Comparison of hepatic extraction of insulin and glucagon in conscious and anesthetized dogs

Previous studies in anesthetized dogs demonstrated that basal hepatic extraction of insulin and glucagon are approximately 50 and 10-20%, respectively. Because of the stress of anesthesia and surgery, these values may not be relevant to normal physiology. In this study, hepatic extraction of insulin and glucagon were compared in conscious and anesthetized dogs. The conscious dogs had chronically implanted catheters in the portal and hepatic vein and the carotid artery and Doppler flow probes on the portal vein and hepatic artery. The mean basal portal vein insulin (42 +/- 10 and 44 +/- 7 microU/ml, respectively) and glucagon (247 +/- 37 and 219 +/- 20 pg/ml, respectively) concentrations were similar in conscious and anesthetized animals. The mean basal portal vein, but not hepatic artery, plasma flow was significantly increased in conscious dogs (462 +/- 62 vs. 294 +/- 35 ml/min, respectively). Despite the increased portal vein plasma flow in conscious animals, the basal hepatic extractions of insulin (42 +/- 6 vs. 39 +/- 6%, respectively) and glucagon (12 +/- 7 vs. 7 +/- 7%, respectively) were similar in both types of animals. Arginine and cholecystokinin-pancreozymin (CCK-PZ) infusion, which increased the amount of insulin and glucagon presented to the liver in conscious and anesthetized dogs, significantly decreased the hepatic extraction of insulin. Hepatic extraction of glucagon did not change in either group of animals. In contrast, infusion of insulin (1.0 mU/kg X min) and glucagon (4 ng/kg X min) into the portal system did not alter hepatic extraction of insulin even though the amounts of insulin and glucagon presented to that organ were similar to those obtained with arginine and CCK-PZ. The basal arterial glucose level was significantly lower in the conscious dogs but the basal hepatic glucose output was similar in the two groups. The glucose response to the infusion of arginine and CCK-PZ and exogenous hormones was significantly greater in the anesthetized animals.     

Lack of gastrointestinal glucagon response to hypoglycaemia in depancreatized dogs

Summary Fasting (24 h) normal dogs and depancreatized dogs were injected intravenously with highly purified porcine insulin (Actrapid) in the doses of 0.2 U/kg and 0.5 U/kg, respectively. Blood glucose decreased from 152±41 (SEM) mg/100 ml to 39±7 mg/100 ml in the depancreatized dog and from 95±3 mg/100 ml to 42±4 mg/100 ml in the normal animal. Using a specific antiserum for “pancreatic” glucagon, the circulating level of glucagon immunoreactivity did not rise from the basal value of 247±31 pg/ml in the depancreatized group whereas it rose significantly from 223±24 pg/ml to 321±41 pg/ml in the normal group. In contrast intravenous infusion of 7 g of arginine increased “pancreatic” glucagon immunoreactivity in both groups. Thus, extrapancreatic glucagon of the pancreatic type does not respond to hypoglycaemia but to arginine infusion.     

Renin response to hemorrhage in awake and anesthetized rats.

Anesthetic agents have been shown to alter survival in animals subjected to hemorrhage. Since survival after hemorrhage is increased by inhibitors of the renin-angiotensin system, we asked whether anesthetic agents altered renin release during hemorrhage. We studied 33 rats which were subjected to one hour of hemorrhagic hypotension at a mean arterial pressure of 40 mm Hg. Animals were either awake or anesthetized with halothane or ketamine. Anesthesia alone did not alter plasma renin activity (PRA), whereas hemorrhage resulted in approximately a ten-fold increase in PRA in both awake and anesthetized animals. After the shed blood was returned to the animal, intravenous saralasin, an angiotensin II competitive inhibitor, produced a 21-24 mm Hg decrease in blood pressure in all animals, regardless of the severe hemorrhage is unaltered by halothane or ketamine anesthesia, that the renin-angiotensin system provides a similar amount of blood pressure support in both awake and anesthetized animals, and that the anesthetic influence on survival following severe hemorrhage does not result from anesthetic-induced alterations of the renin-angiotensin system.     

Subendocardial underperfusion during acute aorticopulmonary shunting in anesthetized dogs

Changes in regional coronary hemodynamics during A-P shunting were studied in open-chest anesthetized dogs. During direct A-P shunting coronary driving pressure fell which resulted in decreased coronary flow to the subendocardial region of the left ventricle and abnormal coronary reactive hyperemic responses. When aortic diastolic pressure was augmented during indirect A-P shungting, underperfusion of the subendocardial region was corrected and the coronary hyperemic responses returned to normal. Since shunt flows were equal in both groups, the magnitude of the shunt was not a factor in reducing coronary flow. The present study indicates that acute A-P shunts may cause underperfusion of the left ventricular subendocardium. Thus, under these conditions, the left ventricle is stressed by a combination of an increased workload in the face of reduced subendocardial coronary flow.     

Ventricular interaction during mechanical ventilation in closed-chest anesthetized dogs

The cardiac effects of positive pressure ventilation and positive end-expiratory pressure are incompletely understood. External constraint due to increased intrathoracic pressure decreases left ventricular end-diastolic volume; the effects on venous return and ventricular interaction are less clear. Phasic changes in inferior vena caval flow, end-diastolic ventricular dimensions and output were measured in seven anesthetized, ventilated normal dogs. During inspiration, caval flow, right ventricular diameter and output decreased; end-diastolic transseptal pressure gradient, septum-to-left ventricular free wall diameter, left ventricular area (ie, left ventricular volume index) and output increased despite the decreased sum of the septum-to-free wall diameters. The reverse occurred during expiration. Increased positive end-expiratory pressure decreased the left ventricular area, but the end-expiratory right ventricular diameter was unchanged. At given airway pressures, right ventricular diameter was greater at higher positive end-expiratory pressures, suggesting that a leftward septal shift (direct ventricular interaction) added to the effect of external constraint on left ventricular end-diastolic volume. In conclusion, positive pressure ventilation reduced right ventricular end-diastolic volume during inspiration and increased the transseptal pressure gradient, which shifted the septum rightward, increasing left ventricular end-diastolic volume and output. The reverse occurred during expiration. Positive end-expiratory pressure constrained left ventricular filling and decreased left ventricular end-diastolic volume further by a leftward septal shift.     

Prostaglandin mediated natriuresis during glucagon infusion in dogs.

Ten mug/min glucagon infused intravenously for 30 min in conscious dogs (weight 15-25 kg) is shown to increase renal prostaglandin activity and to produce a natriuretic effect, which is impaired by indomethacin pretreatment. Cardiac output, heart rate, renal blood flow and urine cAMP excretion are similarly increases in non-pre-treated and indomethacin pre-treated dogs. Glucagon infusion does not consistently change plasma renin activity in non-pre-treated dogs, while the renin secretion is almost totally blocked when glucagon is administered to dogs that are pre-treated with indomethacin. The results are consistent with the view that the natriuretic response to glucagon is largley dependent upon increased renal blood flow. An addition tubular prostaglandin mediated and possible anti-aldosterone effect is, however, also involved.     

Plasma concentrations of glucagon during hyperglycemic clamp with or without somatostatin infusion in obese subjects

Summary The aim of the present study was to evaluate whether the inhibitory effect on pancreatic A-cell exerted by hyperglycemic hyperinsulinemia and/or by somatostatin administration is impaired in human obesity. For this purpose plasma glucagon concentrations were measured in 8 obese and 8 nonobese nondiabetic subjects during a 4-h hyperglycemic clamp. Synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min during the third hour of the study. Fasting plasma glucagon was higher in obese than in nonobese subjects (242±32vs 163±15 pg/ml, p<0.05) (mean±SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100–120 min of the study) plasma glucagon averaged 195±26 pg/ml in obese and 122±13 pg/ml in nonobese subjects (p<0.05), with a reduction of 19±3% in the former and 28±4% in the latter (p=n.s.). In both groups somatostatin infusion did not result in a further decrease in plasma glucagon, which averaged 192±27 pg/ml in obese and 123±16 pg/ml in nonobese subjects (p<0.05) in the 160–180 min period of the study. Also after discontinuing somatostatin infusion plasma glucagon levels did not change. These results suggest that in human obesity hyperglycemic hyperinsulinemia has a normal inhibitory effect on pancreatic A-cell and that somatostatin administration has no additive effect on hyperglycemia and hyperinsulinemia in either obese or nonobese nondiabetic subjects. Supported by grants n^o 83.02749.56, 84.03099.56, 85.00681.56, 86.01873.56, 83.02591.04, 85.00502.04 and 86.00102.04 fromConsiglio Nazionale delle Ricerche, Italy, and by grants fromMinistero della Pubblica Istruzione, Italy.     

Primary intracerebral hemorrhage during asleep period

BACKGROUND: The onset of intracerebral hemorrhage (ICH) has a circadian variation, with a lower risk during the asleep period. It is unclear, however, whether ICH during the asleep period differs from that during the awake period in pathophysiologic nature. The purpose of this study is to elucidate the incidences and clinical features of ICH during the asleep period. METHODS: We studied 129 consecutive patients with primary ICH and classified them into two groups according to the circumstance of their stroke onset, either during the awake period (awake ICH group) or the asleep period (asleep ICH group). Demographic and clinical characteristics were then compared between the two groups. RESULTS: Of the patients, 19 (14.7%) had ICH during the asleep period. The mortality rate at 1 month after the stroke was significantly higher in the asleep ICH group than in the awake ICH group (21.1% v 4.9%, P = .0325). The hemorrhage volume in the asleep ICH group was also significantly larger than that in the awake ICH group (mean volume, 32.6 mL v 16.7 mL, P = .0122). CONCLUSIONS: Our findings indicate that ICH during the asleep period may be more detrimental compared with ICH during the awake period, causing larger hematoma and higher mortality rates.     

Inspiratory muscle activity during pulmonary edema in anesthetized dogs.

Pulmonary edema is known to induce a rapid and shallow breathing pattern. However, its effects on the level and pattern of distribution of motor activity to the respiratory muscles is unclear. In the present study we evaluated the effect of oleic acid induced pulmonary edema on the electrical activity of the inspiratory muscles (costal and crural diaphragm and parasternal and external intercostal muscles) in the dog, and related it to the transdiaphragmatic pressure and ventilatory parameters over the course of CO2 rebreathing. Pulmonary edema, reflected by a 7.1 +/- 0.6 wet to dry ratio, decreased lung compliance by 57%, increased pulmonary shunt to 35%, and was associated with a rapid and shallow breathing pattern. When compared at equal levels of PCO2 during CO2 rebreathing before and during edema, ventilation and mean inspiratory flow were increased only at lower levels of hypercapnia and their responses to increasing levels of PCO2 were significantly diminished during edema. Transdiaphragmatic pressures were elevated during edema as compared to control values. The rate of rise of the electrical activity of all inspiratory muscles increased significantly during edema at all levels of PCO2. Peak activity, however, remained unchanged, due to shortening of the inspiratory duration. The EMG responses to progressive hypercapnia were not affected by edema. Pulmonary edema did not change the pattern of breathing and neural output to the inspiratory muscles in vagotomized dogs. We conclude that stimulation of pulmonary proprioreceptors during edema increases neural output to all inspiratory muscles. The neural response to hypercapnia is not altered by edema, and is additive to the vagal input. The ventilatory response to CO2 is blunted during severe edema, due to alterations in lung mechanics.     

Regional cardiac prostaglandin release during myocardial ischemia in anesthetized dogs.

Cardiac prostaglandin release was studied in closed-chest dogs during acute coronary occlusion. Aortic and coronary sinus blood was obtained before, and at intervals after, balloon occlusion of the left anterior descending artery in seven dogs. Samples were assayed for prostaglandins F, E, and A by randioimmunoassay. All dogs demonstrated prostaglandin F release, Mean +/- SE postocclusion aortic levels were 0.26 +/- 0.01 ng/ml; coronary sinus levels were 0.67 +/- 0.01 ng/ml (P less than 0.001). In six dogs, prostaglandin E also was released. Mean postocclusion aortic levels were 0.24 +/- 0.01 ng/ml; coronary sinus, 0.44 +/- 0.01 ng/ml (P less than 0.001). There was no release of prostaglandin A. To examine the site of prostaglandin release, simultaneous samples from the aorta, the coronary sinus, and the great cardiac vein were obtained before and after left circumflex artery occlusion in six additional studies. The great cardiac vein drained effluent from nonischemic myocardium, whereas the coronary sinus drainage included blood from both ischemic and nonischemic zones. All six dogs demonstrated prostaglandin F release from the ischemic region. Mean postocclusion aortic prostaglandin F was 0.32 +/- 0.01 ng/ml. Coronary sinus prostaglandin F was 1.69 +/- 0.03 ng/ml (P less than 0.001), whereas the great cardiac vein level remained at 0.34 +/- 0.01 ng/ml (P greater than 0.05). Prostaglandin E was released from both ischemic and nonischemic regions. Mean aortic prostaglandin E was 0.21 +/- 0.01 ng/ml; great cardiac vein, 0.55 +/- 0.02 ng/ml (P less than 0.001); and coronary sinus, 1.07 +/- 0.04 ng/ml (P less than 0.001). These results have led us to conclude that the different local availability of prostaglandins E and F may influence the cardiac response to ischemia.     

Effect of hypercapnia on ventilatory response to intravenous nicotine administration in anesthetized dogs

We studied the effects of hypercapnia on the ventilatory response to nicotine in thirty anesthetized mongrel dogs. Ventilatory (VE) and occlusion pressure (P0.2) changes were assessed before and after intravenous injection of nicotine at concentrations of 1, 4, 16 and 64 micrograms/kg in four different groups of five dogs each. An end-tidal CO2 (PETCO2) was set at 40 mm Hg or 60 mm Hg by inspiration of 7% CO2 in oxygen through a non-rebreathing valve. With PETCO2 maintained at 40 mm Hg, P0.2 had increased 1 min after nicotine injection from 1 to 16 micrograms/kg in a dose-dependent manner, and a subsequent decrease in P0.2 below the initial value was observed at around 4 min. Injection of 64 micrograms/kg of nicotine produced a marked increase in P0.2 and subsequent apnea. With PETCO2 at 60 mm Hg, the time course of P0.2 was qualitatively similar to that observed with PETCO2 at 40 mm Hg, except that the change in P0.2 was larger in the former case than in the latter, for a given nicotine dose. The ratio of the difference in maximal P0.2 observed with PETCO2 of 40 mm Hg and that at 60 mm Hg to the difference between PETCO2 values (delta PO2/delta PETCO2) increased with nicotine dose from 1 to 4 micrograms/kg and, with a further increase in nicotine dose, the maximal delta P0.2/delta PETCO2 plateaued, while delta P0.2/delta PETCO2 obtained from the minimal PO2 values decreased in a nicotine dose-dependent fashion. These results suggest that hypercapnia enhances both stimulative and subsequent depressive ventilatory responses to nicotine.     

Effects of pentoxifylline on pulmonary hemodynamics during acute hypoxia in anesthetized dogs

The effects of pentoxifylline on pulmonary hemodynamics were studied in anesthetized dogs during acute alveolar hypoxia. In Series A, 7 dogs received pentoxifylline orally (18 mg/kg/day) for 11 wk and 7 untreated dogs served as control animals. During anesthesia and controlled ventilation, acute alveolar hypoxia was induced (10 to 13% inspired O2) and pulmonary and systemic hemodynamic and blood rheologic measurements were compared with normoxia. In control dogs, cardiac index did not change during hypoxia, but pulmonary vascular resistance index (PVRI) increased 79%, erythrocyte filterability decreased significantly (p less than 0.05), and relative viscosity of blood corrected for hematocrit did not change. In the pentoxifylline-treated dogs, cardiac index increased 28% and PVRI increased only 20%; in contrast to the control dogs, relative viscosity of blood was decreased by 18% and no significant changes in filterability were observed. The increase in PVRI in relation to the drop in arterial O2 saturation was significantly larger (p less than 0.05) in the control dogs. Pentoxifylline also increased P50 by 2.8 mm Hg (p less than 0.05). In Series B, hemodynamic measurements were made during variations in blood flow (induced by restricting venous return) in 3 treated (26 mg/kg/day for 3 wk) and 3 control dogs. In these experiments, pulmonary artery pressure was significantly lower at comparable flows during both normoxia and hypoxia. In both studies, the hemodynamic effects of the drug on the systemic circulation were less than on the pulmonary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs

We investigated the effect of hypercholesterolemia on coronary and cardiac hemodynamic responses to intracoronary norepinephrine (NE) (0.01 to 10.0 micrograms/min as the bitartrate) in a Gregg cannula autoperfusion system. Coronary blood flow was measured by the radioactive microsphere technique in two groups of open-chest dogs anesthetized with pentobarbital: 10 controls and 8 that were fed a cholesterol-rich diet (CD) which doubled the serum cholesterol level. In the control dogs, NE in doses of 0.01 to 1.0 micrograms/min had no effect on coronary vascular resistance (CVR) but 10 micrograms/min caused a significant decrease to 0.58 +/- 0.12 of control. In the CD dogs, NE at doses of 1.0 and 10.0 micrograms/min significantly reduced CVR, to 0.72 +/- 0.06 and 0.52 +/- 0.11 of control, respectively. There was no consistent effect of NE, at these doses, on myocardial oxygen uptake, left ventricular stroke work index, or maximal positive dP/dt. In a second series of experiments we measured coronary flow with electromagnetic flowmeters in 11 chronically instrumented conscious dogs, 5 controls, and 6 CD. In the control dogs, intravenously administered NE hydrochloride, 0.01 microgram/min, reduced CVR to 0.74 +/- 0.07 of control, and 1.0 microgram/min increased CVR to 1.26 +/- 0.09 of control. In the CD animals, these effects were seen at a 10-fold lower NE dose, 0.001 microgram/min (0.83 +/- 0.11 of control) and 0.1 microgram/min (1.32 +/- 0.06 of control). The vasodilation was blocked by propranolol, and vasoconstriction by phentolamine. We conclude that NE at low doses activates beta-adrenoreceptors to reduce CVR and at higher doses activates alpha-adrenoreceptors to increase CVR; the vasoconstrictor response is inhibited in pentobarbital anesthetized dogs, and hypercholesterolemia sensitizes coronary vessels to both the dilator and constrictor effects of NE.     

Pressure-driven hemorrhage: a new experimental design for the study of crystalloid and small-volume hypertonic resuscitation in anesthetized dogs.

Fifty pentobarbital anesthetized dogs were subjected to pressure driven hemorrhage (PDH) in which (a) an initial bleeding rate (25 ml/min) was set, and (b) reset min-to-min in proportion to prevailing mean arterial pressure (MAP). When blood loss reached 40 ml/kg, experimental time was set to zero and dogs were divided into five groups: (1) CTR (untreated controls); (2) HSD (NaCl 7.5%-Dextran70 6%, 6 ml/kg, at zero time); (3) LR (lactated Ringers, 25 ml/min from 0-60 min); (4) HSD-LR (combines HSD and LR); (5) DBL-HSD-LR (as HSD-LR, plus second HSD injection, 4 ml/kg, at 30 min). PDH was continued throughout the postresuscitation period. CTR dogs bled 55.5 +/- 2.1 ml/kg and survived to 34.7 +/- 5.0 min postzero; HSD dogs bled 78.6 +/- 2.0 ml/kg, and survived to 51.2 +/- 2.9 min with transient recovery of MAP, cardiac output (CO), and O2 availability (O2A); LR dogs bled 94.5 +/- 3.4 ml/kg and survived for over 60 min, with sustained, partial recovery of MAP, CO, and O2A. HSD-LR dogs bled 111.5 +/- 3.7 ml/kg and survived for over 60 min with improved hemodynamic and metabolic response. In DBL-HSD-LR dogs, the second HSD produced higher MAP, CO, and O2A, but hematocrit was lowered to a critical level. Thus, standard LR resuscitation is effective in PDH, in spite of increased blood loss; a single HSD lengthens survival when used alone and improves recovery when added to LR.     

The enhanced hyperglycemic response to hemorrhage hypotension in obese rats is related to an impaired baroreflex

The aim of the present study was to assess the metabolic adjustments in adult rats with autonomic imbalance induced by hypercaloric diet. Male Wistar rats (4 weeks of age) were fed a chow diet (CD, n = 12) or hypercaloric diet (HD, n = 13) for 19 weeks. Body weight and dietary intake were measured every week and the basal metabolic rate was assessed. After 19 weeks of diet, six animals from each group were anesthetized with a lethal dose of barbital sodium (100 mg/Kg body weight, intraperitoneal; i.p.). Lee index was evaluated and adipose pads weighted. The remaining animals had a silastic cannula placed into the jugular vein for drug administration, blood collecting, and hemorrhage (1.2 mL/100 g bw/2 min). A polyethylene catheter (PE50) was inserted into the abdominal artery through the femoral artery for cardiovascular monitoring. The assessment of autonomic balance was done by evaluation of baroreflex sensitivity (intravenous (IV) injection of phenylephrine and sodium nitroprusside) and hemorrhage (1.2 mL/100 g bw/2 min). As expected, the HD induced obesity; increased weight gain (28%), adipose pads weight, and baroreflex dysfunction. The plasma level of free fatty acids and triacylglycerols were increased in HD rats by about 124% and 424%, respectively, as well as the basal metabolic rate measured at 19th weeks of diet (p < 0.01). We observed that baroreflex sensitivity to phenylephrine was reduced by about 50%, and the hyperglycemic response to hemorrhage hypotension was increased by 128% in HD rats. We found also a negative correlation between the alteration in baroreflex sensitivity and the increase in hyperglycemic response to hemorrhage in the obese rats (r = 0.72, p < 0.01) and a strong positive correlation between the increased Lee index and the hemorrhagic hyperglycemia (r = 0.93, p < 0.01). Our data demonstrate that obesity induced by hypercaloric diet in Wistar rats promotes an autonomic imbalance, which interferes with metabolic responses dependent on baroreflex sensitivity. In addition, we showed the existence of close correlation between the loss of baroreflex sensitivity and the degree of obesity.     

Cardiac dose response relationship for intravenously infused glucagon in normal intact dogs and men

The mechanism of glucagon's cardiac effects is not well understood. As the cardiac dose response to glucagon in intact animals has not been elucidated, this was determined in normal men and dogs. In man, heart rate, blood pressure, systolic time intervals and echocardiographic indices of ventricular wall motion were determined. Plasma glucagon levels (PGL) were measured by radioimmunoassay. Men received 3 glucagon infusions of 10^?10 to 10^?8 moles/minute followed by a bolus of 0.5 mg. or 1.0 mg. Small but significant changes were observed in ejection fraction and left ventricular posterior wall displacement at the 10^?9 moles/minute infusion rate (mean PGL 1.9 ng./ml.), a PGL close to that of some pathophysiologic states such as burns, ketoacidosis, and acute myocardial infarction, while cardiac output, heart rate, and other indices of cardiac performance were significantly changed only at the 10^?8 moles/minute and bolus injections. Some indices, notably stroke volume, were unchanged.In dogs, left ventricular (LV) pressure, LV pressure derivative (LV $\text{dP}\text{dt}$), and aortic flow were measured with implanted LV solid state pressure transducers and electromagnetic flow probes. Dogs received six infusions from 2.7 × 10^?11 to 2.7 × 10^?8 moles/minute followed by a bolus of 2 mg. In dogs, significant changes occurred in LV $\text{dP}\text{dt}$ at 2.7 × 10^?9 moles/minute (mean PGL 31.5 ng./ml.) and in heart rate at 2.7 × 10^?8 moles/minute only. It appears that substantial hemodynamic effects do not appear in man or dogs until PGL 10 to 100 times those seen in pathophysiologic states are achieved. Thus, it seems unlikely that glucagon contributes substantially to the hyperdynamic circulatory conditions observed in these states. Significant hemodynamic response to glucagon was noted in normal men, however, at a PGL less than that achieved by usual pharmacologic doses of glucagon and this lower PGL was not associated with the gastrointestinal symptoms commonly observed clinically.