Insulin resistance in the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes.

The Zucker diabetic fatty (ZDF) rat is a commonly used animal model of type 2 diabetes yet complete descriptions of insulin resistance in this model are limited. We present a full characterisation of in vivo insulin resistance in obese (fa/fa) animals compared to lean (+/?) littermates. Anaesthetised, ten-week old, obese ZDF rats and their lean littermates underwent a hyperinsulinaemic euglycaemic glucose clamp. Compared with lean littermates, obese ZDF rats required an 89% lower glucose infusion rate to maintain euglycaemia and showed a 35% decrease in peripheral glucose disposal. Insulin-stimulated glucose uptake (R(g')) in obese animals was also significantly less in all skeletal muscles studied. R(g') in cardiac and white adipose tissue was not different between the two groups. Total glycogen content in skeletal and cardiac muscle was significantly less in obese animals, while total glycogen content in the liver was significantly greater than in lean littermates. Glycogen synthesis was also decreased in skeletal muscle of obese animals. Compared with lean animals, total triglyceride content was significantly greater in skeletal muscle, heart and liver of obese ZDF rats. Obese animals also showed significantly increased glucose incorporation into lipid in all of these tissues, indicating an increase in lipogenesis. Collectively, these results provide an integrated characterisation of in vivo insulin resistance in obese ZDF rats and a direct comparison with lean littermates.

Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity.

The role of renal sympathetic nerve activity (RSNA) in the physiological regulation of medullary blood flow (MBF) remains ill defined, yet regulation of MBF may be crucial to long-term arterial pressure regulation. To investigate the effects of reflex increases in RSNA on intrarenal blood flow distribution, we exposed pentobarbital sodium-anesthetized, artificially ventilated rabbits (n = 7) to progressive hypoxia while recording RSNA, cortical blood flow (CBF), and MBF using laser-Doppler flowmetry. Another group of animals with denervated kidneys (n = 6) underwent the same protocol. Progressive hypoxia (from room air to 16, 14, 12, and 10% inspired O(2)) significantly reduced arterial oxygen partial pressure (from 99 +/- 3 to 65 +/- 2, 51 +/- 2, 41 +/- 1, and 39 +/- 2 mmHg, respectively) and significantly increased RSNA (by 8 +/- 3, 44 +/- 25, 62 +/- 21, and 76 +/- 37%, respectively, compared with room air) without affecting mean arterial pressure. There were significant reductions in CBF (by 2 +/- 1, 5 +/- 2, 11 +/- 3, and 14 +/- 2%, respectively) in intact but not denervated rabbits. MBF was unaffected by hypoxia in either group. Thus moderate reflex increases in RSNA cause renal cortical vasoconstriction, but not at vascular sites regulating MBF.

Neural regulation of renal blood flow: a re-examination.

1. The importance of renal sympathetic nerve activity (RSNA) in the regulation of renal function is well established. However, it is less clear how the renal vasculature responds to the different mean levels and patterns of RSNA. While many studies have indicated that small to moderate changes in RSNA preferentially regulate renin secretion or sodium excretion and only large changes in RSNA regulate renal blood flow (RBF), other experimental evidence suggests that small changes in RSNA can influence RBF 2. When RSNA has been directly measured in conjunction with RBF, it appears that a range of afferent stimuli can induce reflex changes in RBF. However, many studies in a variety of species have measured RBF only during stimuli designed to reflexly increase or decrease sympathetic activity, but have not recorded RSNA. While this approach can be informative, it is not definitive because the ability of the vasculature to respond to RSNA may, in part, reflect the resting level of RSNA and, therefore, the vasoconstrictive state of the vasculature under the control conditions. 3. Further understanding of the control of RBF by RSNA has come from studies that have analysed the underlying rhythms in sympathetic nerve activity and their effect on the cardiovascular system. These studies show that the frequency-response characteristic of the renal vasculature is such that higher frequency oscillations in RSNA (above 0.6 Hz) contribute to setting the mean level of RBF. In comparison, lower frequency oscillations in RSNA can induce cyclic vasoconstriction and dilation in the renal vasculature, thus inducing oscillations in RBF. 4. In summary, the present review discusses the neural control of RBF, summarizing evidence in support of the hypothesis that RBF is under the influence of RSNA across the full range of RSNA.

Differential regulation of the oscillations in sympathetic nerve activity and renal blood flow following volume expansion.

Renal sympathetic nerve activity (RSNA) and renal blood flow (RBF) both show oscillations at various frequencies but the functional significance and regulation of these oscillations is not well understood. To establish whether the strength of these oscillations is under differential control we measured the frequency spectrum of RSNA and RBF following volume expansion in conscious rabbits. Seven days prior to experiment animals underwent surgery to implant an electrode for recording renal nerve activity and a flow probe for recording RBF. Volume expansion (Haemaccel, 1.5 ml min(-1) kg(-1) for 15 min) resulted in a 25 +/- 5% decrease in mean RSNA, paralleled by an increase in RBF to 60 +/- 12 ml min(-1) from resting levels of 51 +/- 11 ml min(-1). Renal denervated rabbits did not show an increase in RBF with volume expansion. Arterial baroreflexes were unaltered by volume expansion. Spectral analysis of the different frequencies in RSNA showed oscillations in RSNA between 0.2 and 0.4 Hz were selectively decreased following volume expansion (14 +/- 3 to 6 +/- 1% of total power in RSNA at < 3 Hz). A corresponding decrease in the strength of oscillations in RBF at this frequency was also seen (20 +/- 6 to 8 +/- 2%). In contrast, the strength of respiratory (0.8-2.0 Hz) and cardiac (3-6 Hz) related rhythms did not change with volume expansion. These results show that selective changes in the different frequency components of RSNA can occur. We suggest that input from cardiopulmonary receptors and/or other vascular beds, and/or altered vascular resistance after volume expansion can reduce the strength of the 0.3 Hz oscillation independent of changes in arterial baroreflex control of RSNA.

Biochemical evidence of cannibalism at a prehistoric Puebloan site in southwestern Colorado.

The existence of cannibalism is one of the most controversial issues in the archaeology of the American Southwest. Disarticulated, cut-marked and heat-altered human remains from non-burial contexts at prehistoric Puebloan (Anasazi) archaeological sites in the Four Corners region of the American Southwest have been interpreted by some scholars as evidence of cannibalism. Osteological studies indicate that many of the disarticulated bodies found at these sites were processed in a manner consistent with food preparation. Opponents of this interpretation point out that non-cannibalistic practices such as secondary interment, corpse mutilation and ritualized witch executions might account for the assemblages. Osteological evidence alone does not document the actual ingestion of human flesh. Here we show consumption of human flesh did occur as demonstrated in preserved human waste containing identifiable human tissue remains from a site with osteological evidence of cannibalism.

Differential neural control of intrarenal blood flow.

To test whether renal sympathetic nerve activity (RSNA) can differentially regulate blood flow in the renal medulla (MBF) and cortex (CBF) of pentobarbital sodium-anesthetized rabbits, we electrically stimulated the renal nerves while recording total renal blood flow (RBF), CBF, and MBF. Three stimulation sequences were applied 1) varying amplitude (0.5-8 V), 2) varying frequency (0.5-8 Hz), and 3) a modulated sinusoidal pattern of varying frequency (0. 04-0.72 Hz). Increasing amplitude or frequency of stimulation progressively decreased all flow variables. RBF and CBF responded similarly, but MBF responded less. For example, 0.5-V stimulation decreased CBF by 20 +/- 9%, but MBF fell by only 4 +/- 6%. The amplitude of oscillations in all flow variables was progressively reduced as the frequency of sinusoidal stimulation was increased. An increased amplitude of oscillation was observed at 0.12 and 0.32 Hz in MBF and to a lesser extent RBF, but not CBF. MBF therefore appears to be less sensitive than CBF to the magnitude of RSNA, but it is more able to respond to these higher frequencies of neural stimulation.

Modelling the neural control of intrarenal blood flow.

1. The aim of the present study was to produce a mathematical model that describes the way dynamic changes in renal sympathetic nerve activity affect renal, cortical and medullary blood flow. 2. Cortical blood flow (CBF) and medullary blood flow (MBF) were measured using laser-Doppler flowmetry and (total) renal blood flow (RBF) was measured by transit-time flowmetry in six pentobarbitone-anaesthetized rabbits. The renal nerves were stimulated with rectangular pulses of 2 msec width and constant voltage at frequencies of 0.5, 1, 1.5, 2 and 3 Hz. 3. An exponential function with two parameters was applied; steady state gain and a dynamic constant for the blood flow reduction with stimulation. The steady state gain coefficients were similar for RBF and CBF, but significantly less for MBF. The time taken to reach minimum flow was less for MBF than for RBF and CBF. 4. The model parameters indicate that there is differential neural control of CBF and MBF.

Dissolution testing of nitroglycerin tablets.

The available types of dissolution testing apparatus for tablets and capsules are inapplicable to sublingual tablets, since these tablets are formulated to release their drug content within minutes in a small volume of fluid. A simple dissolution test method was developed for nitroglycerin tablets based on the reduction of nitroglycerin at a rotating platinum electrode, which provides reproducible stirring. The system provides instantaneous and continuous measurement of dissolved nitroglycerin in a small constant volume of buffered isotonic sodium chloride solution over a period of seconds to several minutes, when reduction is complete as shown by the current-time curve. Since the height of the curve is directly proportional to the amount of nitroglycerin in solution, the method also can be used to determine the drug content of individual tablets.