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Mortality rates of the aquacultured shrimp Litopenaeus vannamei injected with Vibrio parahaemolyticus are significantly increased when the bacterial challenge is accompanied by an immediate shift from well-aerated water to sub-lethal hypoxia (acute hypoxia). A more realistic scenario is that shrimp raised in intensive culture or in natural ecosystems would be exposed for longer periods of time to sub-lethal hypoxia (chronic hypoxia). The present study addressed the possibility that animals might adapt to chronic hypoxia, returning to a more disease- resistant status. Juvenile L. vannamei (1.0 - 1.5 g) were either maintained under normoxia or exposed to sublethal hypoxia (4% [O.sub.2], 2% [CO.sub.2] and pH of 6.8-7.0). After seven days animals from both exposure conditions were injected intramuscularly with an [LD.sub.50] dose ([10.sup.5]/shrimp) of V. parahaemolyticus. Both test groups were held under sub-lethal hypoxia for 48 hours and monitored for survival. Mortality rates were compared by a repeated measures two-way ANOVA. Chronic (7 day) hypoxia significantly increased mortality rates in challenged shrimp compared to acute hypoxia. Taken together with our previous studies (Mikulski et al., [2000] J. Shellfish Res. 19:301-311), these data show that both acute and chronic hypoxia increased susceptibility of L. vannameito bacterial challenge. Furthermore, these shrimp did not successfully adapt to overcome the suppressive effects of hypoxia on disease resistance, rather the animals displayed higher mortality rates with increased time of exposure to hypoxia. (USDA CSREES 99-35204-8555)

The effects of two beta(3)-adrenergic receptor agonists, (R)-4-[4-(3-cyclopentylpropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]benzenesulfonamide and (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)- ethyl]amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-indolinesulfonamide, on indices of metabolic and cardiovascular function were studied in anesthetized rhesus monkeys. Both compounds are potent and specific agonists at human and rhesus beta(3)-adrenergic receptors. Intravenous administration of either compound produced dose-dependent lipolysis, increase in metabolic rate, peripheral vasodilatation, and tachycardia with no effects on mean arterial pressure. The increase in heart rate in response to either compound was biphasic with an initial rapid component coincident with the evoked peripheral vasodilatation and a second more slowly developing phase contemporaneous with the evoked increase in metabolic rate. Because both compounds exhibited weak binding to and activation of rhesus beta(1)-adrenergic receptors in vitro, it was hypothesized that the increase in heart rate may be reflexogenic in origin and proximally mediated via release of endogenous norepinephrine acting at cardiac beta(1)-adrenergic receptors. This hypothesis was confirmed by determining that beta(3)-adrenergic receptor agonist-evoked tachycardia was attenuated in the presence of propranolol and in ganglion-blocked animals, under which conditions there was no reduction in the evoked vasodilatation, lipolysis, or increase in metabolic rate. It is not certain whether the beta(3)-adrenergic receptor-evoked vasodilatation is a direct effect of compounds at beta(3)-adrenergic receptors in the peripheral vasculature or is secondary to the release or generation of an endogenous vasodilator. Peripheral vasodilatation in response to beta(3)-adrenergic receptor agonist administration was not attenuated in animals administered mepyramine, indomethacin, or calcitonin gene-related peptide(8-37). These findings are consistent with a direct vasodilator effect of beta(3)-adrenergic receptor agonists.

The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is stimulated in vitro by quinidine. A similar effect is observed in incubations with monkey liver microsomes. We describe an in vivo interaction of diclofenac and quinidine that leads to enhanced clearance of diclofenac in monkeys. After a dose of diclofenac via portal vein infusion at 0.055 mg/kg/h, steady-state systemic plasma drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadministered with quinidine (0.25 mg/kg/h) via the same route, the corresponding plasma diclofenac concentrations were 50, 59, and 18 ng/ml, representing 57, 56, and 56% of control values, respectively. In contrast, steady-state systemic diclofenac concentrations in the same three monkeys were elevated 1.4 to 2.5 times when the monkeys were pretreated with L-754,394 (10 mg/kg i.v.), an inhibitor of CYP3A. Further investigation indicated that the plasma protein binding (>99%) and blood/plasma ratio (0.7) of diclofenac remained unchanged in the presence of quinidine. Therefore, the decreases in plasma concentrations of diclofenac after a combined dose of diclofenac and quinidine are taken to reflect increased hepatic clearance of the drug, presumably resulting from the stimulation of CYP3A-catalyzed oxidative metabolism. Consistent with this proposed mechanism, a 2-fold increase in the formation of 5-hydroxydiclofenac derivatives was observed in monkey hepatocyte suspensions containing diclofenac and quinidine. Stimulation of diclofenac metabolism by quinidine was diminished when monkey liver microsomes were pretreated with antibodies against CYP3A. Subsequent kinetic studies indicated that the K(m) value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus 59 microM), whereas V(max) increased 2.5-fold in the presence of quinidine. These data suggest that the catalytic capacity of monkey hepatic CYP3A toward diclofenac metabolism is enhanced by quinidine.

Administration of human gonadotropins such as hFSH, hLH, and hCG to rhesus macaques can result in formation of anti-human gonadotropin antibodies. To determine whether the presence of these antibodies interferes with subsequent fertility, sixteen female rhesus macaques (Macaca mulatta) with known antibody levels were bred with male rhesus macaques. The presence of antibodies did not interfere with conception or maintenance of pregnancy. Furthermore, antibody titers did not increase during gestation or following the resolution of pregnancy.