1 BW12C, a potent left-shifting anti-sickling compound in vitro, was administered to normal healthy male Caucasian volunteers. 2 Doses of 2-20 mg kg-1 given by intravenous infusion over 1 h caused a dosedependent left-shift of the blood-oxygen saturation curve and at the highest dose some 16% of the haemoglobin existed in a high affinity form. 3 Peak left-shift was observed at the end of infusion and decayed thereafter with a mean half-life of approximately 3 h. 4 There were no adverse systemic effects, either clinical, biochemical or haematological, but there was some local irritation at the intravenous infusion site if the infusion was too concentrated. 5 Pharmacokinetic measurements indicated uptake into erythrocytes, low levels in plasma and a volume of distribution not appreciably greater than the blood volume. A pilot radiolabel study indicated extensive metabolism with elimination into the urine.
Genetically determined obesities, involving leptin- and melanocortin-signaling pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four medial cell groups contain leptin receptors. To determine which of these cell groups normally mediates the effects of leptin on food intake and body weight gain, we injected colchicine bilaterally into each nucleus and determined the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in sham-lesioned rats decreased food intake during the dark period, but not during the light period. Lesions of the arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivity; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivity to leptin on feeding and body weight gain. Although rats with ARC and PVN lesions were obese, they were still capable of reducing caloric efficiency over the 5 days of study and increasing uncoupling protein content in interscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathways. We conclude that the medial hypothalamic cell groups, each with a different role in energy balance, are all necessary for normal leptin responsiveness.
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