Somatostatin-Induced Changes in Insulin and Glucagon Secretion in Normal and Diabetic Dogs

In conscious dogs intravenously infused somatostatin (3.3 mug per min for 1 h) caused prompt and sustained declines in mean plasma insulin and glucagon, even during alanine infusion and intraduodenal casein hydrolysate feeding; plasma glucose declined, but not significantly. 6.7 mug per min of somatostatin significantly lowered pancreatoduodenal vein glucagon and insulin within 2.5 min and profoundly suppressed their secretion throughout the infusion. Consistent bihormonal suppression occurred at rates as low as 24 ng per kg per min, but was variable at 12 and 2.4 ng per kg per min. When somatostatin-induced (3.3 mug per min) hypoglucagonemia was corrected by exogenous glucagon, hyperglycemia occurred. In dogs with long-standing insulin-requiring alloxan diabetes 3.3 mug per min of somatostatin suppressed glucagon to 55 pg per ml throughout the 30-min infusion and lowered glucose by 36.4+/-6.1 mg per dl, about 1 mg per dl per min. Glucagon suppression was maintained despite alanine infusion, and glucose, which rose 29 mg per dl during alanine infusion without somatostatin, declined 58 mg per dl in the somatostatin-treated diabetic dogs despite alanine. Continuous infusion of somatostatin for 24 h in five insulin-requiring alloxan-diabetic dogs suppressed glucagon and lowered glucose significantly, usually to below normal.It is concluded that in normal dogs pharmacologic doses of somatostatin virtually abolish insulin and glucagon secretion in the basal state and during hyperaminoacidemia. Hyperglycemia occurs during somatostatin-induced insulin lack only if hypoglucagonemia is corrected. Somatostatin suppresses glucagon in diabetic dogs and lowers their plasma glucose approximately 1 mg per dl per min, even when the gluconeogenic substrate alanine is abundant. Glucagon suppression can be maintained for several hours in such dogs and hyperglycemia is thereby reduced.     

Inhibition of Free Fatty Acid Oxidation by Acetoacetate in Normal Dogs

Abstract The rate of turnover and oxidation of plasma free fatty acids (FITA) was measured in 7 normal anaesthetized dogs infused at a constant rate with l-¹⁴C-palmitate for 5 h. After a control period, sustained hyperketonaemia was induced by infusing sodium aceto-acetate (AA). This produced a fall in plasma FFA (33%) and in blood sugar (24%), without changes in immuno-reactive insulin (IRI) concentrations. During the control period, the turnover rate of carbon of FFA averaged 131 μat./kg/min, 32% of which were oxidized, thus supplying 17.7% of the total CO₂ production. At the end of the AA infusion, the mean turnover rate of FFA was reduced to 75μat.C/kg/min; since only 13.9 % of these were oxidized, the contribution of FFA to total CO₂ production was reduced to 4.3%. In the light of previous work showing that ketone infusions also reduce the rate of turnover and oxidation of glucose in dogs, we conclude that, under appropriate experimental conditions, ketones may strongly reduce the role of FFA and glucose as sources of energy.     

Effect of Free Fatty Acids on Myocardial Function and Oxygen Consumption in Intact Dogs

Myocardial function and oxygen consumption (MO₂) were studied during increased myocardial uptake of free fatty acids (FFA) induced by intravenous infusion of a fat emulsion (Intralipid) after heparinization in anesthetized and intact dogs. During raised myocardial uptake of FFA, MO₂ increased in all experiments. On the average, MO₂ rose from 8.6 to 10.7 ml/min·100 g, or 26% (P < 0.001). This was mainly due to elevated myocardial oxygen extraction, as myocardial blood flow was unchanged, or increased slightly. In the recovery period, MO₂ returned to normal. Left ventricular pressure, the maximal rate of rise of left ventricular pressure (dP/dt), heart rate, and cardiac output remained unchanged during the raised myocardial uptake of FFA.     

Stimulation of Insulin Secretion by Long-Chain Free Fatty Acids. A DIRECT PANCREATIC EFFECT

A continuous-flow centrifuge was used to infuse sodium salts of oleic, linoleic, lauric, or palmitic acid into the pancreatic artery of anesthetized dogs. In these regional perfusion studies there was no increase in FFA levels in the general circulation. Elevation of pancreatic FFA levels produced an immediate increase in pancreatic venous immunoreactive insulin (IRI). After 10 min of FFA infusion. IRI levels declined somewhat from the initial peak response but soon rose again to high levels which were then sustained until the infusion was terminated. All four long-chain FFA tested produced a similar biphasic IRI response. Clearcut increases in IRI were associated with absolute FFA levels (measured in pancreaticoduodenal venous plasma) as low as 0.6-0.8 mueq/ml and with increments over basal levels of as little as 0.4-0.5 mueq/ml. At higher levels of FFA, absolute IRI levels in the pancreatic venous effluent exceeded 1,000 muU/ml in some experiments and 5- to 10-fold increases over basal values were observed.These studies indicate that long-chain FFA, in physiological concentrations, can markedly stimulate insulin secretion by a direct effect on the pancreas. The results lend support to the concept of insulin as a hormone that is importantly involved in regulating the metabolism of all three principal classes of metabolic substrates and whose release is in turn regulated by all of them. The relative importance and precise nature of its physiologic role in the regulation of lipolysis, lipid deposition, and ketone body formation remains to be established.     

Importance of Free Fatty Acids as a Determinant of Myocardial Oxygen Consumption and Myocardial Ischemic Injury during Norepinephrine Infusion in Dogs

Increased delivery of free fatty acids raises myocardial oxygen consumption (MVO(2)) without influencing mechanical performance. The effects of norepinephrine on MVO(2) and on the size of ischemic injury after acute coronary occlusion were therefore studied before and during inhibition of lipolysis with beta-pyridylcarbinol. In spite of similar mechanical responses to norepinephrine, MVO(2) increased by 57+/-11% before and significantly less, 31+/-6%, (P < 0.01) during inhibition of lipolysis. After coronary occlusion the ischemic injury associated with norepinephrine infusion, as evidenced by epicardial mapping of S-T segment elevation, was larger before (7.9+/-1.1 mV) than during inhibited lipolysis (2.8+/-0.4 mV; P < 0.005). Average S-T segment elevation associated with norepinephrine infusion during inhibited lipolysis (2.8+/-0.4 mV) was even lower (P < 0.05) than during control occlusion alone, before drug administration (4.4+/-0.7 mV). In conjunction with an antilipolytic agent, norepinephrine was shown to reduce the extent and magnitude of the myocardial ischemic injury produced by acute coronary occlusion; this could be due to an improved balance between myocardial oxygen supply and requirement.     

Determination of Splanchnic Secretion Rate of Plasma Triglycerides and of Total and Splanchnic Turnover of Plasma Free Fatty Acids in Man

Abstract. A method has been developed whereby the splanchnic secretion rate of plasma triglycerides (TG) and the splanchnic uptake and mobilization of plasma free fatty acids (FFA) can be measured in man. The method includes constant intravenous infusion of albumin-bound ³H-labelled palmitate, and simultaneous sampling of blood from the hepatic vein and an artery.
The methodological problems associated with the quantitative determination of the small hepatio venous-arterial differences of labelled and unlabelled plasma TG and FFA have been studied. By performing ten estimates on each hepatic vein and arterial sample, analytical precision was increased sufficiently to detect significant hepatic venous-arterial differences in TG concentration and radioactivity.
The splanchnic secretion rates of labelled plasma TG were found to be constant 3 hours after beginning the continous infusion of the precursor ³H-palmitate. The plasma TG turnover was calculated according to three different methods: the chemical, the isotope and the plasma TG clearance methods. The mean values and standard deviations of the three methods were 59 ± 105, 29 ± 12 and 37 ± 22 μmoles/min.
The splanchnic uptake of plasma FFA was estimated to be between 225 and 269 μmoles/min and the splanchnic mobilization of plasma FFA was between 76 and 120 μmoles/min.     

Splanchnic Secretion Rates of Plasma Triglycerides and Total and Splanchnic Turnover of Plasma Free Fatty Acids in Men with Normo- and Hypertriglyceridaemia

Abstract. Plasma triglyceride (TG) “turnover rates” were estimated in the fasting state in three different ways: splanchnic chemical TG secretion, splanchnic isotope TG secretion and plasma TG clearance. Forty-two men with a wide range of fasting plasma TG concentrations, from 0.53 to 16.50 mmol/l were investigated. A constant intravenous infusion of albumin-bound ³H-labelled palmitate was given and blood was simultaneously sampled from the hepatic vein and an artery for determination of hepatic venous-arterial differences of labelled and unlabelled plasma TG. In addition total and splanchnic turnovers of plasma FFA were measured. Similar values were obtained for plasma TG “turnover rate” by the splanchnic chemical TG secretion and the plasma TG clearance method. The values for these two methods varied between 3 and 74 μmol/min. and m² body surface area, except for two cases who had considerably higher values. The splanchnic isotope TG secretion method gave lower values varying from 1 to 34 μmol/min. and m² body surface area. This method probably measures only that fraction of the splanchnic TG secretion which is derived from plasma FFA. No correlations were found among normotriglyceridaemic subjects between plasma total TG or VLDL-TG concentrations and plasma TG “turnover rates” measured by any of the three methods. For patients with hypertriglyceridaemia significant positive correlations were found between plasma VLDL-TG concentrations and plasma “turnover rates”. The “fractional turnover rate” decreased with increasing TG levels in an apparently hyperbolic fashion. The results suggest an impaired plasma TG removal capacity in patients with hypertriglyceridaemia. In 7 out of 14 patients the plasma TG “turnover rates” were in the upper part of the normal range and seemed to have contributed to the hypertriglyceridaemia in these patients. Plasma FFA turnover rate ranged between 102 and 439 μmol/min. and m² body surface area. On the average splanchnic FFA mobilization and uptake were about 30 and 60 per cent respectively of total FFA turnover rate. Significant positive correlations were found for the interrelationships between the three plasma FFA total and splanchnic transport parameters. Significant positive correlations were found between the three plasma TG “turnover rates” and total and splanchnic turnover of plasma FFA in subjects with normal plasma TG concentrations. Some patients with hypertriglyceridaemia fell outside the intervals of 99 per cent confidence of the regression analyses for the normo-triglyceridaemic subjects. This group had higher TG “turnover rates” than “expected” from plasma FFA turnover rates and may represent a distinctive group of hypertriglyceridaemia from the point of view of pathogenesis. It was concluded that all patients with hypertriglyceridaemia who were investigated had decreased “fractional turnover rates” of plasma TG indicating a decreased removal capacity which might be a primary cause of the hypertriglyceridaemia although inflow of plasma TG seemed to be an essential contributing factor in half the number of patients.     

Interrelations in the Oxidative Metabolism of Free Fatty Acids, Glucose, and Glycerol in Normal and Hyperlipemic Patients A COMPARTMENTAL MODEL

Palmitate, glucose, and glycerol oxidation to CO(2) have been investigated in the fasted state in ten normal subjects and nine patients (six hyperlipoproteinemias, one xanthomatosis, and two glycogenosis) after intravenous injection of [1-(14)C]palmitate, [1-(14)C]glucose, or [1-(14)C]glycerol in tracer amounts. The specific activities and concentrations of plasma palmitate, glycerol, or glucose and expired CO(2) were measured at various intervals after the injection for a period of 24 h. All the studies were analyzed in terms of a multicompartment model describing the structure for each of the subsystems, the transfer of carbon label between subsystems, and the oxidation to CO(2). A bicarbonate subsystem was also included in the model to account for its role in shaping the CO(2) curves.All the CO(2) activity following a palmitate injection could be accounted for by a direct oxidative pathway from plasm FFA with the addition of a 20-min delay compartment. The same also applied to glucose, except that the delay compartment had a mean time of about 150 min. Only about a third of the injected glycerol was directly oxidized to CO(2) from plasma; the delay time was about 4 min. Most of the remainder was converted to glucose.In normals about 45% of the FFA is oxidized to CO(2) directly. This constitutes about 30% of the total CO(2) output. In hyperlipemia the CO(2) output is nearly unchanged and the contribution from FFA is nearly the same. There is a considerable increase (factor of 2), however, in FFA mobilization, most of which is probably diverted to triglyceride synthesis.The glucose and glycerol subsystems are roughly the same in normals and hyperlipemics. About 50% of glucose is oxidized by the direct pathways which accounts for about 35% of the CO(2) output. Glycerol accounts for only 1.5% of the CO(2) produced.Major changes occurred in the glycerol and glucose subsystems in glycogenosis. The changes are consistent with the known deficiency in glucose-6-phosphatase in this disorder. There is a considerable reduction (factor of 2 or more) in the release of glucose to plasma (gluconeogenesis) and in the conversion of glycerol to glucose.Despite the integration of the kinetics of the glucose, glycerol, and FFA subsystems over a 24-h period, 36% of the CO(2) production was still unaccounted for in normals and 50% in hyperlipemics. Thus, some of the carbon must wind up in very slowly turning-over pools which supply CO(2) through subsystems not covered in these studies (triglycerides, glycogen, amino acids, etc.).All the modeling was carried out with the aid of the SAAM25 computer program.     

Mutations in UCP2 in Congenital Hyperinsulinism Reveal a Role for Regulation of Insulin Secretion

Although the most common mechanism underlying congenital hyperinsulinism is dysfunction of the pancreatic ATP-sensitive potassium channel, the pathogenesis and genetic origins of this disease remains largely unexplained in more than half of all patients. UCP2 knockout mice exhibit an hyperinsulinemic hypoglycemia, suggesting an involment of UCP2 in insulin secretion. However, a possible pathogenic role for UCP2 protein in the development of human congenital hyperinsulinism or of any human disease has not yet been investigated. We studied ten children exhibiting congenital hyperinsulinism, without detectable mutations in the known congenital hyperinsulinism-causing genes. Parental-inherited heterozygous UCP2 variants encoding amino-acid changes were found in two unrelated children with congenital hyperinsulinism. Functional assays in yeast and in insulin-secreting cells revealed an impaired activity of UCP2 mutants. Therefore, we report the finding of UCP2 coding variants in human congenital hyperinsulinism, which reveals a role for this gene in the regulation of insulin secretion and glucose metabolism in humans. Our results show for the first time a direct association between UCP2 amino acid alteration and human disease and highlight a role for mitochondria in hormone secretion.     

A Specific Role for Saline or the Sodium Ion in the Regulation of Renin and Aldosterone Secretion

It is well established that in normal man the renin-angiotensin-aldosterone system is responsive to changes in volume. The present study was performed to determine whether sodium has an action apart from volume in the regulation of the secretion of renin and aldosterone. Acute volume expansion was induced either by saline, dextran, or glucose infusion in supine, normal subjects in balance on a 10 meq sodium/100 meq potassium diet. Plasma renin activity (PRA), angiotensin II (A II), aldosterone (PA), cortisol, serum sodium, and potassium were measured every 10 min for the first 30 min and then at 1, 2, 4, 6, and 8 h.During saline infusion (500 cm(3)/h for 6 h) mean PRA and A II levels declined very rapidly, falling significantly below control at 10 min (P < 0.01) and by 50% at 60 min. Thereafter, the rate of fall was more gradual, reaching a nadir at 360 min (70-80% below control). PA declined in a parallel pattern except that a significant fall did not occur until 30 min.In contrast to saline, dextran infusion (250 cm(3)/h for 4 h) did not produce a significant fall in PRA, A II, or PA until 4 h after the start of the infusion despite equivalent volume expansion. On the other hand, the infusion of 5% glucose and water (500 cm(3)/h for 6 h) did not produce a significant decline in PRA, A II, or PA over the first 6 h of the study. Although the response rate of PRA, A II, and PA was different in each of the three infusion studies, these parameters were significantly correlated within each study. Serum sodium and potassium levels did not change during any study except dextran infusion, where a significant fall in both occurred at 120 min. In all the infusion studies, plasma cortisol levels gradually declined during the 8-h study period consistent with its expected rhythm of diurnal secretion.These results demonstrate that rate of response of the renin-angiotensin-aldosterone system to acute volume expansion with saline differed from that with dextran and glucose infusion in sodium-depleted man. The data support a specific role for volume expansion with saline or the sodium ion per se in the regulation of renin and aldosterone.     

高游离脂肪酸引起肺损伤的大鼠模型的建立

目的:观察血游离脂肪酸(free fatty acids,FFA)升高对肺组织的损伤及辛伐他汀对此类肺损伤的保护作用。方法:将56只成年雄性SD大鼠随机分为4组,每组14只。4组分别为对照组(不予处理)、高三酰甘油血症组(HTG组)、高游离脂肪酸组(FFA组)、他汀组(实验前给予辛伐他汀,建立高游离脂肪酸模型同FFA组)。4组动物模型建立后各取8只采集其血和肺组织,检测血脂(总胆固醇、三酰甘油、FFA)、脂质过氧化指标[丙二醛(malondialdehyde,MDA)、超氧化物歧化酶(superoxide dismutase,SOD)]、血细胞因子[白细胞介素-6(interleukin-6,IL-6),肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α),内皮素-1(endothelin-1,ET-1),细胞黏附分子-1(intercellular adhesion module-1,ICAM-1)],并进行动脉血气分析和肺组织病理检查。4组各选取6只大鼠进行伊文思蓝试验,测定肺血管通透性。结果:HTG组、FFA组和他汀组血脂指标均较对照组显著升高,FFA组FFA比HTG组升高2倍以上。FFA组肺损伤明显,表现为血氧分压下降、肺毛细血管通透性升高、肺间质增厚和炎症细胞浸润、肺毛细血管淤血;同时MDA升高,SOD降低,IL-6、TNF-α、ET-1和ICAM-1均显著升高。HTG组肺损伤程度较轻,该组除ET-1外,各过氧化指标和细胞因子水平改变均较FFA组小。他汀组血脂水平低于FFA组,血氧、病理、血管通透性、过氧化指标和细胞因子均较FFA组有改善。结论:血FFA升高可能通过脂质过氧化途径和ICAM-1途径引起肺损伤,辛伐他汀对此有保护作用。     

Evidence for a Role of the Microtubular System in the Secretion of Newly Synthesized Albumin and Other Proteins by the Liver

Livers of normal mice were prefused in situ and the secretion of newly synthesized (i.e. labeled) proteins into the perfusate were measured. In control livers, the secretion of newly synthesized proteins was found to be linear with time. In marked contrast, when livers were perfused with vinblastine, vincristine, or colchicine, drugs known to interfere with the hepatic microtubular system, the release of newly synthesized proteins was either strongly inhibited or completely suppressed although total hepatic protein synthesis (estimated by the incorporation of labeled amino acids into hepatic plus perfusate proteins) remained unaltered. Chromatographic separation of the various secreted proteins showed that the release of albumin, globulins, and small polypeptides was decreased to a similar extent by vincristine or colchicine. In the particular case of albumin, it was further observed that total (i.e. liver plus perfusate) labeled amino acid incorporation into albumin was not altered by either vincristine or colchicine, whereas the incorporation of these amino acids into liver albumin was markedly increased but incorporation into perfusate albumin was decreased, suggesting that the translocation of this particular protein from the liver to the perfusate had been affected by the presence of these drugs. It is proposed that the functional integrity of microtubules is necessary for the intracellular movement and eventual release of albumin and other proteins by the liver, and suggested that microtubules might possibly be a site of regulation of hepatic protein secretion.     

Role of Large Arteries in Regulation of Cerebral Blood Flow in Dogs

Previous studies have demonstrated a significant pressure gradient from carotid artery to pial or middle cerebral arteries. This pressure gradient suggests that large cerebral arteries contribute to cerebral resistance. We have tested the hypothesis that large cerebral arteries contribute to regulation of cerebral blood flow during changes in blood gases and arterial pressure. Microspheres were used to measure brain blood flow in anesthetized dogs. Resistance of large cerebral arteries was estimated by determining the pressure gradient between common carotid and wedged vertebral artery catheters. Systemic hypercapnia and hypoxia dilated large cerebral arteries, and hypocapnia constricted large cerebral arteries. Resistance of large arteries was 0.6±0.1 (mean ± SE) mm Hg per ml/min per 100 g during normocapnia. During hypercapnia and hypoxia, large artery resistance decreased significantly to 0.2 ± 0.03 and 0.3 ± 0.05, respectively. During hypocapnia large artery resistance increased significantly to 1.0 ± 0.1. In other experiments, we found that large cerebral arteries participate in auto-regulatory responses to hemorrhagic hypotension. When arterial pressure was reduced from 110 to 58 mm Hg, autoregulation maintained cerebral blood flow constant, and resistance of large cerebral arteries decreased significantly from 1.0 ± 0.2 to 0.6 ± 0.1 mm Hg per ml/min per 100 g. In absolute terms, we calculated that 20-45% of the change in total cerebral resistance during these interventions was accounted for by changes in large artery resistance. These studies indicate that large cerebral arteries, as well as arterioles, participate actively in regulation of cerebral blood flow during changes in arterial blood gases and during autoregulatory responses to hemorrhagic hypotension.     

Effects of Alterations of Plasma Free Fatty Acid Levels on Pancreatic Glucagon Secretion in Man

The present investigation was undertaken to ascertain whether alterations in plasma free fatty acids (FFA) affect pancreatic glucagon secretion in man since FFA have been reported to influence pancreatic alpha cell function in other species. Elevation of plasma FFA from a mean (+/-SE) basal level of 0.478+/-0.036 mM to 0.712+/-0.055 mM after heparin administration caused plasma glucagon levels to fall approximately 50%, from a basal value of 122+/-15 pg/ml to 59+/-14 pg/ml (P < 0.001). Lowering of plasma FFA from a basal level of 0.520+/-0.046 mM to 0.252+/-0.041 mM after nicotinic acid administration raised plasma glucagon from a basal level of 113+/-18 pg/ml to 168+/-12 pg/ml (P < 0.005). Infusion of glucose elevated plasma glucose levels to the same degree that heparin raised plasma FFA levels. This resulted in suppression of plasma glucagon despite the fact that plasma FFA levels also were suppressed. Glucagon responses to arginine were diminished after elevation of plasma FFA (P < 0.01) and during infusion of glucose (P < 0.01). Diminution of plasma FFA by nicotinic acid did not augment glucagon responses to arginine.These results thus demonstrate that rather small alterations in plasma FFA within the physiologic range have a significant effect on glucagon secretion in man. Although the effects of glucose appear to predominate over those of FFA, alterations in plasma FFA may nevertheless exert an important physiologic influence over human pancreatic alpha cell function, especially in the postabsorptive state.     

Difference in Hepatic Metabolism of Long- and Medium-Chain Fatty Acids: the Role of Fatty Acid Chain Length in the Production of the Alcoholic Fatty Liver

Replacement of dietary triglycerides containing long-chain fatty acids (LCFA) by triglycerides containing medium-chain fatty acids (MCFA) markedly reduced the capacity of alcohol to produce fatty liver in rats. After 24 days of ethanol and MCFA, the increase in hepatic triglycerides was only 3 times that of controls, whereas an 8-fold rise was observed after ethanol and LCFA. The triglyceride fatty acids that accumulated in the liver after feeding of ethanol with MCFA contained only a small percentage of the MCFA; their composition also differed strikingly from that of adipose lipids.To study the mechanism of the reduction in steatosis, we compared oxidation to CO(2) and incorporation into esterified lipids of (14)C-labeled chylomicrons or palmitate-(14)C (representing LCFA), and of octanoate-(14)C (as MCFA) in liver slices and isolated perfused livers, in the presence or absence of ethanol. Ethanol depressed the oxidation of all substrates to CO(2); MCFA, however, was much more oxidized and reciprocally much less esterified than LCFA, with a 100-fold difference in the ratio of esterified lipid-(14)C to (14)CO(2). Furthermore, in hepatic microsomal fractions incubated with alpha-glycerophosphate, octanoate was much less esterified than palmitate. This propensity of MCFA to oxidation rather than esterification represents a likely explanation for the reduction in alcoholic steatosis upon replacement of dietary LCFA by MCFA.     

Regulation of Calcitonin Secretion in Normal Man by Changes of Serum Calcium within the Physiologic Range

To examine the relative importance of calcium and gastrin in regulation of calcitonin secretion, we administered graded oral doses of calcium to 10 normal men, ages 23-29 yr. Each subject had previously shown an appropriate increase in calcitonin secretion in response to a pharmacologic (0.5 mug/kg) pentagastrin injection. On separate days and in random order, each man drank 250 ml of distilled water containing 0.0, 0.5, 1.5, and 3.0 g of elemental calcium as the gluconate salt. Blood samples were drawn before and at 30, 60, 90, 120, 180, and 240 min after the oral calcium dose. The samples were analyzed for calcium by atomic absorption spectroscopy, and for gastrin and calcitonin by radioimmunoassays of established sensitivity and specificity. Ingestion of water (control) caused no change in any of the three variables. Calcium ingestion resulted in dose-related increases, within the normal range, of all three variables. Immunoreactive gastrin rose promptly, peaking at 30 min, and returning to basal levels or below by 120 min. In contrast, calcium and immunoreactive calcitonin levels rose slowly and in parallel, peaking at 120-240 min. Changes in calcitonin and changes in calcium were strongly and positively correlated, r = 0.73, when all data were pooled. Furthermore, individual linear regressions for changes in calcitonin and calcium levels (calculated separately for the three oral calcium doses in each subject) had positive slopes in 28 out of 30 sets (P < 0.01). The changes in calcitonin concentrations were much more poorly correlated with the corresponding changes in serum gastrin levels; in fact, the regression coefficient was weakly negative, r = -0.20. These results show that, at least in young adult men, changes of ambient calcium concentration within the normal range may be of major importance in physiologic regulation of calcitonin secretion. The findings are consistent with the hypothesis that calcitonin functions to prevent excessive postprandial hypercalcemia.     

The Influence of Plasma Free Fatty Acids and Cholesterol on the Aggregation of Blood Platelets in Migraine Patients

SYNOPSIS
The Platelet Aggregate Ratio (PAR) was determined in 34 women with common migraine during headache-free intervals. Fourteen of them were studied also during migraine attacks.
The levels of FFA and total cholesterol in the blood were determined simultaneously to assess their influence on aggregation of blood platelets.
Plasma FFA levels rose significantly during headache (r<0.001). The levels of total blood cholesterol did not show a homogenous distribution. In 20 patients blood cholesterol was elevated; in the remaining 14 patients levels were within the standard range.
The migraineurs with high cholesterol showed a significantly lower PAR during headache-free intervals than did the control subjects (r<0.001). There was no significant difference between PAR in migraineurs with normal cholesterol and the controls. A significant fall of PAR during migraine attacks was observed only in migraineurs with high cholesterol (r<0.01). There was a significant correlation between the falling of PAR and the level of blood cholesterol (r<0.05). The same correlation was found between the falling of PAR and the rising of FFA during migraine attacks (r<0.05).
We suggest that FFA can raise the number of circulating platelet aggregates during migraine episodes. Total blood cholesterol is one of the factors which define migraine populations with respect to platelet aggregation.     

The Physiological Role of Thyrotropin-Releasing Hormone in the Regulation of Thyroid-Stimulating Hormone and Prolactin Secretion in the Rat

The physiological role of thyrotropin-releasing hormone (TRH) in the regulation of thyrotropin (thyroid-stimulating hormone, TSH) and prolactin (Prl) secretion has been assumed but not proven. Stimulation of their release requires pharmacologic doses of TRH. Lesions of the hypothalamus usually induce an inhibition of TSH secretion and an increase in Prl. To determine whether TRH is essential for TSH and Prl secretion in the rat, 0.1 ml of TRH antiserum (TRH-Ab) or normal rabbit serum was administered to normal, thyroidectomized, cold-exposed, and proestrus rats through indwelling atrial catheter. Serum samples were obtained before and at frequent intervals thereafter. Serum TSH concentrations in normal, thyroidectomized, cold-exposed, and proestrus rats were not depressed in specimens obtained up to 24 h after injection of normal rabbit serum. In contrast, serum TSH was significantly decreased after the administration of TRH-Ab in all normal (basal, 41+/-8 muU/ml [mean+/-SE]; 30 min, 6+/-2; 45 min, 8+/-3; 75 min, 4+/-2); thyroidectomized (basal, 642+/-32 muU/ml; 30 min, 418+/-32; 60 min, 426+/-36; 120 min, 516+/-146); coldstressed (basal, 68+/-19 muU/ml; 30 min, 4+/-3; 180 min, 16+/-8); and proestrus (basal, 11 a.m., 57+/-10 muU/ml; 1 p.m., 20+/-3; 3 p.m., 13+/-4; 5 p.m., 19+/-3) rats. However, 0.1 ml of TRH-Ab had no effect on basal Prl concentrations in normal or thyroidectomized rats and did not prevent the Prl rise in rats exposed to cold (basal, 68+/-7 ng/ml; 15 min, 387+/-121; 30 min, 212+/-132; 60 min, 154+/-114), or the Prl surge observed on the afternoon of proestrus (basal 11 a.m., 23+/-2 ng/ml; 1 p.m., 189+/-55; 3 p.m., 1,490+/-260; 5 p.m., 1,570+/-286). These studies demonstrate that TRH is required for TSH secretion in the normal, cold-exposed and proestrus rat and contributes, at least in part, to TSH secretion in the hypothyroid rat, but is not required for Prl secretion in these states.