The sensitivity of adrenal responses to synthetic adrenocorticotrophin in the conscious unrestrained calf.

1. Changes in cortisol and corticosterone output and blood flow from the adrenal gland have been determined in the conscious unrestrained calf during I.V. infusions of synthetic adrenocorticotrophin (Synacthen) at 0-5 ng-kg(-1) min- minus 1 (low dose), 5 ng-kg- minus 1 (medium dose), 50 ng-kg- minus 1 min- minus 1 (high dose) and 500 ng-kg- minus 1 min- minus 1 (medium dose), 50 ng-kg- minus 1 min- minus 1 (high dose) and 500 ng-kg- minus 1 min- minus 1(very high dose). 2. Infusions at the low dose produced a rise in adrenal output of both cortisol and corticosterone to maximum values of approximately 100 and 30 ng-kg- minus 1 min- minus 1 respectively. Mean output of both steroids was significantly increased within 5 min, reached a maximum within 10 min and had fallen to resting levels 10 min after the infusion was discontinued. 3. The effects of infusions at both the high and very high doses were closely similar; maximal cortisol outputs were within the range 600-800 ng-kg- minus 1 min- minus 1 and corticosterone 350-500 ng-kg- minus 1 min- minus 1 in both groups. 4. When the infusions were terminated, pronounced differences were observed in the rates at which steroid outputs declined. Basal levels were restored within 10 min following the low dose and within 60 min in medium dose animals, but both cortisol and corticosterone output were still elevated 2 hr after infusion in high dose animals. In calves infused at the very high dose, cortisol output did not fall significantly during 2 hr period. The ratio of cortisol: corticosterone released from the adrenal gland immediately before infusion (3-2 +/- 0-3) approximated to the proportions in which the two steroids were found in the arterial plasma, but fell progressively to a minimum (1-3 +/- 0-1) with increasing doses of Synacthen. Conversely, the ratio of the steroids in the arterial plasma was increased during infusions at the low dose, but not at the higher doses. 6. No significant change in adrenal blood flow occurred during Synacthen infusion in low dose animals despite the increase in steroid output. In medium dose animals blood flow through the gland rose during infusion by approximately 75 per cent while in both high and very high dose animals the flow increased by up to 300 percent. 7. In the three groups in which adrenal hyperaemia occurred, blood flow had fallen to within the resting range 45 min after infusion: in each case this fall was much more rapid than the fall in steroid output. No significant increase in aortic blood pressure or heart rate accompanied infusion of Synacthen, indicating that adrenal hyperaemia was dependent upon vasodilatation with the gland. 8. Administration of cycloheximide (10 mg/kg) by I.V. injection either before or during an infusion of Synacthen, inhibited steroidogenesis without affecting the vasodilator response.     

The effects of insulin on the new-born calf

1. The normal variations in the concentrations of glucose, fructose and lactic acid in the blood of the calf which occur during the first few weeks after birth have been examined.

2. The responses of calves of different ages to intravenous injections of insulin have been examined by recording both the incidence of convulsions and the changes in the concentration of glucose, fructose and lactic acid in the blood.

3. New-born calves rarely convulsed during prolonged and severe hypoglycaemia and, if convulsions occurred, the onset was delayed by 6-8 hr. At 7 days of age convulsions usually followed the injection of insulin within 1½-2 hr.

4. No relationship could be found between the duration of hypoglycaemia and the incidence of convulsions at different ages. Hypoglycaemia was most prolonged in new-born calves which rarely convulsed.

5. Insulin hypoglycaemia during the first 24 hr after birth was associated with a rise in the concentration of lactate in the blood. Similar changes did not occur in calves at 7 days of age, in which the incidence of convulsions was much higher, or in weaned animals.

6. After both splanchnic nerves had been cut, insulin always caused convulsions in 24-hr-old calves. There was no rise in the blood lactate concentration in these animals.

7. Intravenous infusions of adrenaline but not noradrenaline in amounts similar to those known to be released from the adrenal medulla of the calf of this age prevented convulsions in 24-hr-old calves after section of the splanchnic nerves. These infusions had little effect on the blood glucose concentration but caused a similar rise in the lactic acid concentration to that found in normal animals at this age during hypoglycaemia.

8. At 7 days of age convulsions could only be prevented during hypoglycaemia by infusing larger doses of adrenaline which significantly raised the blood glucose concentration. The increase in the blood lactate concentration was less than that in the new-born animals.

9. The resistance to insulin hypoglycaemia which occurs immediately after birth is transient; it depends upon the release of adrenaline from the adrenal medulla and is associated with high concentrations of lactate in the blood during hypoglycaemia.

     

The role of nitric oxide in mediating pancreatic endocrine responses to insulin-induced hypoglycaemia in the conscious calf

The role of nitric oxide (NO) in mediating pancreatic endocrine responses to moderate hypoglycaemia has been investigated in conscious unrestrained calves. The synthesis of endogenous NO was inhibited by the administration of N-nitro-L-arginine methyl ester (L-NAME; 100 mg kg-1 I.A.), while sodium nitroprusside was infused continuously (2-4 microg min-1 kg-1 I.V.) to mimic the tonic production of NO. This effectively abolished the rise in plasma pancreatic polypeptide (PP) concentration during moderate hypoglycaemia (0.7 nmol kg-1 insulin I.V.) and significantly reduced the response to more intense hypoglycaemia (2.0 nmol kg-1 insulin I. V.). In contrast, the glucagon response was not significantly affected in either group, although consistently higher plasma glucagon values were obtained in response to the higher dose of insulin following the administration of L-NAME. It is concluded that, in the absence of L-NAME, production of NO contributes to the PP response, but not the glucagon response to hypoglycaemia in this species under physiological conditions.     

Adrenal and pancreatic endocrine responses to hypoxia in the conscious calf.

1. Pancreatic and adrenal responses to intense hypoxia have been examined in conscious unrestrained calves 3-5 weeks after birth. 2. The outputs of both cortisol and corticosterone from the right adrenal gland rose steadily in response to hypoxia and this cortical secretory response was accompanied by a pronounced increase in blood flow through the gland. The changes in both steroid output and adrenal blood flow corresponded with those which occur in response to supramaximal doses of corticotrophin in calves of the same age. 3. Neither adrenaline nor noradrenaline were released in significant amounts from the adrenal medulla until the arterial PO2 had fallen below 15 mmHg. Such severe hypoxia caused secretion of catecholamines at rates comparable with those recorded during maximal stimulation of the sympathetic innervation to the gland in anaesthetized calves. The response to intense hypoxia in these conscious calves differed from that which occurs under anaesthesia in that the amount of adrenaline released was invariably greater than that of noradrenaline. 4. Severe hypoxia produced a rapid but transient increase in plasma glucagon concentration, followed by a pronounced rise in plasma glucose concentration in animals with abundant liver glycogen. No change in plasma insulin concentration was observed during hypoxia although it rose subsequently in response to hyperglycaemia. 5. Bilateral section of the splanchnic nerves virtually abolished the release of catecholamines in response to hypoxia but the adrenal cortical and pancreatic responses did not appear to be affected.     

Modification of prenatal stress effects in rats by dexamethasone and adrenocorticotrophin.

To determine if effects of prenatal stress on offspring are mediated by the maternal pituitary-adrenocortical (PAC) system, female rats were stressed during gestation while manipulating their PAC output and the growth and behavior of their offspring examined. Specifically, females were injected with ACTH, dexamethasone (DEX), or saline (SAL) during pregnancy or were untreated (CON). Half the females in each group received daily electric shock sessions from Day 7 to Day 21 of gestation. Significantly more females in the ACTH and SAL groups delivered their litters late. Although DEX produced a significant reduction in birth and weaning weights of offspring whereas ACTH did not, both DEX and ACTH blocked the increase in birth weights produced by prenatal stress in offspring of SAL treated females. However, the significant effect of stress on mortality from birth to weaning was potentiated by ACTH and mortality was increased by either DEX or ACTH alone (compared to SAL). In addition, ACTH reversed the effect of stress on open-field activity of 86–96 day old offspring: stress reduced activity of SAL offspring but increased that of ACTH offspring. DEX itself significantly increased activity of female, but not male, offspring and ACTH significantly decreased activity of unstressed offspring of both sexes. Open-field behavior of 32–38 day offspring and active and passive avoidance conditioning of 86–96 day offspring were unaffected by prenatal drug or stress treatments. Attenuation of the maternal PAC response to stress consistently blocks the effects of prenatal stress on birth weights of offspring but can potentiate, reverse, or fail to modify the effects of stress on behavior. It thus seems unlikely that prenatal stress effects on offspring behavior are mediated by the maternal PAC system.     

The effects of burimamide and metiamide on gastric secretion in the conscious cat

Burimamide has been shown to have an acid stimulating action in the conscious cat when injected during basal conditions. Metiamide does not stimulate gastric acid secretion and when injected in addition to burimamide reduces the acid secretion seen to that drug. These results suggest a possible partial agonist action of burimamide, an action not shared by metiamide.     

Cardiovascular effects of fentanyl in conscious rats

The polymicrobial sepsis induced by cecal ligation and puncture (CLP) in the rat is widely used in shock research. For ethical reasons, narcotic analgesics are often administered in this model, with the potential risk of confounding effects. In conscious non-septic rats, we investigated the cardiovascular effects of a continuous i.v. infusion of fentanyl (20 microg/kg per h) administered with fluid loading (10 ml/kg per h) for 24 h, a regimen commonly applied in rat CLP. Animals were randomly allocated to receive analgesia with fluid loading (Fentanyl group), or fluid loading alone (Control). All endpoints were assessed after 24 h of infusion. At that time, Control animals had mild respiratory alkalosis, which was essentially abolished by fentanyl. Analgesia mildly elevated the plasma norepinephrine levels [median (interquartile range): Control 232 pg/ml (0-292), Fentanyl 302 pg/ml (234-676), P=0.045] but was devoid of any effect on blood pressure, heart rate, cardiac output (mean +/-SD: Control 388+/-61 ml/kg per min, Fentanyl 382+/-62 ml/kg per min, P=0.87) and indices of left ventricular function derived from high-fidelity recordings of left ventricular pressure (dP/dtmax: Control 11782+/-2324 mmHg/s, Fentanyl 12107+/-2816 mmHg/s, P=0.77). In ex vivo experiments carried out immediately after animal sacrifice, no differences were noted between the Control and Fentanyl groups in the sensitivity of endothelium-intact aortic rings to norepinephrine-induced vasoconstriction (-logEC50: Control 8.78+/-0.28, Fentanyl 8.83+/-0.26, P=0.52) or acetylcholine-induced vasodilatation (-logEC50: Control 7.00+/-0.37, Fentanyl 7.06+/-0.26+/-0.53, P=0.75). In conclusion, the present data provide no contraindication, and even some support for the ethical use of a high dose i.v. infusion of fentanyl in cardiovascular studies of conscious catheterized rats undergoing CLP or other painful procedures.     

Oxytocin infusions increase plasma levels of insulin and VIP but not of gastrin in conscious dogs

In the present study, a radioimmunoassay for oxytocin determinations is presented. In addition, we investigated whether the elevation of insulin, VIP and gastrin levels demonstrated to occur in response to suckling in lactating dogs may be induced by released oxytocin. Therefore, oxytocin was infused i.v. into conscious dogs in amounts calculated to give rise to plasma levels observed during physiological circumstances. Plasma levels of oxytocin, insulin, VIP (vasoactive intestinal polypeptide) and gastrin were measured by radioimmunoassay. When oxytocin was infused at a rate of 0.22 and 2.2 nmol kg-1 h-1, plasma oxytocin levels rose to 176 +/- 25 fmol ml-1 and to 1490 +/- 400 fmol ml-1, respectively, 10 min after the infusions were started. Plasma insulin levels rose in response to oxytocin administered at a rate of 0.22 and 2.2 nmol kg-1 h-1. A peak was recorded within 5 min of oxytocin infusion, that is, before maximal oxytocin levels were recorded, and basal levels were reached within about 20 min. The VIP levels rose slightly following infusion of oxytocin at 0.22 nmol kg-1 h-1, but a clear-cut response that lasted for 60 min was observed following infusion of oxytocin at the highest dose. In contrast, gastrin levels were not influenced by the oxytocin infusions. Suckling in dogs is followed by rapidly occurring short-lasting elevations of oxytocin levels in plasma which amount to 50-100 fmol ml-1. Since insulin and VIP were released by oxytocin when administered in amounts that give rise to plasma levels close to those levels, it is suggested that the secretion of insulin and VIP that occurs in response to suckling in lactating dogs may in part be caused by previously released oxytocin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The satiety effects of intragastric macronutrient infusions in fatty and lean Zucker rats

To evaluate satiety in the hyperphagic, genetically obese Zucker “fatty” (fafa) rat, food-deprived fatty and lean (FaFa) control rats were given equicaloric intragastric infusions consisting largely of fat, carbohydrate, or protein. Relative to distilled water infusion, these infusions resulted in immediate reductions of food intake in both fatty and lean rats allowed to feed 20 min post-infusion. Cumulative food intakes remained reduced throughout the 2 hr period of observation. Thus, despite its hyperphagia, the fatty rat is responsive to the satiating effect of infused nutrients. However, the relative satiating effectiveness of the macronutrient infusions differed for the two genotypes. In lean rats, the different macronutrient infusions resulted in equivalent reductions of feeding. In contrast, in fatty rats, fat was the least satiating and protein was the most satiating macronutrient. Moreover, compared to lean rats, fatty rats displayed less initial suppression of feeding after fat infusion and greater overall suppression after protein infusion. These effects are consistent with the long-term feeding behavior of the fatty rat for the different macronutrients and may be related to pre- and postabsorptive metabolic alterations that have been documented in this animal.