Metformin, but not exercise training, increases insulin responsiveness in skeletal muscle of Sprague-Dawley rats.

We assessed the effects of combined metformin treatment and exercise training on body composition, on insulin concentration following glucose loading, on insulin-stimulated glucose transport in skeletal muscle, and on muscle glycogen content. Male Sprague-Dawley rats were treated for 35 days with or without metformin (320 mg/kg/day) and/or treadmill exercise training (20 min at 20 m/min, 5 days/wk). Because metformin reduces food intake, pair-fed controls were included. Metformin, training, and pair-feeding all decreased food intake, body weight, and insulin concentration following glucose loading. Metformin and training reduced intra-abdominal fat, but pair feeding did not. In isolated strips derived from soleus, epitrochlearis and extensor carpi ulnaris muscles, metformin increased insulin-stimulated transport of [3H]-2-deoxyglucose by 90%, 89% and 125%, respectively (P < 0.02) and training increased [3H]-2-deoxyglucose transport in the extensor carpi ulnaris muscle only (66%, P < 0.05). Pair-feeding did not alter [3H]-2-deoxyglucose transport. Training increased gastrocnemius muscle glycogen by 100% (P < 0.001). Metformin and pair-feeding did not alter muscle glycogen. We conclude that metformin reverses the maturation-induced impairment of insulin responsiveness in Sprague-Dawley rats by increasing insulin-stimulated glucose transport in skeletal muscle and that this effect is not secondary to reduced food intake. We also conclude that metformin and exercise training may increase insulin sensitivity by different mechanisms, with training causing increased glucose transport only in some muscles and also causing increased muscle glycogen storage.

Metformin treatment enhances insulin-stimulated glucose transport in skeletal muscle of Sprague-Dawley rats.

Although the glucose-lowering properties of metformin are well-established, its effects on glucose metabolism in skeletal muscle have not been clearly defined. We tested the effects of metformin in young adult male Sprague-Dawley rats, which have a documented reduced response to insulin in skeletal muscle. Rats were treated with metformin for 20 days (320 mg/kg/day) in the drinking water. During this period, metformin completely prevented the increase in food intake and decreased adiposity by 30%. Metformin also reduced insulin secretion by 37% following an intra-peritoneal injection of glucose. Finally, metformin enhanced transport of [3H]-2-deoxyglucose in isolated strips of soleus muscle. Metformin substantially increased insulin-stimulated transport, while having no effect on basal transport. In control rats, a maximal concentration of insulin stimulated transport 77% above basal. In metformin-treated rats, insulin stimulated transport 206% above basal. We conclude that in the Sprague-Dawley rat model, metformin causes a significant increase in insulin-responsiveness.

Validation of miniature ultrasonic transit-time flow probes for measurement of renal blood flow in rats.

This study validates the accuracy of miniature ultrasonic transit-time flow probes for measuring renal blood flow (RBF) in the rat. Probes for 1-mm and 2-mm vessels were calibrated ex vivo using excised arteries at varying flow rates and hematocrit (Hct). Correlation between measured and true flow rates for the 2-mm probe were identical (r = 1.0) at both normal and subnormal Hct values. Correlation for the 1-mm probe was high (r = 0.994) at normal Hct, but varied at both high flow rates and subnormal Hct values. In vivo correlation of RBF measurements using the 1-mm probe with the clearance and extraction of p-aminohippuric acid showed a high correlation (r = 0.84; n = 72, P < 0.0001) over a wide range of flow rates (0.5-21 ml/min) and Hct (36-74%). Zero flow levels remained steady, averaging -0.2 +/- 0.2 ml/min during occlusion in the living animal and -0.1 +/- 0.3 ml/min after exsanguination. This study shows that the ultrasonic transit-time flowmeter (1-mm and 2-mm probes) is a reasonably accurate and reliable method with which to measure RBF in the anesthetized, acute-instrumented rat.

Nitric oxide mediates renal vasodilation during erythropoietin-induced polycythemia.

The renal blood flow (RBF) of patients with polycythemia rubra vera is increased despite the high hematocrit (Hct) which elevates the whole blood viscosity. Since blood viscosity determines the shear force on the endothelium which is a major stimulus to nitric oxide (NO) release, we investigated the hypothesis that renal vasodilation during erythropoietin-induced erythrocytosis is mediated by the L-arginine-NO pathway. Groups of Sprague-Dawley rats received thrice weekly injections of erythropoietin (E) for two to five weeks; responses were contrasted with normal rats (N) which received sham injections. The first group was studied after five weeks of erythropoietin injections which led to sharp increases in Hct (E: 72 +/- 3 vs. N: 44 +/- 1%) and mean arterial pressure (MAP: 126 +/- 3 vs. 107 +/- 3 mm Hg). These rats had an elevated basal RBF whether measured by the clearance and renal extraction of PAH or by a transit-time renal blood flow meter. Subsequent groups were studied after two to three weeks of erythropoietin which raised the Hct more modestly to 59 +/- 2%. In this group, the basal MAP was similar in E and N rats. Graded doses of the NO synthase inhibitor, N omega-monomethyl-L-arginine (L-NMA) led to a steeper rise in MAP in E than N; at the highest doses, the MAP had increased by 36 +/- 2 in E and 23 +/- 3 mm Hg in N (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Clutch size in a larval-pupal endoparasitoid : 1. Variation across and within host species.

Clutch size decisions by Aphaereta minuta (Nees) (Hymenoptera: Braconidae), a polyphagous, gregarious, larval-pupal endoparasitoid, were studied under laboratory conditions. This parasitoid attacks larvae of Diptera inhabiting ephemeral microhabitats such as decaying plant and animal material. Females oviposit in young larval stages, but the eventual size of the host pupa determines host food availability for competing offspring. The size of the pupa can differ greatly between host species. We questioned how A. minuta females deal with this delay between the moment of oviposition and eventual host food availability, and whether they make clutch size decisions that benefit their fitness. It was shown that females indeed vary their clutch size considerably and in an adaptive way: (1) females lay larger clutches in larvae of host species that produce larger pupae, even when the larvae are the same size at the moment of oviposition, and (2) females lay larger clutches in larger larvae than in smaller larvae of the same host species. The latter seems functional as larvae parasitized at an older stage indeed developed into larger pupae compared to larvae parasitized at a younger stage. Furthermore, mortality of parasitized young host larvae was greater than that of both unparasitized larvae and parasitized older larvae. Under field conditions the risk of mortality of young host larvae is expected to be even higher due to the limited period of microhabitat (host food) availability, strong scramble type competition between the host larvae, and the longer period of being exposed to predation.

Thromboxane mediates renal hemodynamic response to infused angiotensin II.

UNLABELLED: Since we had found that angiotensin II (Ang II), but not phenylephrine (PE), increased the excretion of thromboxane (Tx) and raised mean arterial pressure (MAP) by a Tx-dependent mechanism, we tested the role of TxA2 in mediating Ang II-induced changes in renal hemodynamics. For series 1, groups of anesthetized rats received an i.v. infusion of Ang II (50 ng.kg-1.min-1). When infused with a vehicle, Ang II increased MAP, renal vascular resistance (RVR) and the excretion of TxB2 factored by GFR. A PGH2-TxA2 receptor antagonist, SQ-29,548, or three days of pretreatment with a TxA2 synthase inhibitor UK-38,485, which reduced excretion of TxB2 by 80%, blunted the rise in MAP and RVR induced by Ang II. In contrast, three days of pretreatment with indomethacin did not alter the renal vascular response to Ang II. For series 2, groups of rats received Ang II at a higher rate (500 ng.kg-1.min-1) while the RPP was stabilized at +11 to +15 mm Hg with a suprarenal aortic clamp. SQ-29,548 and UK-38,485 both prevented Ang II-induced reductions in GFR and blocked 80% of the increase in RVR. For series 3, infusions of phenylephrine at an equipressor dose to series 2 of 30 micrograms.kg-1.min-1 with control of RPP at +14 mm Hg also increased RVR but this was not blunted by SQ-29,548. IN CONCLUSION: 1.) infusion of Ang II increases excretion of filtered TxB2, causes dose-dependent increases in RVR and, at high doses, reduces GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of anomalous pulmonary venous drainage.

All of our cases of abnormal pulmonary venous connections collected to the middle of 1965 and verified at surgery or autopsy have been reviewed by means of diagrams and tabulations, using a specially devised code to facilitate the survey. The material consisted of 52 autopsy cases (half of them obtained after surgery) and the cases of 72 patients who survived operation. The postmortem group was much younger than the surgical group and differed also from the latter by showing male preponderance as well as relatively many instances of total abnormal pulmonary venous connection and frequently associated cardiac anomalies. Partial anomalous connection of right pulmonary veins was 10 times more frequent than that of the left pulmonary veins. This was caused by (1) the frequent drainage of some of the right pulmonary veins into the junctional area between right atrium and superior vena cava in the presence of normal left pulmonary veins, and (2) the complete absence of isolated left pulmonary venous connection to the right atrium. Abnormal connection of solitary pulmonary veins was always effected to the most proximal venous structure among the four possible ones which are derived from the main embryonic channels (superior vena cava and inferior vena cava on the right side, and left superior vena cava and coronary sinus on the left side). Common pulmonary veins from one lung also drained in accordance with this proximity rule, if this may be taken to apply also to the drainage of right pulmonary veins into the right atrium. The one exception in our material was the drainage of all right pulmonary veins into the portal venous system. Total abnormal pulmonary venous connection may be found with all structures mentioned, but most frequently with the left superior vena cava, or coronary sinus, or both, usually by way of a common pulmonary vein. In a few cases however, drainage into different sites, all of them abnormal, did occur. Then again the proximity rule seemed to apply. A tentative embryological explanation is given for the patterns described.