Regulation of Adrenoceptor Responses in Isolated Rat Hepatocytes

1. Both alpha1- and beta-adrenoceptors stimulate glycogenolysis in the liver. In the adult male rat, however, the a-response predominates. Under several conditions including primary culture of isolated hepatocytes, there is a switch from the predominantly alpha- to a beta-adrenergic response. The primary goal of this study was to arrest this time-dependent increase in beta-adrenergic responsiveness and thus, to elucidate the factors that regulate these changes. 2. Glycogenolysis was measured as an increase in glycogen phosphorylase a activity. Initial experiments, showed that cells were responsive to drugs and hormones such as noradrenaline, isoprenaline, glucagon and insulin. The cells were also responsive to Bt2cAMP and the ionophore, A23187, which act intracellularly. 3. Responses to phenylephrine (alpha-agonist) and isoprenaline (beta-agonist) was respectively inhibited by prazosin (alpha-antagonist) and propranolol (beta-antagonist). Bmax and KD for alpha1-adrenoceptors, deteimined by [3H]prazosin binding, were 0.13 +/- 0.03 nM and 319.8 +/- 18.5 fmol mg-1 protein respectively. Values for beta-adrenoceptors, determined by [3H]dihydroaIprenoloI binding, were 1.17 +/- 0.22 nM and 56.2 +/- 4.6 fmol mg-1 protein. 4. The results showed for the first time that the relative expression of the alpha- and beta-adrenergic response depended on the culture medium in which the hepatocytes were kept. In comparison to Krebs-Henseleit buffer, beta-responses were greatly enhanced in cells cultured in Williams' E. In Krebs-Henseleit, phenylephrine was ~7 fold more potent and ~2.5 fold more effective than isoprenaline. On the contrary, results obtained in cells kept in Williams' E, showed isoprenaline to be equally potent and almost as effective as phenylephrine. Also, the addition of amino acids to Krebs-Henseleit buffer increased the beta-response in the hepatocytes. This observation, therefore, suggests that the amino acid fraction of Williams' E was responsible for the increased beta-response. 5. To examine further the role of culture medium on adrenergic responses, individual amino acids were added to Krebs-Henseleit buffer. The effects of eight amino acids (glycine, L-arginine, L-cysteine, L-glutamic acid, L-lysine, L-methionine, L-proline, and L-valine) were investigated. Addition of L-proline (30 mg l-1) to Krebs' increased the beta-response in a manner similar to that in Williams' E. Furthermore, L-arginine, L-glutamic acid, and L-methionine caused an increase in the affinity but not the efficacy of isoprenaline. L-Glutamic acid, also, decreased the affinity of phenylephrine. 6. Consistent with previous workers, incubation of hepatocyte suspensions for up to 6 hours led to increased beta-adrenergic responsiveness. Increased beta-responsiveness was not necessarily accompanied by a complete switch from ?- to beta-response-in some instances, the beta-responses did not decrease with time. 7. Measurement of cyclic AMP accumulation showed no correlation between the generation of cyclic AMP and the activation of glycogen phosphorylase induced by isoprenaline in freshly isolated cells. These, data probably, suggest the involvement of a cAMP-independent mechanism in responses to the beta-agonist, isoprenaline. 8. Dimethyl sulfoxide (2%) and sodium butyrate (2 mM), two differentiating agents used successfully to maintain some liver-specific functions, failed to arrest the time-dependent increase in beta-response in hepatocyte suspensions. Furthermore, butyrate appeared to accelerate the process. However, both agents suppressed the emergence of the beta-response in short-term (24-48 h) monolayer cultures. This may suggest that the actions of DMSO and sodium butyrate require a much longer period to exert their effects, probably, through the synthesis of new, and not through the modification of preformed, protein(s). 9. Dexamethasone (0.1-1.0muM) failed to prevent the increased beta-adrenergic response in cultured hepatocytes. On the contrary, dexamethasone increased the beta-response, presumably, by upregulation of beta-adrenoceptors. The effect of dexamethasone was blocked by cycloheximide (2 muM). However, it must be pointed out that cycloheximide, also, inhibited the increased beta-adrenergic responses in control (untreated) cells. 10. The ornithine decarboxylase and arginase inhibitor, (+)-S-2-amino-5- iodoacetamidopentanoic acid (200 ?M), suppressed the time-dependent increase in adrenergic response in isolated hepatocyte suspensions. Also, putrescine (200 muM), a poly amine and a competitive inhibitor of poly amine biosynthesis, arrested the increased beta-adrenergic responsiveness

Preclinical evidence of a rapid-onset antidepressant-like effect of Pseudospondias microcarpa hydroethanolic leaf extract in a chronic depression model

Background: Depression is a widespread, devastating mental illness and currently available treatments have significant limitations including low response rates and delayed onset of action. N-methyl-D-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects. Pseudospondias microcarpa produces an antidepressant-like effect via inhibition of the glycine/NMDA receptor complex, and could therefore possess a rapid onset of action. Therefore, the present study investigated the possible rapid-onset antidepressant action of P. microcarpa in mice.Methods: In this study, rapid-onset and sustained antidepressant effects of the hydroethanolic leaf extract of P. microcarpa (PME) was investigated in the open-space swim test, a chronic model of depression. Antidepressant effect was further assessed in the tail suspension test (TST). In addition, the effect of the extract on cognitive function in the Morris water maze (MWM) test was investigated.Results: Depressed mice showed a significant increase in immobility and decrease in distance swum. However, treatment with PME and the classical antidepressants significantly decreased immobility time and increased distance swum. Furthermore, unlike the classical antidepressants which required 10-14 days to significantly improve mobility behaviour, PME treatment significantly decreased immobility time (P<0.001) on the first day of treatment (day 5 of stress procedure). This effect was also sustained for the remainder of the experiment. The extract also significantly decreased immobility time in the TST (F3,16=4.881, P=0.0135) and decreased escape latency (F4,24=12.07, P<0.0001) in the MWM procedure.Conclusions: The leaves of P. microcarpa exhibits rapid and sustained antidepressant effects and improve cognitive function in depressed mice

Antidepressant-like properties of Antiaris toxicaria aqueous extract

Background: Depression is a global burden whose therapy is plagued with inconsistent efficacy. Hence, the need for the discovery of newer therapies.Methods: In this study, Antiaris toxicaria extract (200, 400 and 800 mg/kg, p.o.), was evaluated for antidepressant activity using behavioral tests battery particularly the forced swim test (FST) and tail suspension test (TST). In order to investigate its mechanism of action, animals groups were pretreated with α-methyldopa (α-MD), para-chlorophenylalanine (PCPA), reserpine, D-serine and 5-hydroxytryptophan.Results: It increased the mobility periods and decreased immobility periods significantly in both the FST and the TST when compared to the control group. But the TST showed more promising effect than the FST. Pre-treatment with α-MD reversed the antidepressant property of A. toxicaria aqueous extract as did PCPA, reserpine and reserpine combined with α-MD. The extract increased the number of head twitches produced by 5-hydroxytryptophan confirming the involvement of serotonin in the antidepressant property and inhibited carbachol-induced contractions on the isolated rat uterus, which was non-competitively antagonized by propranolol.Treatment with D-serine produced no significant increase in the immobility time produced by the extract at the doses studied. This excludes the involvement of N-methyl-d-aspartate in the possible mechanisms of action.Conclusion: A. toxicaria possesses antidepressant-like action in rodents

Sexual dysfunction among Ghanaian men presenting with various medical conditions

<p>Abstract</p> <p>Background</p> <p>Several medical conditions can affect and disrupt human sexuality. The alteration of sexuality in these medical conditions often hinder effective communication and empathy between the patients and their sexual partners because of cultural attitudes, social norms and negative feelings such as anxiety and guilt. Validated and standardized sexual inventories might therefore help resolve this problem. The objective of this cross-sectional study was to obtain data on the prevalence of male sexual dysfunction (SD) among Ghanaians with various medical conditions residing in Kumasi.</p> <p>Methods</p> <p>The Golombok Rust Inventory of Sexual Satisfaction (GRISS) was administered to 150 Ghanaian men with various medical conditions between 19 and 66 years old (mean ± standard deviation: 40.01 ± 12.32 years) domiciled in the Kumasi metropolis.</p> <p>Results</p> <p>Out of the total 150 questionnaires administered, 105 (70.0%) men returned the questionnaires. Questionnaires from 3 men were incomplete, leaving 102 complete and evaluable questionnaires, indicating a 68.0% response rate. Of the remaining 102 men, 88.2% were married, 70.6% had attained higher education, 88.2% were non-smokers. Whereas 54.9% were engaged in exercise, 61.8% indulged in alcoholic beverages. The prevalence of the various medical conditions include: diabetes (18%), hypertension (24.5%), migraine (11.8%), ulcer (7.8%), surgery (6.9%), STD (3.9) and others (26.5%). The prevalence of SD among the respondents in the study was 59.8%. The highest prevalence of SD was seen among ulcer patients (100%), followed by patients who have undergone surgery (75%), diabetes (70%), hypertension (50%), STD (50%) and the lowest was seen among migraine patients (41.7%).</p> <p>Conclusions</p> <p>SD rate is high among Ghanaian men with medical conditions (about 60%) and vary according to the condition and age.</p

Adequacy of pain management in oncology patients at a tertiary hospital in Ghana

Background: Although cancer pain is well documented, efficient management is largely inadequate in most patients especially in developing countries. This study evaluated the adequacy of pain management as well as potential social factors that may be associated with inadequate pain management.Methods: 204 ambulatory oncology patients (82% female; mean age 53.5) attending clinic at the Oncology Directorate, of a tertiary hospital in Ghana from January to December, 2015 were recruited and their pain severity and functional interference assessed with the Brief Pain Inventory (BPI). The adequacy of pain management was computed as the pain management index (PMI) using the BPI.Results: Although 62% of respondents were prescribed high potency opioids, 56.9% of them exhibited significant pain while 34.9% required a stronger analgesic to manage their pain. Majority of patients (56%) were over-managed for their pain (had PMI score >0). Only 26.4% had optimal cancer pain management. Pain interfered mostly with patients’ sleep (46.2%) and general activity (42.5%). Patients with high pain intensity were more likely to have it affect their daily activity (P<0.0001). Men were more likely to have inadequate pain management than females.Conclusions: This study has shown that whereas pain management may be adequate, there is the tendency for opioid tolerance and abuse as over 50% of patients receive more analgesics than required. The tenets of the WHO 3-step analgesic ladder should be strictly adhered to achieve optimum cancer pain relief

ANTI-INFLAMMATORY AND ANTIOXIDANT EFFECTS OF AN ETHANOLIC EXTRACT OF THE AERIAL PARTS OF HILLERIA LATIFOLIA (LAM.) H. WALT. (PHYTOLACCACEAE)

Various parts of the perennial herb Hilleria latifolia (Lam.) H. Walt. (Family: Phytolaccaceae) are used in Ghanaian traditional medicine for the treatment of several inflammatory-related disorders. The present study examined the anti-inflammatory effect of an ethanolic extract of the aerial parts of Hilleria latifolia (HLE) in acute and chronic inflammation models. Since free radicals and reactive oxygen species are implicated in inflammatory diseases, the antioxidant potential of HLE was also investigated in in vitro experimental models. HLE (10-300 mg kg-1, p.o.), either pre-emptively or curatively, significantly inhibited carrageenan-induced foot oedema in 7-day old chicks. Similarly, the NSAID diclofenac (10-100 mg kg-1, i.p.) and the steroidal anti-inflammatory agent dexamethasone (0.3-3 mg kg-1, i.p.) dose-dependently reduced the oedema in both pre-emptive and curative treatments. In the Freund’s adjuvant induced-arthritis model in rats, HLE as well as the positive controls, dexamethasone and methotrexate, showed significant anti-arthritic properties when applied to established adjuvant arthritis. HLE (10-300 mg kg-1, p.o.) significantly reduced oedema in the ipsilateral paw of rats but failed to prevent systemic arthritic spread. The DMARD methotrexate (0.1-1 mg kg-1, i.p.) and dexamethasone (0.3-3 mg kg-1, i.p.) reduced significantly the total polyarthritic oedema as well as the spread of the arthritis from the ipsilateral to the contralateral paws of the treated animals. The extract (0.03-1.00 mg ml-1) exhibited Fe3+ reducing activity, scavenged DPPH and prevented lipid peroxidation. These findings suggest that the extract exerts in vivo anti-inflammatory activity after oral administration and also has antioxidant properties which may contribute to its activity

Incidence of sexual dysfunction: a prospective survey in Ghanaian females

<p>Abstract</p> <p>Background</p> <p>Sexuality is a complex phenomenon that is being influenced by psychological as well as physiological factors. Its dysfunction includes desire, arousal, orgasmic and sex pain disorders. The present study aimed to assess the incidence of sexual dysfunction (SD) and related risk factors in a cohort of Ghanaian women.</p> <p>Method</p> <p>The Golombok Rust Inventory of Sexual Satisfaction (GRISS) was administered to 400 healthy women between 18 and 58 years old (mean +/- SD: 30.1 +/- 7.9) domiciled in the Kumasi metropolis.</p> <p>Results</p> <p>The response rate was 75.3% after 99 were excluded. Of the remaining 301 women, 50% were engaged in exercise, 26.7% indulge in alcoholic beverages and only 2% were smokers. A total of 62.1% of the women had attained high education, whilst, 28.9% were married. After logistic regression analysis, alcohol emerged (OR: 2.0; CI: 1.0 - 3.8; p = 0.04) as the main risk factor for SD. The overall prevalence of SD in these subjects was 72.8%. Severe difficulties with sexual function were identified in 3.3% of the studied population. The most prevalent areas of difficulty were anorgasmia (72.4%), sexual infrequency (71.4%), dissatisfaction (77.7%), vaginismus (68.1%), avoidance of sexual intercourse (62.5%), non-sensuality (61.5%) and non-communication (54.2%). Whereas 8% had severe difficulties with anorgasmia, only 6% had severe difficulties with vaginismus.</p> <p>Conclusion</p> <p>SD affects more than 70% of Ghanaian women who are sexually active. Alcohol significantly influences sexual activity.</p

A review of pharmacological effects of xylopic acid

Xylopic acid (15β-acetyloxy-kaur-16-en-19-oic acid) is a kaurene diterpene that can be obtained from various Xylopia spp. Xylopic acid has demonstrated several pharmacological activities in vitro and in vivo. The compound has shown promising effect as a potent analgesic, anti-inflammatory and anti-allergic agent. Xylopic acid is a CNS depressant and was able to ameliorate anxiety-like symptoms in mice in addition to its neuroprotective effects. Deleterious effects of xylopic acid on the reproductive system of mice have been well documented but extensive toxicity study detailing effect of the acid upon chronic exposure needs to be determined. Due to the heavy consumption of X. aethiopica fruits, it is recommended that the pharmacokinetics of xylopic acid be determined to ascertain the possible food-drug interaction that may occur when conventional drugs are taken together with foods containing xylopic acid

Synedrella nodiflora extract depresses excitatory synaptic transmission and chemically-induced in vitro seizures in the rat hippocampus

Extracts of the tropical Cinderella plant Synedrella nodiflora are used traditionally to manage convulsive conditions in the West African sub-region. This study sought to determine the neuronal basis of the effectiveness of these plant extracts to suppress seizure activity. Using the hippocampal slice preparation from rats, the ability of the extract to depress excitatory synaptic transmission and in vitro seizure activity were investigated. Bath perfusion of the hydro-ethanolic extract of Synedrella nodiflora (SNE) caused a concentration-dependent depression of evoked field excitatory postsynaptic potentials (fEPSPs) recorded extracellularly in the CA1 region of the hippocampus with maximal depression of about 80% and an estimated IC50 of 0.06 mg/ml. The SNE-induced fEPSP depression was accompanied by an increase in paired pulse facilitation. The fEPSP depression only recovered partially after 20 min washing out. The effect of SNE was not stimulus dependent as it was present even in the absence of synaptic stimulation. Furthermore, it did not show desensitization as repeat application after 10 min washout produced the same level of fEPSP depression as the first application. The SNE effect on fEPSPs was not via adenosine release as it was neither blocked nor reversed by 8-CPT, an adenosine A1 receptor antagonist. In addition, SNE depressed in vitro seizures induced by zero Mg2+ and high K+ -containing artificial cerebrospinal fluid (aCSF) in a concentration-dependent manner. The results show that SNE depresses fEPSPs and spontaneous bursting activity in hippocampal neurons that may underlie its ability to abort convulsive activity in persons with epilepsy

ANTIHYPERGLYCAEMIC AND ANTIOXIDANT EFFECTS OF ADENIA LOBATA ENGL. (PASSIFLORACEAE) IN STREPTOZOTOCIN-INDUCED DIABETIC RATS

The antihyperglycaemic and antioxidant activities of a Ghanaian medicinal plant namely Adenia lobata Engl (Passifloraceae), used to treat diabetes mellitus in traditional medicine, was investigated. The dried stem powder of A. lobata was successively extracted by Soxhlet with petroleum ether and 70% ethanol to obtain the crude petroleum ether (PEAL: yield =1.1w/w %) and ethanol (EEAL: yield = 5.4 w/w %) extracts. The extracts were assessed for their antihyperglycaemic and antioxidant activities. The antihyperglycaemic activity of PEAL and EEAL were determined in streptozotocin-induced diabetic rats (70 mg/kg body weight). Five groups of diabetic rats were given 150, 300 and 600 mg/kg body weight of PEAL and EEAL orally once daily for 20 days. Glibenclamide (5 mg/kg body weight) was used as positive control while distilled water (5 ml) acted as the normal diabetic control. The blood glucose levels were monitored initially for 6 hours and subsequently over 24 days. Both extracts exhibited statistically significant (p< 0.001) antihyperglycaemic activity throughout the study period, with EEAL showing the greatest activity. The antioxidant properties of the petroleum ether and ethanol extracts of A. lobata (PEAL and EEAL) were evaluated using five assays; total phenolic content, total antioxidant capacity, reducing power, DPPH scavenging effect and lipid peroxidation activity. In all these assays, the antioxidant properties increased with increasing concentration of the extracts