R N Hardy

The role of the autonomic nervous system in the control of glucagon, insulin and pancreatic polypeptide release from the pancreas.

1. The mechanisms of release of pancreatic glucagon, insulin and pancreatic polypeptide (PP) in response to hypoxia and to 2‐deoxyglucose have been investigated in conscious calves 3‐5 weeks after birth. 2. A single injection of 2‐deoxyglucose (200 mg/kg I.V.) produced an abrupt rise in the concentrations of pancreatic glucagon, insulin and PP in the arterial plasma. The changes in plasma insulin and PP concentration were unaffected by prior section of the splanchnic nerves but were effectively abolished by atropine (0‐2 mg/kg I.V.). The rise in plasma pancreatic glucagon concentration was prevented in calves with cut splanchnic nerves that were given atropine but neither procedure alone suppressed the response. 3. 2‐deoxyglucose also caused a substantial increase in the output of glucocorticoids from the right adrenal gland together with a pronounced rise in adrenal blood flow. There was also a small but significant increase in catecholamine output from the adrenal medullae in these animals. 4. Intense hypoxia caused a pronounced increase in the concentration of PP in the arterial plasma. This was found to resemble the glucagon response to intense hypoxia in that it persisted in animals with cut splanchnic nerves that were given atropine. Less intense hypoxia caused a rise in plasma pancreatic glucagon concentration (but not PP) that was abolished by section of the splanchnic nerves. The changes in plasma insulin concentration in these experiments were consistent with the conclusion that they were secondary to changes in plasma glucose concentration. 5. It is concluded that pancreatic endocrine responses to both moderate hypoxia and 2‐deoxyglucose are mediated by the autonomic innervation.

Cardiovascular and endocrine responses to feeding in the young calf.

A number of cardiovascular and endocrine responses which occur during and after feeding in the unweaned calf are described. 2. There was a substantial increase in both heart rate and mean aortic blood pressure during feeding in these animals. This occurred within the first few seconds and persisted throughout the period of ingestion. 3. The concentrations of glucose, insulin and gastrin in arterial plasma rose abruptly during, or immediately after, feeding and elevated values persisted for at least 2 hr. A transient increase in glucagon concentration was also observed. In contrast, feeding appeared to produce no immediate rise in enteroglucagon concentration. 4. The adrenal output of glucocorticoids rose transiently in response to feeding but that of catecholamines was unaffected. 5. Cardiovascular responses to feeding were also examined in other species. In unweaned kids the changes were essentially similar to those observed in the calf but were less pronounced. In lambs a persistent hypertension occurred which was associated with a brief initial tachycardia. In adult dogs ingestion of solid food also caused tachycardia but although the aortic blood pressure rose for a short period at the beginning of feeding, hypotension developed thereafter. 6. The possibility that both the cardiovascular and endocrine responses, which occur during or immediately after feeding, are mediated by the autonomic nervous system is discussed.

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

1. Adrenal and pancreatic endocrine responses to hypoxia and hypercapnia, of differing degrees of intensity, have been examined in conscious, unrestrained calves 3‐5 weeks after birth. 2. The outputs of cortisol and corticosterone from the right adrenal gland were found to vary inversely with arterial Po2 between 17 and 55 mmHg. Significant increase in mean adrenal blood flow was not observed at arterial oxygen tensions above about 30 mmHg. 3. Release of physiologically effective amounts of catecholamines from the adrenal medulla occurred only in response to intense hypoxia (arterial Po2 17‐1 +/‐ 2‐8 mmHg) and was effectively abolished by section of both splanchnic nerves. Release of pancreatic glucagon in response to such intense hypoxia was unaffected by section of both splanchnic nerves and administration of atropine. In contrast, the rise in plasma pancreatic glucagon concentration during less intense hypoxia was abolished by autonomic blockade. 4. Hypercapnia produced by inhalation of either 5% or 10% CO2 for 30 min stimulated maximal release of adrenal glucocorticoids and caused a substantial rise in plasma glucagon concentration. In contrast, the adrenal medulla was found to be extremely resistant to hypercapnia. Significant release of catecholamines was only observed during intense hypercapnia (inhalation of 10% CO2) and noradrenaline was invariably found to be the predominant amine. 5. The results of these experiments show how endocrine responses to hypoxia and hypercapnia are graded in the conscious calf. Of the mechanisms we have examined the pituitary‐adrenal cortical axis is the most sensitive and the adrenal medulla the most resistant, while the pancreatic alpha cell occupies an intermediate position.

Endocrine responses to insulin hypoglycaemia in the young calf.

1. Variations in the output of glucocorticoids and catecholamines from the right adrenal gland, in response to insulin hypoglycaemia, have been investigated in calves 2‐5 weeks after birth. These have been correlated with changes in the concentration of glucocorticoids and glucagon in arterial plasma. 2. Moderate hypoglycaemia for a limited period (0–1 u. insulin/kg), elicited a prompt increase in steroid output from the adrenal gland followed by a significant rise in plasma glucagon concentration. By comparison, changes in both catecholamine output and peripheral plasma glucocorticoid concentrations were found to be trivial in this group of animals. 3. Administration of a larger dose of insulin (0–5 u./kg) produced a more substantial fall in plasma glucose concentration followed by spontaneous recovery within 2‐3 hr. This stimulus elicited the release of greater amounts of both cortisol and corticosterone, followed by a significant increase both in the output of adrenaline and in plasma glucagon concentration. Increase in steroid output was accompanied by an increase in adrenal blood flow and was associated with elevated concentrations of both steroids in arterial plasma. 4. The adrenal cortical response and associated changes in plasma steroid concentration were found to be transient even in response to persistent and intense hypoglycaemia (4 u. insulin/kg). The increase in plasma glucagon concentration in this group of animals was not significantly greater than that produced by smaller doses of insulin. However, substantial amounts of adrenaline (78 plus or minus 14 ng. kg‐minus 1 min‐minus 1; maximum; n equals 9) together with a little noradrenaline (10 plus or minus 3 ng.kg‐minus 1 min‐minus 1; maximum; n equals 9) were released from the right adrenal gland under these conditions. 5. Changes in adrenal blood flow could be related to adrenal glucocorticoid output in calves given 0–1 or 0–5 u. insulin/kg. In animals given the largest dose of insulin adrenal blood flow was found to increase coincidentally with rising steroid output but this hyperaemia then persisted after steroid output had subsided to values within the normal range. 6. Calves given the largest dose of insulin (4–0 u./kg) invariably collapsed and convulsed after 2‐3 hr, but these symptoms could not be related to any particular endocrine response. No clinical signs of hypoglycaemia were observed in the other animals. 7. The results are discussed in relation to previous studies of adrenal function in this and other species.

The effects of infusions of synthetic adrenocorticotrophin in the conscious calf.

1. A technique is described by which the whole of the effluent blood from the right adrenal gland can be collected as required from conscious, unrestrained calves. The technique may be used to measure adrenal blood flow gravimetrically and to compute the output of adrenal hormones under various conditions in the normal calf.

The role of the autonomic nervous system in the control of pancreatic endocrine responses to milk ingestion in the calf.

1. Pancreatic endocrine responses to ingestion of milk have been investigated in conscious unweaned calves, 3‐5 weeks after birth. Passage of gastric content from abomasum to small intestine was prevented by means of a cannula placed in the duodenum adjacent to the pylorus and food was witheld for at least 22 h in order to deplete liver glycogen. 2. Under these conditions ingestion of milk was followed by a prompt rise in the concentrations of pancreatic glucagon, PP and gastrin in the arterial plasma but the usual rises in plasma glucose and insulin concentration were absent. 3. Evidence was obtained to show that absorption of glucose from the small intestine occurs sufficiently rapidly to account for the initial rise in plasma glucose concentration after feeding in normal animals. However, the rise in plasma glucagon concentration was sufficient to contribute to alimentary hyperglycaemia by promoting hepatic glycogenolysis in calves with abundant liver glycogen. 4. None of the neuroendocrine responses to ingestion of milk was affected by prior section of the splanchnic nerves whereas each was blocked by atropine (0.2 mg/kg), showing that all depend upon muscarinic, parasympathetic rather than sympathetic activity, in the absence of extraneous stress.

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.

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.

Adrenal responses to hypoxia and hypercapnia in the young calf.

Quantitative analysis of adrenal responses to moderate hypoxia and hypercapnia in the conscious calf shows that the sensitivity of the adrenal cortical response far exceeds that of the adrenal medulla.