Clonal origin of inherited medullary thyroid carcinoma and pheochromocytoma.

A black female with inherited medullary thyroid carcinoma and pheochromocytoma was a mosaic for glucose-6-phosphate dehydrogenase types A and B in normal tissues (blood, thyroid, and adrenal gland); both the medullary carcinoma and pheochromocytoma tissue showed a B pattern only. This finding suggests a single clone origin for each of the tumors. Other inherited tumors similarly studied in man have appeared to be multiclonal in origin.

Inherited medullary thyroid carcinoma: a final monoclonal mutation in one of multiple clones of susceptible cells.

Inherited medullary thyroid carcinomas contain one form of glucose-6-phosphate dehydrogenase (G6PD) in black female patients who are mosaic in normal tissues for G6PD types A and B. The same individual may have several tumors each containing either G6PD A or G6PD B. The data suggest that the inherited defect is an initial mutation producing multiple clones of defective cells; each tumor then arises as a final mutation in one clone of these cells.

Response of plasma adrenocorticotropin to injections of L-glutamate or norepinephrine in the dorsal rostral pons of cats.

Previously, electrical stimulation of several nuclei in the dorsal rostral pons of the cat was shown to modulate the release of ACTH. However, the stimulation may have activated fibers of passage. To determine if there are specific groups of neurons within the pons that modulate plasma ACTH when stimulated with glutamate, 30 cats were prepared acutely under chloralose anesthesia. Microinjections of several agents were made at each of 2 sites in the pons of each cat. ACTH was measured by RIA. Injections of 150 mM L-glutamate (100 nl/min.2 min) elicited increases in arterial pressure that were related to the loci of injection. The responses did not decrease significantly when the rate and volume of the injection were reduced by half. Eight sites in a lateral area that extended rostrally from the parabracheal nucleus elicited a significant pressor response that was greater in duration and magnitude than a second significant pressor response that was obtained from 18 sites in a medial area that included the rostral locus coeruleus. Pressor responses did not occur when 0.1 mM norepinephrine or vehicle was substituted for L-glutamate in any area. The larger, but not the smaller, dose of L-glutamate elicited changes in plasma ACTH that were related to the loci of injection. Eight sites in a caudal area that included the ventral locus coeruleus and was within the medial pressor area elicited a significant increase in ACTH. Seven sites in an area rostral to the ventral locus coeruleus that included the rostromedial locus subcoeruleus elicited a significant decrease in plasma ACTH. ACTH responses were not observed when 0.1 mM norepinephrine or vehicle was substituted for L-glutamate in any area. In conclusion, the ventral locus coeruleus and the rostrally adjacent locus subcoeruleus contain neurons with receptors for L-glutamate that can modulate plasma ACTH and arterial pressure independently of a second pathway that includes the parabracheal region and influences arterial pressure. Because the neurons in the coeruleus are known to respond to hemodynamic input, they may participate in the hemodynamic control of ACTH release.

Alpha-adrenergic input in the locus coeruleus modulates plasma adrenocorticotropin in cats.

Previous evidence suggested that noradrenergic activity in the vicinity of the ventrorostral locus coeruleus (LC) increased in response to hemorrhage. To investigate the possible role of this response in the control of ACTH release, microinjections (100 nl/min for 2 min) of several agents were made at 59 sites in 35 cats anesthetized with chloralose. Injections were as follows: vehicle (all sites); 150 mM L-glutamate (GLU; 51 sites); an alpha 2-agonist, 1 mM clonidine (19 sites); an alpha 2-antagonist, 1 mM yohimbine (32 sites); an alpha 1-agonist, 1 mM phenylephrine (PE; 42 sites); and an alpha 1-antagonist, 0.05 mM prazosin (20 sites). Plasma ACTH was measured by RIA. Responses were tested statistically by repeated measures analysis of variance. GLU at 12 sites in the region of the ventrorostral LC facilitated plasma ACTH (P less than 0.01), whereas GLU at 6 sites in the caudal LC inhibited ACTH (P less than 0.05). Clonidine at 9 sites in an area that included the ventrorostral LC inhibited ACTH (P less than 0.05), and yohimbine at 7 sites within this latter area facilitated ACTH (P less than 0.01). PE within the ventrorostral LC had no effect on ACTH. However, PE at 10 sites within the caudal LC and along the ventromedial border of the ventrorostral LC facilitated ACTH. The responses for all of these areas to the respective agents differed from those to vehicle, whereas responses from other areas to the former agents or from all areas to prazosin did not. An increase in noradrenergic turnover in the LC may provide inhibitory alpha 2 modulation to the neurons in the LC that are activated by hemorrhage. This modulation and possible alpha 1 input in areas adjacent to the ventrorostral LC may influence the hemodynamic control of ACTH release.

Inhibitory and facilitatory areas of the dorsal medulla mediating ACTH release in the cat.

To define the role of the dorsal medulla in the control of release of ACTH, the authors stimulated electrically (30 sec, 100 muA, 50 Hz) 50 sites in the vicinity of the solitary nuclei of 11 cats anesthetized with chloralose/urethane. Responses of arterial pressure to electrical stimulation were not correlated significantly with release of ACTH. Indirect effects of changes in arterial pressure could not explain changes in release of ACTH. Concentrations of ACTH were measured by radioimmunoassay. Active areas associated with the solitary nucleus were : 1) lateral inhibitory: ventral and lateral to the solitary tract (mean delta ACTH:-153, -86, -97 pg/ml at 1.5, 3.0 and 6.0 min respectively; P less than 0.01); 2) medial inhibitory: medial dorsal motor nucleus of the vagus and extending to the midline (mean delta ACTH: -81, -107, -67 pg/ml; P less than 0.01); and 3) intermediate facilitatory: lateral nucleus intercalatus and adjacent reticular formation (mean delta ACTH: +105, +158, +4 pg/ml; P less than 0.01). The former two areas contain neurons activated by atrial stretch, and the latter area contains neurons inhibited by atrial stretch. Since changes in ACTH levels are inversely correlated with atrial stretch, the results suggest that the changes in release of ACTH are the result of direct stimulation of neural systems of the solitary nuclei mediating release of ACTH in response to hemodynamic changes.

Anterior pituitary vasodilation after hemorrhage in the dog.

A miniature thermoelectric probe was used to record continuously tissue blood flow in the anterior pituitary gland of anesthetized dogs. The output of the flow probe is linear in the range of tissue blood flow encountered in the pituitary. Probe placement required minimal tissue trauma, and zero blood flow was recorded at the end of each experiment. Little or no change in flow followed hemorrhage of 10 ml/kg body weight. However, hemorrhages of 20 or 30 ml/kg were followed by a biphasic deviation from control level, with an initial transient decrease in flow, followed by recovery to control at about 19 min and a rise above control to 90% of maximum at about 32 min. Hypothalamohypophysial vascular resistance was found to decrease significantly following hemorrhages of 20 or 30 ml/kg, and this was shown to be independent of resistance changes in the femoral vascular bed. It is concluded that anterior pituitary blood flow is well maintained following moderate hemorrhage as a result of intrinsic vasodilation in the hypothalamo-hypophysial vascular bed.

Increased cortisol secretion after small hemorrhage is not attributable to changes in adrenocorticotropin.

Adrenal secretory rates of cortisol and corticosterone and arterial concentrations of ACTH and cortisol were measured in conscious trained dogs subjected to 10 ml/(kg . 3 min) or 20 ml/(kg . 3 min) hemorrhage. All four variables increased substantially after 20 ml/(kg . 3 min) hemorrhage. Secretion rates of cortisol and corticosterone increased significantly after 10 ml/(kg . 3 min) hemorrhage, without a change in ACTH. The responses of ACTH and the secretion rates of cortisol to 10 ml/(kg . 3 min) hemorrhage and iv infusion of ACTH were compared. Infusions of ACTH required to match the secretory response of cortisol after 10 ml/(kg . 3 min) hemorrhage resulted in concentrations of ACTH significantly higher than those observed after 10 ml/(kg . 3 min) hemorrhage. These results suggest that 10 ml/(kg . 3 min) hemorrhage induces an acute increase in adrenocortical sensitivity to ACTH.

Effects of vasopressin antiserum on the response of adrenocorticotropin and cortisol to hemorrhage.

To determine if arginine vasopressin (AVP) is involved in the response of ACTH and cortisol (F) to hemorrhage, we examined the effect of injections of AVP-antiserum into the third ventricle in chronically prepared awake cats. Cats were trained to remain unrestrained in a cardboard box. Cats were prepared under halothane and nitrous oxide with aseptic technique. Two to 3 days later, experiments began. Antiserum (5 microliters) to AVP or to oxytocin (OXY) as a control was given 26 min before hemorrhage conducted over 3 min. Thirty minutes after hemorrhage, reinfusion was conducted over 3 min. Each cat received each antiserum in randomized sequence 2-3 days apart. Plasma ACTH and F were measured by RIA. Data were analyzed statistically by analysis of variance. In 12 experiments in 6 cats, ACTH and F increased significantly with 10 ml/kg hemorrhage (P less than 0.01) and to the same extent (P greater than 0.1) after either antiserum. In 20 additional experiments in 10 cats, a submaximal dose of dexamethasone was administered sc 2-3 h before hemorrhage of 15 or 17.5 ml/kg. Under this circumstance, ACTH increased significantly (P less than 0.05) after anti-OXY, but not after anti-AVP (P greater than 0.2) so that during hemorrhage the values of ACTH differed significantly (P less than 0.025). F increased significantly more after anti-OXY than after anti-AVP (P less than 0.025). Changes in arterial pressure, heart rate, and plasma glucose with or without pretreatment with dexamethasone did not differ between groups. Changes in F and ACTH in cats receiving sham injections did not differ from those after anti-OXY. These findings suggest that normally a corticotropin-releasing factor (CRF) or factors act independently of AVP to mediate the response to hemorrhage. However, in the presence of steroid feedback by dexamethasone, the release or action of this CRF(s) is suppressed so that AVP is necessary for a full response. As has been proposed previously by others, AVP could potentiate the action of other CRFs, stimulate their release, or act as a CRF.

Organization of the lateral hypothalamus for control of adrenocorticotropin release in the cat.

Regions in the ventral midbrain that project to the lateral hypothalamus have been implicated in the control of ACTH release. To define further those areas in the lateral hypothalamus through which afferent signals might pass, we electrically stimulated 188 sites in the lateral hypothalamus of 20 cats anesthetized with chloralose-urethane. Stimulations were monophasic pulses of DC (200 microA; 0.2 msec; 100 Hz; 20 sec). Venous samples were drawn over 30 sec 0.5 min before and 1.5 min after stimulation. Equal volumes of warmed isoncotic dextran were infused during sampling to prevent hypovolemia. ACTH was assayed by RIA. Areas were defined in which stimulation led to increased, decreased,, or unchanged ACTH. Mean changes in ACTH were tested by analysis of variance. The present data indicate that the ACTH-active areas defined previously in the midbrain may join the medial forebrain bundle in the subthalamic area and nucleus to traverse the lateral hypothalamus. At the level of the mammillary bodies, a facilitatory area occupied the ventral portion of the medial forebrain bundle. This area extended rostrally and medially to join the medial aspect of the medial forebrain bundle. Continuity with the mediobasal hypothalamus was seen only anteriorly in the area of the supraoptic decussations. An inhibitory area occupied the dorsal extent of the medial forebrain bundle at the level of the mammillary bodies. It extended rostrally and laterally around the caudal pole of the supraoptic nucleus and then medially at the level of the optic chiasm. There appear to be no other medial projections of the lateral lying ACTH-active areas to the mediobasal hypothalamus. The lateral hypothalamus may serve as a site of passage and/or of processing of information that ascends from the midbrain and descends from the limbic system.

Dissociation between changes in plasma bioactive and immunoreactive adrenocorticotropin after hemorrhage in awake dogs.

The secretion of cortisol increases in awake dogs after small hemorrhage, with little or no change in plasma immunoreactive (IR) ACTH. To determined if IR-ACTH reflects bioactive (B) ACTH after hemorrhage, changes in B-ACTH and IR-ACTH were determined in awake dogs. Trained dogs were prepared with adrenal venous and femoral arterial and venous cannula. Experiments performed 48-96 h after surgery consisted of blood sampling from the adrenal vein and femoral artery before and after a 7.5-10 ml/kg hemorrhage done over 3 min. Cortisol was assayed by HPLC with UV detection, and adrenal secretory rates were calculated using adrenal blood flow. Arterial B-ACTH was assayed after extraction using rat adrenal cells dispersed with collagenase; corticosterone produced was assayed by HPLC-UV. Arterial IR-ACTH was assayed by RIA using antisera directed against ACTH-(1-24). Dogs in which hypotension occurred (change in mean arterial pressure, -31 +/- 3; n = 6) were compared to dogs in which mean arterial pressure did not change (change in mean arterial pressure, -6 +/- 2; n = 5). In the absence of hypotension, B-ACTH increased by 10 min after the onset of hemorrhage coincident with increased cortisol secretion, whereas IR-ACTH did not increase until 20 min. Resting IR-ACTH was greater than B-ACTH (11 +/- 1 vs. 2 +/- 1 pg/ml), but the peak response of B-ACTH was greater than that of IR-ACTH (13 +/- 4 vs. 8 +/- 3 pg/ml). In the presence of hypotension, B-ACTH increased by 4 min, and IR-ACTH and cortisol secretion increased by 8 min after the onset of hemorrhage. Resting IR-ACTH was greater than B-ACTH (27 +/- 5 vs. 6 +/- 1 pg/ml), and the peak response of B-ACTH was less than that of IR-ACTH (64 +/- 26 vs. 112 +/- 33 pg/ml). In dogs subjected to blood sampling without hemorrhage (n = 4), resting IR-ACTH was greater than B-ACTH (34 +/- 5 vs. 5 +/- 1 pg/ml), but there was no change in B-ACTH, IR-ACTH, or cortisol secretion. The results show that small hemorrhage elicits changes in B-ACTH that are dissociated in time and magnitude from changes in IR-ACTH, are coincident with changes in cortisol secretion, and are greater in dogs that fail to maintain arterial pressure. These data indicate that B-ACTH predicts more accurately the change in cortisol secretion than does IR-ACTH after small hemorrhage.

Inhibitory and facilitatory areas of the ventral midbrain mediating release of corticotropin in the cat.

To examine the role of the ventral midbrain in the control of release of ACTH, we stimulated electrically 92 sites in the mesencephalon of 15 cats anesthetized with chloralose/urethane. Responses of arterial pressure could not account for change of release of ACTH. Three active areas were identified. First, in a dorsal facilitatory area that includes the dorsal longitudinal fasciculus, electrical stimulation led to changes in ACTH of +106, +117, and +90 pg/ml at 1.5, 3.5, and 6.5 min, respectively (P less than 0.05). Second, in a more ventral inhibitory area that includes the mammillary peduncle, electrical stimulation led to changes in ACTH of -63, -72, and -47 pg/ml, respectively (P less than 0.05). Third, in a ventral facilitatory area that includes the ventral tegmental area of Tsai, electrical stimulation led to changes in ACTH of +57, +56, and +59 pg/ml, respectively (P less than 0.01). The inhibitory and facilitatory areas of the ventral midbrain appeared to be continuous, respectively, with the inhibitory and facilitatory areas mediating control of ACTH in the dorsal rostral pons and in the hypothalamus. Anatomical evidence indicates projections from these ACTH-active areas of the midbrain and of the pons to ACTH-active areas of the hypothalamus. Thus, the present results suggest that the midbrain areas identified may represent pathways from ACTH-active areas of the pons to the hypothalamus.

Hypotensive hemorrhage elevates corticotropin-releasing hormone messenger ribonucleic acid (mRNA) but not vasopressin mRNA in the rat hypothalamus.

We examined the effect of acute hypotensive hemorrhage on corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) messenger RNAs (mRNAs) in neurons of the rat hypothalamus. Sprague-Dawley male rats were cannulated (femoral artery and vein) and received a 15 ml/kg.3 min hemorrhage on the morning of the fourth day. Time controls received no hemorrhage. After light halothane anesthesia, the rats were decapitated at 1 or 4 h (six to nine rats per group). The hypothalami were removed, frozen, and sectioned at 12 microns. In situ hybridization was performed using two 48-base oligodeoxynucleotide probes for CRH and AVP message, respectively. Hemorrhage led to a fall in arterial blood pressure and heart rate that recovered by 1 h. Plasma ACTH, corticosterone, and AVP were elevated 20, 60, and 90 min after hemorrhage, but returned to near control levels by 4 h. CRH mRNA was significantly elevated 1 and 4 h after hemorrhage, as compared to time controls, in parvocellular neurons of the paraventricular nuclei. However, AVP mRNA was not different from controls at 1 or 4 h after hemorrhage in the magnocellular or parvocellular paraventricular nuclei, or in the supraoptic or accessory nuclei of the hypothalamus. AVP mRNA was also found in neurons of the suprachiasmatic nuclei, but there was no difference in the amount of mRNA between the 1-h hemorrhage and control groups. These data suggest that neural signals, originating for cardiovascular receptors activated by hemorrhage, up-regulate message for CRH but not for AVP in the paraventricular nuclei of the rat hypothalamus.

Inhibitory and facilitatory areas of the rostral pons mediating ACTH release in the cat.

To define the role of the rostral pons in the control of release of ACTH, we stimulated electrically (30 sec, 200 muA, 50 Hz) 128 sites in the dorsal rostral pons of 20 cats anesthetized with chloralose/urethane. Responses of arterial pressure to electrical stimulation were prevented by lesions placed previously in the medulla. Plasma concentrations of ACTH were measured by radioimmunoassay. Active areas consisted of three regions: 1) lateral inhibitory: Locus subcoeruleus and anteroventral locus coeruleus (mean deltaACTH: -189, -164, -145 pg/ml at 1.5,3.0 and 6.0 min respectively, P less than 0.01);2) intermediate facilitatory:principal locus coeruleus and lateral ventral tegmental nucleus (mean deltaACTH: +81, +68, +37 pg/ml; P less than 0.05); and 3) medial inhibitory: dorsal tegmental nucleus, dorsal raphé and medial ventral tegmental nucleus (mean deltaACTH; -211, -212, -115 pg/ml; P less than 0.01). The former two areas received direct projections from medullary neurons activated or inhibited by atrial stretch, and, in turn, give rise to adrenergic and cholinergic projections to the medial hypothalamus. Since the release of ACTH is inversely correlated with right atrial stretch, the results suggest that the lateral inhibitory area and the intermediate facilitatory area are involved in mediation of changes in release of ACTH in response to hemodynamic changes.

Potentiation of the ACTH response to metyrapone by L-dopa in the monkey.

The intravenous injection of L-Dopa (15 mg/kg) to monkeys (Macaca mulatta) failed to alter plasma concentrations of ACTH and of 11-deoxy-cortisol. When cortisol synthesis was blocked with iv metyrapone, potentiation of ACTH secretion by L-Dopa became apparent. Simultaneous injection of L-Dopa and metyrapone resulted in a marked increase in plasma ACTH from 93 +/- 18 pg/ml to 432 +/- 80 pg/ml, whereas plasma 11-deoxycortisol increased from 1.5 +/- 0.2 mug/100 ml to 14.6 +/- 1.0 mug/100 ml 90 min after treatment. Throughout the experiment the rise in ACTH and in 11-deoxycortisol following coadministration of L-Dopa and metyrapone was significantly (P less than 0.01) higher than that produced by metyrapone administration alone. The results suggest that acute administration of L-Dopa in monkeys enhances the response of ACTH to metyrapone. L-Dopa (or one of its metabolites) probably acts upon a noradrenergic or a dopaminergic system located in the hypothalamus to alter the release of hypothalamic corticotropin regulatory factor(s) and thereby enhance the release of ACTH.

Sympathetic adrenal denervation decreases adrenal blood flow without altering the cortisol response to hemorrhage.

To test whether or not adrenal sympathetic innervation is required for the adrenocortical response to small hemorrhage, awake dogs were studied after unilateral adrenal sympathetic denervation. Bilateral adrenal vein cannulas were placed chronically to permit measurement of cortisol, epinephrine, and norepinephrine secretion rates and adrenal blood flow simultaneously from the intact and the denervated adrenal. Plasma ACTH concentration was measured and the presentation rate of ACTH was calculated as the product of plasma ACTH concentration and adrenal plasma flow. Unilateral isolation of the sympathetic chain from the spinal cord at thoracic levels 9-12 (T9-12) had no effect on adrenal blood flow, on the presentation rate of ACTH, or on cortisol secretion after 10 mg/kg hemorrhage. However, thoracic levels 9-12 denervation prevented the secretory response of catecholamines to hemorrhage without lowering basal catecholamine secretion. Unilateral splanchnicotomy, the sectioning of the thoracic and upper lumbar splanchnic nerves, reduced adrenal blood flow and the presentation rate of ACTH, suppressed basal catecholamine secretion, and prevented the catecholamine response to hemorrhage. However, there was no reduction in the secretory response of cortisol to 10% or 20% hemorrhage. These findings suggest that in the absence of sympathetic innervation to the adrenal, increases in adrenal sensitivity to ACTH occur to offset decreased ACTH presentation rate resulting in a normal cortisol response to hemorrhage. However, adrenal sensitivity to exogenous ACTH was not increased in non-hemorrhaged dogs after unilateral splanchnicotomy. Thus, hemorrhage must activate a non-ACTH mechanism that is independent of sympathetic adrenal innervation to augment adrenal sensitivity to ACTH. Sympathetic innervation to the adrenal has profound effects on catecholamine secretion and on adrenal blood flow but is not required for the secretory response of cortisol to small hemorrhage.

Selective opiate modulation of the physiological responses to hemorrhage in the cat.

To assess the role of endogenous opiates on the hormonal and cardiovascular responses to moderate hemorrhage (H) and/or nociceptor activation, naloxone (Nx; 100 micrograms/kg, iv) was given coincident with H (10 ml/kg), tooth pulp nerve stimulation (TP), or H plus TP in anesthetized cats. We have previously reported that TP potentiated the ACTH response to H. Nx treatment did not affect this TP potentiation of ACTH after H, nor did Nx affect the ACTH response to H alone. This suggested that the interaction between nociceptor and baroreceptor afferent nerves, which may underlie the observed TP potentiation of ACTH release after H in the anesthetized cat, was not dependent upon naloxone-sensitive opiate pathways. In contrast, Nx attenuated the fall in arterial pressure during H or H plus TP and completely blocked the normally observed hyperglycemia. Catecholamines showed a prompt rise during H or H plus TP in Nx-treated animals. Thus, altered adrenomedullary hormone release cannot account for the attenuated fall in blood pressure or the inhibition of hyperglycemia during H or H plus TP. Nx presented alone or in combination with TP did not significantly affect any measured variable. To determine if Nx acted directly at the level of the liver to block H-induced hyperglycemia, a second group of animals received intraportal injections of Nx (20, 50, or 100 micrograms/kg) before H. Nx did not block the rise in glucose after H, although each of the three doses of Nx significantly attenuated the early (at +1 min) fall in blood pressure. Portal venous samples of glucagon and insulin during H were not significantly affected by Nx. These results suggest that 1) naloxone-sensitive endogenous opiate receptors are not necessary for the rise in ACTH during H or for the TP potentiation of H-induced increases in ACTH; 2) the fall in mean arterial pressure and the rise in glucose during H are selectively attenuated by Nx independent of significant changes in peripheral catecholamine levels when compared to Nx untreated animals; and 3) finally, Nx does not act directly at the liver to block the H-induced rise in glucose, but, rather, is effectively cleared from the circulation by the liver.

Responses of cortisol secretion to repeated hemorrhage in the anesthetized dog.

We used two sequential 7.5 ml/kg hemorrhages, spaced 24 h apart, in the chronically prepared, pentobarbital-anesthetized dog to study the effects of repeated stimuli on the adrenocortical system. Adrenal secretion of cortisol, peripheral cortisol, and ACTH were measured. All three variables increased after an initial 7.5 ml/kg hemorrhage. When the hemorrhage was repeated 24 h later, the secretory response of cortisol began more rapidly (by 4 min), reached a higher peak, and was more prolonged than the response on day 1. ACTH rose to significantly higher values than on day 1, but only after 8 min. There was no differences in cardiovascular variables after hemorrhage on the 2 days. A repeated 3.75 ml/kg hemorrhage did not lead to a potentiated response. These results confirm reports that after physiological stimulation, changes occur in the pituitary-adrenal system that may lead to a potentiated response to later stimuli. The mechanism of these changes is unknown, but our results suggest that both an increase in circulating ACTH and a change in adrenal sensitivity to ACTH may be involved.

The pituitary-adrenocortical response to hemorrhage depends on the time of day.

The response of plasma ACTH and the secretory response of cortisol to moderate hemorrhage were determined in awake dogs in the morning (AM) and evening (PM). Whereas the magnitudes of the response of ACTH were similar in the AM and PM, the magnitude of the secretory response of cortisol was significantly greater in the AM compared to that in the PM. At both times of day, heart rate, mean arterial pressure, and secretory rates of epinephrine after hemorrhage were similar. These findings suggest that AM-PM differences in stimuli produced by moderate hemorrhage cannot explain the differences in the secretion of cortisol. Instead, AM-PM changes in adrenocortical sensitivity to endogenous ACTH after hemorrhage determine the AM-PM differences in the secretion of cortisol.

Restitution of blood volume after hemorrhage: inhibition by somatostatin.

To determine whether glucagon plays a significant role in the restitution of blood volume after hemorrhage, pentobarbital-anesthetized dogs were treated with somatostatin (SRIF). The administration of SRIF (14 micrograms/kg.h) prevented the increase in osmolality and the complete restitution of plasma protein and blood volume that normally occur after 10% hemorrhage. The intraportal addition of glucagon (20 ng/kg.min) during the initial 4 h after hemorrhage reversed the SRIF-induced block in hyperosmolality and was followed by complete restitution of plasma protein and blood volume. These data suggest that increases in glucagon may be a part of the multi-hormonal response to hemorrhage, and this may be a part of a reflex that mediates the homeostasis of blood volume.

Tooth pulp stimulation potentiates the adrenocorticotropin response to hemorrhage in cats.

Stimulation of the maxillary tooth pulp nerve (TP), a predominantly nociceptive afferent fiber system, was assessed for its effect on peripheral plasma ACTH in chloralose-urethane anesthetized cats. These results were compared to those after a transient 10 ml/kg hemorrhage (H), a submaximal neurogenic stressor for ACTH release, and to H plus TP in combination. TP alone for 3 min had no significant effect on ACTH. However, TP during H greatly potentiated the increase in plasma ACTH concentration compared to that seen after H alone. The TP potentiation of the H-induced rise in ACTH was not accompanied by altered cardiovascular responsiveness nor by differences in plasma norepinephrine or glucose relative to that seen after H alone. The data indicate that nociceptive and baroreceptor afferents share a common neural substrate for selective facilitation of ACTH release, but do not interact to potentiate several other physiological responses, such as sympathetic efferent activity. Furthermore, under the conditions of these experiments, selective nociceptor activation in the anesthetized cat is not an adequate stimulus for the release of ACTH.