Hemodynamic actions of corticotropin-releasing hormone and proopiomelanocortin derivatives in septic patients.

Proopiomelanocortin (POMC) derivatives and mRNA of POMC have been detected in cardiomyocytes and vascular smooth muscle cells. Increased plasma levels of POMC derivatives have been found in septic patients during cardiovascular deregulation; therefore, we evaluated whether corticotroph-type (ACTH, ß-endorphin, ß-lipotropin) or melanotroph-type (α-melanocyte-stimulating hormone and N-acetyl-ß-END) POMC derivatives have influences on patients' hemodynamics during sepsis. Seventeen septic patients were monitored by pulmonary artery catheter and corticotropin-releasing hormone (CRH) tests were performed by intravenous administration of 100 µg CRH. Before, 15, 30, 45, and 60 minutes after CRH administration, hemodynamic variables were measured, and plasma concentrations of POMC derivatives were determined. After CRH administration, heart rate, cardiac index, and stroke index increased, and the systemic vascular resistance index decreased; moreover, a correlation between ACTH concentration and stroke index as well as an inverse correlation between (α-melanocyte-stimulating hormone concentration and systemic vascular resistance index was observed. CRH and ACTH may have opposite effects on the blood pressure (mean arterial pressure). Immediately after CRH injection mean arterial pressure decreased. ACTH (in contrast to ß-endorphin or ß-lipotropin), released into the cardiovascular compartment 15 minutes after CRH injection, might have raised mean arterial pressure as compatible with the correlation between ACTH levels and stroke index. (α-melanocyte-stimulating hormone appears to have a vasodilative effect during sepsis.

Release of melanotroph- and corticotroph-type proopiomelanocortin derivatives into blood after administration of corticotropin-releasing hormone in patients with septic shock without adrenocortical insufficiency.

The aim of the study was to assess the adequacy of pituitary function by determining the plasma concentrations of corticotroph-type (corticotropin, beta-endorphin immunoreactive material [beta-END IRM], authentic beta-END, and beta-lipotropin IRM) as well as melanotroph-type (alpha-melanocyte-stimulating hormone [alpha-MSH] and N-acetyl-beta-END [Nac-beta-END] IRM) proopiomelanocortin (POMC) derivatives in patients under septic shock upon administration of corticotropin-releasing hormone (CRH). The objectives were to assess whether an insufficient release of corticotroph- or melanotroph-type POMC derivatives from the pituitary into the cardiovascular compartment correlates with the 28-day mortality rate. Seventeen patients with septic shock but without adrenocortical insufficiency and 16 healthy volunteers were enrolled in the study, and CRH stimulation tests were performed with an i.v. bolus injection of 100 microg human CRH. After treatment with CRH, plasma concentrations of corticotroph-type POMC derivatives increased in survivors and nonsurvivors, melanotroph-type POMC derivatives such as alpha-MSH or Nac-beta-END IRM increased only in survivors in contrast to nonsurvivors. The release of alpha-MSH and Nac-beta-END IRM was suppressed by dexamethasone in survivors but not in nonsurvivors. In patients with septic shock, the response of the pituitary to CRH stimulation in terms of alpha-MSH or Nac-beta-END IRM release was impaired in nonsurvivors compared with survivors or controls. Reduced responses of alpha-MSH or Nac-beta-END IRM to CRH and the invalid suppression by dexamethasone reflect a state of dysfunction of the melanotroph-type POMC system in nonsurvivors. Considering anticytokine and anti-inflammatory effects of alpha-MSH, this dysfunction may increase the risk of death in patients with septic shock.

Response of proopiomelanocortin and gonado- or lactotroph systems to in-vitro fertilisation procedures stress.

OBJECTIVE: To analyse for the first time the response of the corticotroph-type and the melanotroph-type pituitary proopiomelanocortin (POMC) system with regard to in-vitro fertilisation (IVF) treatment using self-developed highly specific non-cross-reacting radioimmunoassay. SETTING: University hospital. patients: A total of 28 patients undergoing IVF oocyte retrieval. Cross sectional exploratory study, one factorial design with repeated measurements on one factor, non-parametric tests. Blood was collected before anaesthesia (t(A)) (n=28) and immediately after oocyte retrieval (t(B)) (n=28). MAIN OUTCOME MEASURE(S): beta-endorphin immunoreactive material (IRM), acetyl-N-beta-endorphin IRM, beta-lipotropin IRM, ACTH, cortisol, estradiol, progesterone, prolactin, luteinizing hormone, and follicle-stimulating hormone. For determination of authentic beta-endorphin [beta-endorphin (1-31)] a highly specific two-site fluid phase immunoprecipitation radioimmunoassay was developed, which did not cross-react with any beta-endorphin derivative or any other opioid peptide tested. RESULTS: No response of acetyl-N-beta-endorphin IRM and of authentic beta-endorphin (1-31) was observed to oocyte retrieval in contrast to a significant increase of corticotroph-type proopiomelanocortin derivatives. A significant rise in prolactin plasma concentration indicates a pronounced lactotroph response to oocyte retrieval stress. No significant correlation between POMC derivates and prolactin and between POMC derivatives and gonadotropins or sexual steroids except for ACTH and progesterone and for beta-endorphin IRM and estradiol was observed. CONCLUSION: IVF treatment stress led to significant corticotroph-type POMC and lactotroph responses, but not to responses of authentic beta-endorphin or melanotroph-type POMC in women undergoing oocyte retrieval.

Response to delivery stress is not mediated by beta-endorphin (1-31).

OBJECTIVE: The aim of the study was to determine the reaction of the melanotroph and corticotroph-type pituitary proopiomelanocortin (POMC) response to vaginal delivery and caesarean section stress. Furthermore, the relationship between the release of pituitary POMC fragments, gonadotropins and sexual steroids were examined. STUDY DESIGN: Blood samples were obtained from 10 women in labour on arrival in the birth room (t(A)), at cervix dilatation of 5 cm (t(B)) and immediately after spontaneous delivery (t(C)) and in 16 patients undergoing elective caesarean section before induction of anaesthesia (t(B)) and immediately after delivery (t(C)). Samples were analysed for cortisol, ACTH, authentic beta-endorphin, beta-endorphin immunoreactive material (IRM), acetyl-N-beta-endorphin IRM (NAC), beta-lipotropin (beta-LPH) IRM, oestradiol (E(2)), progesterone (P), prolactin (PRL), FSH and LH. RESULTS: NAC representing the melanotroph-type pituitary POMC system did not increase during the course of caesarean section or spontaneous labour. In contrast, a significant increase of beta-endorphin IRM, beta-LPH IRM and ACTH were observed, representing an activation of the corticotroph-type POMC system. Highly significant correlations between POMC fragment concentrations during caesarean section and spontaneous labour were also observed. Sexual steroids (E(2) and P) decreased significantly. Except for beta-endorphin IRM and E(2) in course of spontaneous delivery no significant correlation was observed between POMC fragment and gonadotropins or sexual steroids. CONCLUSION: Caesarean section and spontaneous delivery activated the corticotroph but not the melanotroph POMC system.

Patients with ARDS show improvement but not normalisation of alveolar surface activity with surfactant treatment: putative role of neutral lipids.

BACKGROUND: Extensive biochemical and biophysical changes of the pulmonary surfactant system occur in the acute respiratory distress syndrome (ARDS). METHODS: The effect of intrabronchial administration of a recombinant surfactant protein C-based surfactant preparation (Venticute) on gas exchange, surfactant composition and function was investigated in 31 patients with ARDS in a randomised controlled phase I/II clinical pilot trial. Bronchoalveolar lavage fluids for surfactant analysis were obtained 3 h before and 48 and 120 h after the first surfactant application. Potentially deleterious effects of surfactant neutral lipids in patients with ARDS were also identified. RESULTS: Before treatment all patients had marked abnormalities in the surfactant phospholipid and protein composition. In response to surfactant treatment, gas exchange improved and surfactant phospholipid and protein content were almost normalised. Alveolar surface activity was dramatically impaired before treatment and only partially improved after surfactant administration. Further analysis of the bronchoalveolar lavage fluids revealed a twofold increase in neutral lipid content and altered neutral lipid profile in patients with ARDS compared with healthy controls. These differences persisted even after administration of large amounts of Venticute. Supplementation of Venticute or natural surfactant with a synthetic neutral lipid preparation, mimicking the profile in ARDS, caused a dose-dependent deterioration of surface activity in vitro. CONCLUSION: Intrabronchial surfactant treatment improves gas exchange in ARDS, but the efficacy may be limited by increased concentration and altered neutral lipid profile in surfactant under these conditions.

Plasma levels of corticotroph-type pro-opiomelanocortin derivatives such as beta-lipotropin, beta-endorphin(1-31), or adrenocorticotropic hormone are correlated with severity of postoperative pain.

BACKGROUND: In the pituitary of lower species, pro-opiomelanocortin is expressed in corticotroph cells of the anterior and in melanotroph cells of the neurointermediate lobe; enzymatic processing in the corticotrophs results in the release of adrenocorticotropic hormone, beta-lipotropin, or beta-endorphin. In the melanotrophs, these fragments are further modified, eg, by N-terminal acetylation. In the human pituitary, these enzyme systems are located within the same cells in the anterior lobe. We studied the reactions of the pro-opiomelanocortin system under preoperative conditions as well as under postoperative pain. METHODS: In 17 patients undergoing hip or knee arthroplasty, we determined plasma concentrations of N-acetyl-beta-endorphin immunoreactive material, authentic beta-endorphin [beta-endorphin(1-31)], adrenocorticotropic hormone, beta-lipotropin immunoreactive material, and cortisol, as well as pain severity rated by the patients using a visual analogue scale before surgery, after surgery but still under spinal anesthesia, under postoperative pain, and 1 day after surgery. RESULTS: Only low levels of N-acetyl-beta-endorphin immunoreactive material were measured in 16 out of 17 patients. High concentrations (1st quartile/median/3rd quartile; pmol/L) of adrenocorticotropic hormone (22.5/55.8/124) and beta-lipotropin immunoreactive material (6.6/34.6/142) were observed under postoperative pain, accompanied by a small increase of beta-endorphin(1-31) concentrations (0.0/6.1/10.9). Preoperatively small but significantly elevated levels of corticotroph-type and melanotroph-type pro-opiomelanocortin derivatives were observed; in contrast, spinal anesthesia suppressed all pro-opiomelanocortin fragment release. Postoperative pain severity correlated with postoperative adrenocorticotropic hormone, beta-lipotropin immunoreactive material, and beta-endorphin(1-31) concentrations. CONCLUSIONS: We conclude that the melanotroph-type pro-opiomelanocortin system is not activated under postoperative pain; the increase of corticotroph-type pro-opiomelanocortin fragment levels is different in quantity and proportion under preoperative conditions or postoperative pain, respectively.

Corticotropin-releasing hormone reduces pressure pain sensitivity in humans without involvement of beta-endorphin(1-31), but does not reduce heat pain sensitivity.

In the present study the effects of intravenously administered corticotropin-releasing hormone (CRH) on the release of proopiomelanocortin (POMC) derivatives such as adrenocorticotropic hormone (ACTH), beta-lipotropin (beta-LPH) and beta-endorphin (beta-END) as well as direct effects of CRH on pain sensitivity were examined. In 16 healthy volunteers we studied the effects of 100 microg intravenously administered CRH in absence or presence of 12 mg naloxone on heat or pressure pain sensitivity, using a double-blind, cross-over and placebo-controlled design. To evaluate analgesic effects of CRH via release of POMC derivatives, we determined plasma concentrations of beta-END-immunoreactive material (IRM), authentic beta-END (beta-END(1-31)) and beta-LPH IRM, in parallel with heat and pressure pain tolerance thresholds before and 15 and 30 min after treatment with CRH (or placebo), and 5 min after naloxone (or placebo) administration which was administered 40 min after CRH (or placebo) injection. CRH increased levels of beta-END IRM, beta-END(1-31) and beta-LPH IRM. As compared to beta-END IRM levels measured by a commercial RIA kit, the beta-END(1-31) levels determined by a highly specific two-site RIA, proved to be remarkably small. Furthermore, CRH did not induce increases of heat pain tolerance thresholds, but of pressure pain tolerance thresholds, which, however, were not reversible by naloxone. Neither beta-END nor beta-LPH IRM nor beta-END(1-31) levels correlated with heat or pressure pain tolerance thresholds. We conclude that CRH does not modulate heat, but pressure pain; POMC derivatives like beta-END IRM, beta-END(1-31) or beta-LPH do not mediate this effect.

Effects of tourniquet-induced ischemia on the release of proopiomelanocortin derivatives determined in peripheral blood plasma.

Proopiomelanocortin (POMC) is expressed in pituitary, central nervous system, and in a few peripheral tissues. This study addresses the hypothesis that metabolic stressors, such as acidosis, may induce the release of POMC derivatives into the cardiovascular system not only from the pituitary but also from other sites of POMC expression. In our study, we investigated the liberation of POMC derivatives from peripheral tissues under a state of acidosis achieved by tourniquet-induced ischemia, alteration of lactate concentration, and base excess. In eight patients undergoing knee arthroplasty under spinal anesthesia, catheters were inserted into the femoral vein proximally to thigh tourniquet location. Blood was drawn from these catheters 5 min before and 40 s, 5 min, and 10 min after tourniquet deflation to measure plasma concentrations of N-acetyl-beta-endorphin immunoreactive material (IRM), beta-endorphin IRM, authentic beta-endorphin, adrenocorticotropin, lactate, pH, and base excess. In five of eight patients, we found a significant increase of beta-endorphin IRM levels 40 s after tourniquet deflation compared with predeflation levels; 5 and 10 min after tourniquet deflation, the beta-endorphin IRM levels were below the detection limit. Thus beta-endorphin IRM was released from ischemic limb tissues into the cardiovascular system. Only a small part of the determined beta-endorphin IRM corresponded to authentic beta-endorphin. Forty seconds after tourniquet deflation, the beta-endorphin IRM concentration correlated with base excess (r < 0.71; P < 0.05); no significant correlations were found with pH or lactate levels. Thus it was shown here for the first time that ischemic stress may induce the release of beta-endorphin IRM from nonpituitary tissues.