during duodenal cholic acid infusion. At low bile acid secretion rates, during bile acid pool depletion and during cholic acid infusion, the lecithin secretion rate was significantly correlated to the cholesterol secreation rate. The bile acid and cholesterol secretion rates were not significantly correlated during chenodeoxycholic acid infusion. However, under this experimental condition a significant curvilinear relationship between lecithin and cholesterol secretion rates was found. The hepatic bile became unsaturated in cholesterol at significantly lower bile acid secretion rate during chenodeoxycholic acid infusion (10.7 +/- 0.3 mumol min-1) than during cholic acid infusion (15.6 +/- 0.5 mumol min-1).

Significant neuroprotective effects of angiotensin II type 2 (AT) receptor (AT receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

Total bile acid concentration was determined in systemic and portal serum and in liver tissue from patients with presumably normal liver function, and from patients with extrahepatic cholestasis. Systemic and portal serum bile acids were also determined in patients with alcoholic liver cirrhosis. In 5 patients, in whom a portal catheter was inserted through the umbilical vein, the diurnal variation in systemic and portal serum bile acid concentration was studied. In patients with presumably normal liver function the fasting systemic serum bile acid concentration was 4.8+/-0.5 mumol times 1(-1), and the portal concentration was 12.9+/-1.5 mumol times 1(-1). In cholestasis and liver cirrhosis the systemic and portal bile acid concentration was substantially elevated. The bile acid concentration gradient between systemic serum, portal serum, liver tissue, and hepatic bile was 1:3:80:2600 in the patients with normal liver function. In both the cholestatic and cirrhotic condition the systemic and portal serum bile acid concentration was equilibrated. Postprandially both the systemic and portal bile acid concentration increased, but the gradient between these concentrations was unchanged. The results are compatible with the hypothesis that portal and systemic serum bile acid concentrations are determined by the intestinal absorption rate in subjects with normal liver function and by the hepatic and renal clearance capacity in cholestatic and cirrhotic conditions.

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