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Biomedical subjects

H Raff

Publications and source records attributed to H Raff.

At least 91 records · Page 5Linked to original sources
PubMed1989

Regional adrenal blood flow during hypoxia in anesthetized, ventilated dogs.

The effect of hypoxic hypoxia (HH) and carbon monoxide hypoxia (COH) on adrenal medullary (MQ) and cortical (CQ) blood flow (radiolabeled microsphere technique) was studied in pentobarbital sodium-anesthetized, mechanically ventilated dogs. Animals were exposed to 60 min of hypoxia (arterial O2 content 8 vol%) induced by adding either nitrogen (HH, n = 6) or carbon monoxide (COH, n = 6) to the inspired gas. Whole adrenal Q and CQ increased by 70 and 50%, respectively, with HH but were unchanged during COH. MQ, however, increased threefold during both HH and COH. HH and COH both increased arterial levels of epinephrine, corticosteroids, and adrenocorticotropic hormone (ACTH). To determine whether the increase in CQ during HH was because of HH-induced increases in mean arterial blood pressure (MAP, approximately 20 mmHg), an additional group of animals (n = 6) was exposed to HH but had MAP maintained at control levels using a pressurized-bottle system. MAP control did not alter the CQ response to HH. We conclude that MQ appears to be associated with medullary secretory activity during hypoxia and that HH and COH stimulate adrenal medullary secretion equally. In contrast, CQ increases only with HH, despite similar increases in ACTH and corticosteroid levels during HH and COH, suggesting that an alternative mechanism is responsible for increased cortical blood flow during HH.

Adrenal Cortex Hormones↗
PubMed1989

Adrenal blood flow and secretory relationships during hypoxia in anesthetized dogs.

To evaluate whether hypoxia-induced increases in adrenal cortical (CQ) and medullary (MQ) blood flow (radiolabeled microspheres) occur secondary to hypoxia-induced secretory activity, pentobarbital-anesthetized ventilated dogs were pretreated with dexamethasone (DEX) to prevent adrenocorticotropic hormone (ACTH) and corticosteroid secretory changes or underwent unilateral adrenal denervation to prevent adrenal catecholamine secretory responses. In nonsurgically stressed dogs, DEX completely prevented increases in ACTH or corticosteroid levels during reduction of arterial oxygen content to 8 vol% but had no effect on hypoxia-induced doubling of CQ. In dogs in which adrenal oxygen consumption (VO2) was measured, DEX reduced VO2 by 50% without altering CQ. Unilateral adrenal denervation prevented hypoxia-induced increases in adrenal catecholamine secretion and MQ but had no effect on the CQ response. These results suggest that hypoxia-induced medullary vasodilation is associated with adrenal catecholamine secretory activity but that increases in CQ occur independent of secretory activity and likely represent direct vascular effects of hypoxia.

Adrenal Glands↗
PubMed1989

Short loop adrenocorticotropin (ACTH) feedback after ACTH-(1-24) injection in man is an artifact of the immunoradiometric assay.

A recent report measured a decrease in plasma ACTH concentration by immunoradiometric assay (IRMA) during infusion of ACTH-(1-24) in humans. It was concluded that this decrease in ACTH concentration was due to short loop ACTH autoregulation. The present study demonstrates that the decrease in ACTH concentration measured by IRMA was due to an artifact of the IRMA. We injected 250 micrograms ACTH-(1-24), iv, into five normal male volunteers after overnight 2.5-g metyrapone administration. The ACTH concentration measured by IRMA decreased from 59.6 +/- 9.7 pmol/L before to 4.8 +/- 2.0 pmol/L 1 min after ACTH-(1-24) injection. The ACTH concentration measured by IRMA increased thereafter in a mirror image of the decline in ACTH-(1-24) measured by RIA. Addition of ACTH-(1-24) to plasma in vitro resulted in a decrease in the ACTH concentration measured by IRMA which was of similar magnitude to that observed in vivo. ACTH-(1-24) infusion in vivo or addition to ACTH-(1-39)-containing plasma in vitro decreased ACTH-(1-39) measured by IRMA by binding to N- but not C-terminal antibody without forming a detectable sandwich complex. We conclude that although ACTH short loop feedback may exist, it cannot be detected after ACTH-(1-24) injection with the use of a two-site IRMA.

Adrenocorticotropic Hormone↗
PubMed1989

Feedback control of vasopressin and corticotrophin secretion in conscious dogs: effect of hypertonic saline.

Glucocorticoids are known to inhibit the ACTH response to a variety of stimuli. It has been suggested that vasopressin secretion is also inhibited by glucocorticoid negative feedback. The purpose of this study was to (1) determine the ACTH response to hypertonic saline and its sensitivity to glucocorticoid negative feedback and (2) to determine whether physiological elevations of plasma cortisol inhibit subsequent vasopressin responses to hypertonic saline. Five mongrel dogs (15-18 kg) were prepared with chronic arterial and venous catheters and studied while conscious. Ten experiments were performed on each dog in a randomized design separated by at least 5 days. Each experiment consisted of a pretreatment period (from -60 to -30 min except for dexamethasone administration) during which a glucocorticoid feedback signal was applied and a stimulus period (from 0 to 30 min) during which hypertonic saline was infused. The pretreatment and stimulus periods were separated by 30 min. Pretreatments were as follows: isotonic saline (control), half-maximal and maximal cortisol infusion (5.5 or 11 nmol/kg per min), ACTH(1-24) infusion (6.8 pmol/kg per min) which produces increases in endogenous cortisol, and dexamethasone (1.5 mg i.m.) given at 17.00 h the day before experimentation. Stimuli were as follows: hypertonic saline was infused at 0.2 or 0.4 mmol/kg per min which increased plasma sodium by about 6 or 12 mmol/l respectively. NaCl infusion at 0.2 mmol/kg per min had no effect on plasma ACTH or cortisol except when subsequent to ACTH(1-24) pretreatment when plasma ACTH actually increased to 41.4 +/- 2.9 pmol/l in response to hypertonic saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1989

A new immunoradiometric assay for corticotropin evaluated in normal subjects and patients with Cushing's syndrome.

We evaluated a new, commercially available two-site immunoradiometric assay (IRMA) for corticotropin (ACTH) in human plasma. The precision and detection limit were an improvement over radioimmunoassay (RIA). Addition of ACTH 1-24 or ACTH 18-39 to plasma containing ACTH 1-39 resulted in a decrease in measured ACTH. Results by both IRMA and RIA are reported and compared for normal subjects, patients with Cushing's disease, and patients with ectopic ACTH. Effects of administering dexamethasone, metyrapone, ACTH 1-24, and corticoliberin were evaluated. The present assay is more sensitive, specific, and reproducible than RIA. The presence of fragments of ACTH or "big" ACTH that are reactive in RIA may lead to artifactually low ACTH concentrations by IRMA. Therefore, RIA may still be necessary for differential diagnosis of ectopic ACTH syndromes. However, the IRMA is an improvement for evaluating pituitary--adrenal function in patients with low concentrations of ACTH in plasma.

ACTH Syndrome, Ectopic↗
PubMed1988

Renin response to graded haemorrhage in conscious rats.

1. A haemorrhage volume/plasma renin activity (PRA) response relationship was established for five levels of acute haemorrhage ranging from 1.5 to 15 ml/kg in conscious rats. In addition, the effects of chronic indomethacin and/or acute propranolol administration on the PRA response to 5 and 10 ml/kg haemorrhage was assessed. 2. Mean arterial pressure decreased in a haemorrhage volume dependent manner which was not significantly altered by indomethacin and/or propranolol. 3. Haemorrhage volumes of 1.5 and 3.0 ml/kg did not significantly alter PRA. At haemorrhage volumes of 5.0 ml/kg and higher, PRA increased in a volume-dependent manner. Propranolol decreased basal PRA levels but had little effect on the response to haemorrhage. Indomethacin had no effect on basal PRA, but attenuated the response to haemorrhage somewhat. When propranolol and indomethacin were combined, the PRA response to haemorrhage was significantly attenuated. 4. The conscious cannulated rat model exhibits predictable and reproducible renin responses to haemorrhage and is an excellent model for studying the control of renin secretion.

Animals↗
PubMed1988

Renin, ACTH, and aldosterone during acute hypercapnia and hypoxia in conscious rats.

The control of aldosterone secretion may be altered during acute changes in arterial blood gases. We studied the blood gas, plasma electrolyte, renin (PRA), adrenocorticotropic hormone (ACTH), and aldosterone (ALDO) responses to acute hypercapnia (4 and 8% CO2), acute hypocapnic hypoxia (10% O2), acute severe normocapnic hypoxia (7% O2-4% CO2), and acute hypercapnic hypoxia (7% O2-8% CO2) in conscious, cannulated Long-Evans rats. Normoxia resulted in normal levels of PRA (6.9 +/- 2.0 ng.ml-1.h-1), ACTH (96 +/- 32 pg/ml), and ALDO (10 +/- 3 ng/dl). Hypercapnia had no effect on PRA but did lead to an increase in ACTH (to 298 +/- 69 pg/ml) and ALDO (to 33 +/- 7 ng/dl) during 8% CO2 exposure. Normocapnic hypoxia resulted in a significant increase in ACTH (to 196 +/- 14 pg/ml) and ALDO (to 30 +/- 3 ng/dl). Hypercapnic hypoxia resulted in the greatest increases in PRA (to 30 +/- 2 ng.ml-1.h-1), ACTH (to 397 +/- 114 pg/ml), and ALDO (to 41 +/- 5 ng/dl). We conclude that in conscious rats 1) hypercapnia (less than 80 Torr) had no significant effect on PRA, 2) isocapnic, severe hypoxia (Po2 approximately 34 Torr) increased ACTH, and 3) the combination of hypercapnia and hypoxia was a very potent stimulus to PRA, ACTH, and ALDO. The ALDO responses to increases in endogenous ACTH and angiotensin II appear to be normal in conscious rats during acute hypoxia and/or hypercapnia.

Acute Disease↗
PubMed1988

Evaluation of a blood sample-transfusion protocol in rats: blood gases, renin, and ACTH.

The present study evaluated a protocol for drawing large volumes of blood over an acute time frame in conscious cannulated rats with blood from cannulated donor rats simultaneously infused to maintain isovolemia. During time control (n = 6), three successive 1.5-ml blood samples were drawn at 10-min intervals with equal volumes of donor blood infused simultaneously. One milliliter of blood was drawn quickly and saved for analysis followed by an additional 3 ml of blood withdrawal to total a 15-ml/kg hemorrhage. Two subsequent 1.5-ml samples were replaced with autologous (hemorrhage) blood. During hypoxia inspired O2 was decreased to 10% after the first sample-transfusion. The sampling-transfusion protocol (time control) had no effect on blood pressure (MAP), hematocrit (Hct), blood gases, renin, or adrenocorticotropic hormone (ACTH). Hemorrhage resulted in a significant decrease in MAP, Hct, base excess, and arterial PCO2 and an increase in arterial PO2, renin activity, and ACTH. Ten percent O2 resulted in significant hypoxemia, respiratory alkalosis, and a small degree of hypotension at the 20-min sample with no change in renin and a moderate increase in ACTH. The consistency of the results with previous studies confirms the utility and efficiency of large sample-transfusion protocols for the study of blood gas and endocrine dynamics in conscious rats.

Adrenocorticotropic Hormone↗
PubMed1988

Control of adrenocorticotropin secretion and adrenocortical sensitivity in neurohypophysectomized conscious dogs: effects of acute and chronic vasopressin replacement.

We examined the effect of neurohypophysectomy with and without vasopressin replacement on the ACTH response to hypotension and ovine CRF infusion and on the adrenocortical response to ACTH and angiotensin II infusion in conscious dogs. Nitroprusside hypotension (decrease in mean arterial pressure of 25 mm Hg) in the intact state resulted in large increases in plasma arginine vasopressin (pAVP; from 2.6 +/- 0.3 to 296 +/- 63 pg/ml) and ACTH (from 35 +/- 6 to 395 +/- 92 pg/ml). Neurohypophysectomy resulted in greatly attenuated pAVP (8.4 +/- 1.6 pg/ml) and ACTH (80 +/- 10 pg/ml) responses to hypotension which were not normalized by physiological low dose vasopressin replacement (6-18 pg/kg.min continuously, iv, for 2 weeks). However, acute administration of vasopressin (4-6 ng/kg.min) simultaneously with hypotension in the neurohypophysectomized (neurohypox) dog, which produced pAVP levels equivalent to the hypotensive response to intact dogs, almost completely normalized the ACTH response to hypotension (to 248 +/- 74 pg/ml). The ACTH response to 20 ng/kg.min ovine CRF, iv (from 43 +/- 8 to 268 +/- 77 pg/ml), was not attenuated by neurohypophysectomy. The cortisol responses to infusion of 0.5 and 2 ng/kg.min ACTH-(1-24), iv, were essentially normal in neurohypox dogs. However, the ACTH and aldosterone responses to 5 ng/kg.min angiotensin II infusion iv were attenuated in neurohypox dogs off AVP replacement. Histological examination revealed normal adrenal glands and anterior pituitaries in neurohypox dogs. Immunocytochemical staining for vasopressin and neurophysin revealed normal cell bodies in the paraventricular and supraoptic nuclei of the hypothalami from neurohypox dogs. However, median eminence staining for AVP and neurophysin was greatly diminished in neurohypox dogs. In summary, neurohypophysectomy 1) attenuated the ACTH response to hypotension and angiotensin II, but not to CRF, and 2) attenuated the aldosterone response to high dose angiotensin II. Furthermore, the deficit in ACTH secretion was almost completely normalized by increasing plasma AVP levels to those observed in the intact dogs. We conclude that an action of circulating pAVP increases ACTH secretion by a direct effect at the pituitary and by activating afferent input to the hypothalamus.

Adrenal Cortex↗
PubMed1988

Fast cortisol-induced inhibition of the adrenocorticotropin response to surgery in humans.

Glucocorticoid negative feedback is exerted in at least two time domains: fast feedback (within minutes of the feedback signal) and delayed feedback (within hours of the feedback signal). Although delayed feedback is known to inhibit ACTH responses to a variety of stimuli in humans, whether there is fast feedback inhibition of the ACTH responses to such stimuli is not known. The purpose of this study was to evaluate the efficacy of a pharmacological injection of cortisol sodium succinate (CORT) as a rapid inhibitor of the ACTH response to surgery in patients undergoing thoracotomy for myocardial revascularization. Thirty patients were premedicated with diazepam and induced with thiopental sodium. They were assigned to one of four groups: group I, general anesthesia was maintained with enflurane (n = 8); group II, patients were anesthetized as in group I, but received a bolus injection of 500 mg CORT within 5 s of the start of surgery (n = 7); group III, anesthesia was maintained with 50-100 mg fentanyl (FENT; n = 8); and group IV, patients were anesthetized as in group III and given CORT as in group II (n = 7). Surgery induced a large increase in plasma ACTH in group I (no CORT, no FENT); the mean plasma ACTH level was 57 +/- 14 (+/- SE) pmol/L 10 min after the start of surgery, and it peaked at 92 +/- 18 pmol/L 50 min after the start of surgery. Administration of CORT at time zero (group II) resulted in a significant but attenuated ACTH response to surgery both 10 min (36.5 +/- 9.7 pmol/L) and 50 min (42.5 +/- 7.3 pmol/L) after the start of surgery. FENT per se (group III) significantly attenuated the ACTH response to surgery (e.g. plasma ACTH was 13 +/- 5 pmol/L 10 min and 21 +/- 7 pmol/L 50 min after the start of surgery). The combination of CORT and FENT (group IV) eliminated the ACTH response to surgery at all time points. In fact, plasma ACTH levels became undetectable (less than 4.4 pmol/L) from 30-50 min after the start of surgery. We conclude that a pharmacological dose of CORT administered at the time of stimulus introduction significantly attenuated the ACTH response to the stimulus (surgery). FENT not only inhibited the ACTH response to surgery per se, but amplified the effect of CORT, such that ACTH actually declined even during a large surgical stimulus. CORT clearly attenuates the ACTH response to surgery in humans in the fast feedback time domain.

Adrenocorticotropic Hormone↗
PubMed1987

Glucocorticoid inhibition of neurohypophysial vasopressin secretion.

Several lines of evidence have suggested that neurohypophysial vasopressin secretion is under the influence of glucocorticoid negative feedback. Studies in clinical and experimental adrenal insufficiency have suggested that the impaired water excretion accompanying that syndrome may be due to elevated vasopressin levels. Furthermore, both the impaired water excretion and elevated vasopressin levels observed in adrenal insufficiency may be normalized by glucocorticoid treatment. This topic remains controversial, with a considerable body of evidence suggesting that vasopressin is elevated during adrenal insufficiency not because of a loss of central steroid negative feedback but because of alterations in plasma volume osmolality (renal mechanisms). Vasopressin responses to a variety of stimuli (hemorrhage, hypoxia, hypertonic saline) in normal humans and animals appear to be attenuated or eliminated by pretreatment with glucocorticoids. However, the vasopressinergic system appears to be considerably less sensitive to negative feedback than the corticotropin-releasing factor-adrenocorticotropic hormone (ACTH) system. There is evidence that the locus for this inhibitory effect is both directly at the posterior pituitary and within the hypothalamus. It is unlikely that corticosteroid negative feedback closes a direct hypothalamo-neurohypophysial-adrenocortical feedback loop. Since neurohypophysial vasopressin is involved in the control of ACTH secretion, it is more likely that the modulation of neurohypophysial vasopressin by glucocorticoid is an integral part of the overall negative-feedback control of ACTH secretion. The physiological role of glucocorticoid inhibition of vasopressin secretion remains speculative.

Adrenocorticotropic Hormone↗
PubMed1987

The dissociation of renin and aldosterone during critical illness.

A syndrome of elevated PRA accompanied by inappropriately low plasma aldosterone (ALDO) levels has been identified in some critically ill patients. To determine whether this phenomenon is due to a disturbance in factors that stimulate ALDO, we measured PRA, angiotensin II (AII), potassium (K+), and ACTH levels in 83 patients admitted to an intensive care unit. In 59 patients, PRA was greater than 2.0 ng/ml X h. Of these, 24 had an ALDO to PRA ratio (ALDO/PRA) below 2 (group I), and 35 had an ALDO/PRA ratio of 2 or more (group II). An ALDO/PRA ratio below 2 was deemed inappropriately low. Despite markedly elevated PRA [34 +/- 12 (+/- SE) ng/ml X h], the group I patients had inappropriately low ALDO levels (19 +/- 5 ng/dL). Patients in group II had significantly higher ALDO levels (48 +/- 6 ng/dL) despite lower PRA (9 +/- 1 ng/ml X h). AII levels were appropriately elevated in group I (39 +/- 26 pg/mL) and significantly greater (P less than 0.5) than those in group II. PRA correlated well with AII in both groups. There were no differences in plasma ACTH or K+ in these 2 groups, and plasma cortisol levels were similarly elevated in both groups of patients. Of 66 consecutively studied patients, 14 (21%) had inappropriate ALDO (group I). Mortality was significantly greater in group I (75%) than in group II (46%; P less than 0.001). In summary, a significant subset (21%) of seriously ill patients have inappropriately low ALDO levels despite elevated PRA. This dissociation is not due to an impairment of AII production or changes in plasma ACTH or K+. This phenomenon is associated with a higher mortality during critical illness. In light of evidence of decreased adrenal androgen secretion during severe illness, this dissociation of renin and aldosterone may represent an additional adrenal adaptation designed to promote cortisol production in critically ill patients.

Adrenocorticotropic Hormone↗
PubMed1987

Inhibition of the adrenocorticotropin response to surgery in humans: interaction between dexamethasone and fentanyl.

We examined the plasma ACTH and cortisol responses to surgery in 25 patients with atherosclerotic heart disease undergoing myocardial revascularization. The patients were all premedicated with diazepam, and general anesthesia was induced with thiopental. They were randomly assigned to one of four groups: I) no dexamethasone (DEX), enflurane anesthesia, II) 40 mg DEX, iv, 45-60 min before sternotomy, enflurane anesthesia, III) no DEX, fentanyl [N-(1-phenethyl-4-piperidyl)propionanilide] anesthesia (50-100 micrograms/kg), and IV) DEX, fentanyl anesthesia. Isokalemic hemodilution of significant magnitude occurred during cardiopulmonary bypass. All groups had significant increases in plasma ACTH during surgery, which returned to control levels 22 h after the bypass. Group I (no DEX, no fentanyl) and group III (no DEX, fentanyl) patients had large similar increases in plasma ACTH, which peaked 2-4 h postbypass [400 +/- 83 (+/- SEM) pg/mL; 88 +/- 18 pmol/L]. The group II (DEX, no fentanyl) patients also had large increases in ACTH which were similar to those in groups I and III, except 2-4 h postbypass (183 +/- 91 pg/mL; 40 +/- 20 pmol/L). The group IV (DEX, fentanyl) patients had a significantly attenuated ACTH response to surgery; the mean plasma ACTH level 2-4 h postbypass was only 54 +/- 21 pg/mL (12 +/- 5 pmol/L). Therefore, although DEX or fentanyl alone had a minimal effect on the ACTH response to surgery, a significant attenuation occurred when DEX and fentanyl were used in combination. We conclude that glucocorticoids and morphine agonists exert interactive inhibitory effects on ACTH release in humans, probably by virtue of their suppression of CRH release from the hypothalamus.

Adrenocorticotropic Hormone↗
PubMed1986

Renin, ACTH, and adrenocortical function during hypoxia and hemorrhage in conscious rats.

We studied the effect of chronic hypoxia on the renin, adrenocorticotropin (ACTH), aldosterone, and corticosterone responses to acute hemorrhage in conscious male rats with chronic femoral arterial catheters. Rats were exposed to 21, 12.5, or 10% O2 (n = 7 per group). At 42 h of exposure, animals underwent a rapid 6 ml/kg hemorrhage. O2 at 12.5 and 10% led to significant hypoxemia (arterial PO2 = 52 +/- 1 and 43 +/- 1 Torr, respectively) and respiratory alkalosis. Significant increases in plasma sodium to 145 +/- 2 meq/l and decreases in plasma potassium to 3.53 +/- 0.12 meq/l were also observed during hypoxia. Hypoxia per se had no significant effect on blood pressure, plasma renin activity, ACTH, and corticosterone. O2 at 12.5% led to a significant reduction in aldosterone levels (0.9 +/- 0.8 ng/dl) compared with normoxia (4.2 +/- 0.9 ng/dl). The mean arterial pressure, plasma renin activity, and aldosterone responses to hemorrhage were unaltered by hypoxia. ACTH and corticosterone responses to hemorrhage were potentiated by exposure to 10% O2. We conclude that chronic exposure to severe hypoxia augments the pituitary-adrenal but not the renin-aldosterone response to hemorrhage.

Adrenal Cortex↗
PubMed1986

Total peripheral resistance during cardiac tamponade: adrenergic and angiotensin roles.

During progressive cardiac tamponade in conscious dogs, cardiac output falls continuously while arterial blood pressure is maintained until cardiovascular decompensation by increases in total peripheral resistance (TPR). Plasma renin activity (PRA) is known to increase at decompensation. We hypothesized that the increase in TPR during cardiac tamponade was mediated by alpha-adrenergic and renin-angiotensin mechanisms. Twelve adult dogs were instrumented to measure cardiac output (electromagnetic flow probe), aortic and right atrial blood pressures, and intrapericardial pressure (IPP). TPR was calculated as the conscious euvolemic animals underwent cardiac tamponade induced by intrapericardial saline infusion at 20 ml/min. Six dogs underwent cardiac tamponade in the control condition (no medications) and during independent alpha- and beta-adrenergic and angiotensin-converting enzyme (ACE) inhibition. PRA and angiotensin II (ANG II) were measured during control tamponade. We found that TPR increased continuously to levels of greater than 200% of base line as IPP rose during cardiac tamponade (P less than 0.01). This increase in TPR was unaffected by beta-adrenergic or ACE blockade but was blunted by alpha-adrenergic blockade. PRA and ANG II increased only at decompensated tamponade (P less than 0.05) when arterial blood pressure had fallen by 30%. These changes in PRA and ANG II during tamponade were not altered by beta-blockade in six separate animals. We conclude that cardiac tamponade stimulates renin release and ANG II generation by a non-beta-receptor-mediated mechanism. The increase in TPR during cardiac tamponade is primarily dependent on alpha-adrenergic mechanisms, with a limited late contribution from the renin-angiotensin system.

Angiotensin II↗