Desamino arginine vasopressin (DDAVP) as a diagnostic agent.

The use of 1-desamino-8-arginine vasopressin (DDAVP) was examined as a diagnostic agent, within the context of the comprehensive one day renal function test. Thirty-three normal young subjects were examined in an 8 1/2 hour day. It was found that a 20 microgram intranasal dose of DDAVP consistently resulted in the production of a urinary osmolality to 800mosmol/kg or more, with no untoward effect. DDAVP can advantageously replace pitressin tannate in oil as a diagnostic agent.     

The HPA axis in cocaine use: implications for pharmacotherapy.

The role of the hypothalamic-pituitary-adrenal (HPA) axis in cocaine use is reviewed within the context of two approaches to developing pharmacological treatments in humans: (1) reducing the reinforcing effects of cocaine and (2) reducing cocaine addict's susceptibility to stress-induced relapse. This review suggests that HPA-axis-suppressing medications are unlikely to block cocaine's reinforcing effects completely but may be useful in decreasing the frequency of use by increasing the addicted individual's resistance to stress-induced relapse. Implications for designing inpatient studies to test the safety and efficacy of candidate pharmacological agents are discussed.     

A comparison of des-amino arginine vasopressin with pitressin tannate as diagnostic agents.

A reappraisal of a previous opinion, and subsequent comparative work leads to the conclusion that 40 microgram desamino arginine vasopressin (DDAVP) administered instransally, is a preferable dose to 20 microgram to use as a urinary concentrating agent in the diagnostic context, and that it is quite comparable to the standard agent, five units of pitressin tannate in oil.     

Macrophage-mediated killing of splenic lymphocytes in adjuvant-induced arthritis.

After 72 hrs in culture, unseparated spleen cells from rats with adjuvant-induced arthritis (AA) stimulated with high concentrations of Con A (greater than 0.63 micrograms/ml) leaked more lactate dehydrogenase (LDH) than did either unstimulated cultures or cultures stimulated with lower concentrations of Con A. This reflects an increase in dead or dying cells at concentrations of Con A greater than 0.63 micrograms/ml. Since Con A did not increase LDH leakage in macrophage-depleted cultures of AA splenocytes, the decreased viability in unseparated, Con A-stimulated cultures appears to be a macrophage-dependent phenomenon. Since the increase in LDH release at high concentrations of Con A paralleled the decrease in [3H]-thymidine incorporation, these results suggest that Con A (greater than 0.63 micrograms/ml) induces macrophages from AA rats to kill splenic lymphocytes in culture.     

HPA轴功能紊乱干预药物的研究进展

目的对近年来基于下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal ,HPA）轴功能调节治疗2型糖尿病和其他代谢疾病的药物做以综述,为H PA轴功能紊乱引起的相关疾病的治疗提供理论参考。方法查阅国内外文献,分析、总结 H PA轴功能紊乱干预药物的研究现状和研究前景。结果 HPA轴功能紊乱,尤其是 HPA轴功能亢进在2型糖尿病、抑郁症等疾病的发病过程中发挥重要作用;目前有以下几类通过作用于HPA轴不同靶点调节HPA轴功能的药物,即11β-HSD1抑制剂、糖皮质激素受体拮抗剂、多巴胺受体拮抗剂和选择性5-H T再摄取抑制剂等,具体机制还有待进一步阐明。结论通过调节H PA轴活性有可能达到预防和治疗2型糖尿病及其他相关疾病的目的。     

Dose response of arginine vasopressin to the CCK-B agonist pentagastrin.

Cholecystokinin (CCK) is a peptide neurotransmitter that modulates hypothalamic-pituitary-adrenal (HPA) axis activity and may be involved in fear or anxiety states. Arginine vasopressin (AVP) also modulates HPA axis activity and may play a role in fear conditioning. Few human studies have examined interactions between CCK and AVP systems. To explore relationships between CCK-B receptor activation, the HPA axis response, and AVP release, a dose-response study using the CCK-B receptor agonist pentagastrin was conducted. Adrenocorticotropin (ACTH) and cortisol results have been previously reported and AVP data is presented here. Thirty-five healthy subjects were randomly assigned to receive placebo, or 0.2, 0.4, 0.6, or 0.8 microg/kg doses of pentagastrin. AVP release appeared to increase with increasing doses of the CCK-B agonist. However, this may have been due to a greater percentage of subjects releasing AVP in the higher dose groups, rather than a direct effect of dose on magnitude of response. AVP and ACTH responses were correlated, but AVP response alone could not account for the magnitude of the ACTH response. AVP release was significantly correlated with anxiety symptom responses. These findings suggest a possible role for the CCK-B receptor in AVP release, which may be at least partially separate from its role in modulation of the HPA axis. Further work is needed to determine whether these are physiologically meaningful interactions and to determine their functional implications.     

The effects of flurbiprofen on the passive transfer of adjuvant-induced arthritis.

The effect of flurbiprofen on the passive transfer of adjuvant-induced arthritis was studied to determine if flurbiprofen acted in the donor and/or recipient arms of this model. Groups of donor and recipient rats were treated with either placebo or flurbiprofen 4 mg/kg. Joint scores were markedly decreased in recipient rats treated with flurbiprofen irrespective of the whether donor animals were treated with placebo or flurbiprofen (p less than 0.01). There was also a moderate decrease in the ability of donor cells from rats treated with flurbiprofen to suppress the severity of arthritis (p less than 0.01); however, this effect was less marked than that seen in recipient animals. These data imply that flurbiprofen may act at multiple sites in adjuvant-induced arthritis, but the major site of action of flurbiprofen in this model is in the recipient animals.     

HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment.

The authors discuss literature evidence on the possible dysfunctioning of HPA axis and the inflammatory response system (IRS) in schizophrenia in relation to a more comprehensive bio-pathogenetic hypothesis of the disorder and to the development of specific clinical patterns or 'core' schizophrenic symptoms, like those included in the so called negative/depressive dimension. The dysfunctions of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant brain areas like hippocampus and it could involve mainly the glutamatergic pathways (e.g. NMDA receptors). Moreover, these changes could have some predictive value for response to typical antipsychotics (specifically for negative symptoms and drug resistance) in schizophrenia. Finally, the differential activity of typical versus atypical antipsychotic compounds on the basic HPA axis and IRS dysregulations in schizophrenia could account, at least partly, for the better clinical stabilization achieved in patients treated with the latter drugs compared to those receiving conventional neuroleptics.     

Flavonoids of St. John's Wort reduce HPA axis function in the rat

A common biological alteration in patients with major depression is the activation of the hypothalamic-pituitary-adrenal (HPA) axis, manifested as hypersecretion of adrenocorticotropic hormone (ACTH) and cortisol. The hyperactivity of the HPA axis in depressed patients can be corrected during clinically effective therapy with standard antidepressant drugs such as imipramine, indicating that the HPA axis may be an important target for antidepressant action. We previously showed that a methanolic extract of St. John's Wort (SJW) and hypericin, one of its active constituents, both have delayed effects on the expression of genes that are involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis , whereas the phloroglucinol derivative hyperforin was inactive in the same model . Since flavonoids of SJW are also discussed as active constituents it was of interest to determine whether these compounds can modulate HPA axis function. Imipramine (15 mg/kg), hypericin (0.2 mg/kg), hyperoside (0.6 mg/kg), isoquercitrin (0.6 mg/kg) and miquelianin (0.6 mg/kg) given daily by gavage for two weeks significantly down-regulated circulating plasma levels of ACTH and corticosterone by 40 - 70 %. However, none of the compounds tested had an effect on plasma ACTH and corticosterone levels after chronic treatment (daily gavage for 8 weeks). Our data suggest that besides hypericin, flavonoids of SJW play an important role in the modulation of HPA axis function. Furthermore, the results support the hypothesis that flavonoids are involved in the antidepressant effects of SJW.     

The role of the HPA axis in psychiatric disorders and CRF antagonists as potential treatments

An overview of the links between the Hypothalamic-Pituitary-Adrenal (HPA) axis and psychiatric disorders is presented. The current treatments are outlined, indicating that they are insufficient to meet the needs of those that suffer from these affective disorders. Therefore, there is an urgent need for the generation of new therapeutics, in particular, against new targets. The association of the corticotrophin releasing factor (CRF) and the HPA axis indicates that CRF antagonists should be beneficial as potential therapeutics.     

Disturbances of the stress response: the role of the HPA axis during alcohol withdrawal and abstinence

Interactions among the brain, the pituitary gland, and the adrenal glands (i.e., the hypothalamic-pituitary-adrenal [HPA] axis) help regulate the body's response to stress. The adrenal hormone cortisol plays a key role in stress reduction through its effects on multiple body systems. Excessive cortisol activity during both chronic alcohol administration and withdrawal may underlie some of the clinical complications of alcoholism, including increased risk of infectious diseases; bone, muscle, and reproductive system changes; altered energy metabolism; and disorders of mood and intellect. Despite excessive cortisol levels during intoxication and withdrawal, however, the HPA axis becomes less responsive to stress during abstinence, potentially resulting in an impaired capacity to cope with relapse-inducing stressors.     

Allopregnanolone modulation of HPA axis function in the adult rat

Rationale

GABAergic neuronal circuits regulate neuroendocrine stress response, and the most potent positive endogenous modulator of GABA_A receptor function is allopregnanolone. This neurosteroid acts in a nongenomic manner to selectively increase the inhibitory signal meditated by GABA_A receptors; in addition, it also induces long-lasting changes in the expression of specific GABA_A receptor subunits in various brain regions, with consequent changes in receptor function.

Objective

The objective of this review is to summarize our findings on emotional state and stress responsiveness in three animal models in which basal brain concentrations of allopregnanolone differ. It is postulated that individual differences in allopregnanolone levels can influence general resilience.

Results

The results showed that there is an apparent correlation between endogenous levels of brain allopregnanolone and basal and stress-stimulated HPA axis activity.

Conclusion

The relationship between endogenous brain levels of allopregnanolone and HPA axis activity and function sustains the therapeutic potential of this neurosteroid for the treatment of stress-associated disorders.     

Renal effects of specific antagonists of arginine vasopressin in dogs.

To investigate the effects on renal hemodynamics of specific antagonists of arginine vasopressin (AVP), CGP 29325 (d(CH2)5-D-Tyr(Et)VAVP), which has both anti-vasopressor and anti-antidiuretic activities against AVP, and CGP 25838E (d(CH2)5-Tyr(Me)AVP), which has only anti-vasopressor activity, were administered to normally hydrated anesthetized dogs, and the effects on renal function were examined. The pressor response and constriction of renal and mesenteric arteries induced by AVP were dose-dependently blocked by intravenous CGP 25838E. Following intrarenal arterial administration (i.r.a.) of CGP 29325 at 3 micrograms/min, water diuresis occurred and urine osmolality (UOsm) decreased to less than 250 mOsm/kg. Renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNaV) remained unchanged. A higher dose (10 micrograms/min, i.r.a.) of CGP 29325 further decreased UOsm to about 110 mOsm/kg. Although arterial blood pressure (BP), GFR and UNaV remained unchanged, RBF decreased from the control value 3.7 +/- 0.35 to 2.4 +/- 0.40 ml/g.min. CGP 25838E (10 micrograms/min, i.r.a.) had no effect on renal hemodynamics and urine formation. When administered into the mesenteric artery, CGP 25838E (10 micrograms/min) increased mesenteric blood flow (MBF) from 199 +/- 34 to 240 +/- 40 ml/min without any alteration in blood pressure. We tentatively conclude that CGP 29325, at a lower dose, exerted anti-antidiuretic effects through a specific inhibition of V2 receptors, while the higher dose of CGP 29325 altered RBF, through yet to be determined mechanisms. The vasoconstrictive activity of AVP may contribute to the regulation of mesenteric circulation, but not to renal hemodynamics, in anesthetized dogs.     

Mechanism responsible for altered propranolol disposition in adjuvant-induced arthritis in the rat

Arthritis was induced in Sprague-Dawley rats by the injection of a heat-killed bacterial suspension into the right hind foot pad. The animals were deemed arthritic if their erythrocyte sedimentation rate was greater than 2 mm/hr. A pithed rat preparation was employed to investigate simultaneously the pharmacokinetics and pharmacodynamics of propranolol in this disease state. Propranolol administered via the hepatic portal vein to simulate oral administration resulted in elevated blood concentrations in the arthritic rats, but the pharmacological effect, measured by the inhibition of an electrically induced tachycardia, was not altered. Propranolol administered iv also resulted in increased blood drug concentrations, but, in addition, the pharmacological effect was decreased. Hepatic blood flow was determined in control and arthritic rats using radiolabeled microspheres, but no change was observed. These results, taken together with previous in vitro studies, suggest that the elevated blood concentrations of propranolol can be attributed to increased plasma protein binding, rather than to decreased hepatic metabolism or altered hepatic blood flow.     

Diacerein suppresses the increase in plasma nitric oxide in rat adjuvant-induced arthritis.

We investigated the effects of rhein, an active metabolite of diacerein, on the interleukin-1alpha-stimulated production of nitric oxide (NO) in rabbit articular chondrocytes, and the effects of diacerein on NO production in rat adjuvant-induced arthritis. At doses of 10 and 30 microM, rhein significantly inhibited the interleukin-1alpha-stimulated NO production in chondrocytes. In the rat adjuvant-induced arthritis model, diacerein was administered for 21 days, starting at the time of adjuvant injection. Paw swelling and plasma NO level were measured in order to assess the effect of diacerein on arthritis and NO biosynthesis in the whole body. At doses of 30 and 100 mg/kg/day, diacerein significantly suppressed the development of adjuvant-induced arthritis and the increase in plasma NO. These results suggest that the inhibitory effect of diacerein on rat adjuvant-induced arthritis is partly related to its reduction of the NO production induced by adjuvant-induced arthritis.