Supporting active engagement of adults with intellectual disabilities in lifestyle modification interventions: a realist evidence synthesis of what works, for whom, in what context and why.

BACKGROUND: Lifestyle modification interventions for adults with intellectual disabilities have had, to date, mixed effectiveness. This study aimed to understand how lifestyle modification interventions for adults with intellectual disabilities work, for whom they work and in what circumstances. METHODS: A realist evidence synthesis was conducted that incorporated input from adults with intellectual disabilities and expert researchers. Following the development of an initial programme theory based on key literature and input from people with lived experience and academics working in this field, five major databases (MEDLINE, EMBASE, CINAHL, PsycINFO and ASSIA) and clinical trial repositories were systematically searched. Data from 79 studies were synthesised to develop context, mechanism and outcome configurations (CMOCs). RESULTS: The contexts and mechanisms identified related to the ability of adults with intellectual disabilities to actively take part in the intervention, which in turn contributes to what works, for whom and in what circumstances. The included CMOCs related to support involvement, negotiating the balance between autonomy and behaviour change, fostering social connectedness and fun, accessibility and suitability of intervention strategies and delivery and broader behavioural pathways to lifestyle change. It is also essential to work with people with lived experiences when developing and evaluating interventions. CONCLUSIONS: Future lifestyle interventions research should be participatory in nature, and accessible data collection methods should also be explored as a way of including people with severe and profound intellectual disabilities in research. More emphasis should be given to the broader benefits of lifestyle change, such as opportunities for social interaction and connectedness.

Lifestyle modification interventions for adults with intellectual disabilities: systematic review and meta-analysis at intervention and component levels.

BACKGROUND: Adults with intellectual disabilities (IDs) are susceptible to multiple health risk behaviours such as alcohol consumption, smoking, low physical activity, sedentary behaviour and poor diet. Lifestyle modification interventions can prevent or reduce negative health consequences caused by these behaviours. We aim to determine the effectiveness of lifestyle modification interventions and their components in targeting health risk behaviours in adults with IDs. METHODS: A systematic review and meta-analysis were conducted. Electronic databases, clinical trial registries, grey literature and citations of systematic reviews and included studies were searched in January 2021 (updated February 2022). Randomised controlled trials and non-randomised controlled trials targeting alcohol consumption, smoking, low physical activity, sedentary behaviours and poor diet in adults (aged ≥ 18 years) with ID were included. Meta-analysis was conducted at the intervention level (pairwise and network meta-analysis) and the component-level (component network meta-analysis). Studies were coded using Michie's 19-item theory coding scheme and 94-item behaviour change taxonomies. Risk of bias was assessed using the Cochrane Risk of Bias (ROB) Version 2 and Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I). The study involved a patient and public involvement (PPI) group, including people with lived experience, who contributed extensively by shaping the methodology, providing valuable insights in interpreting results and organising of dissemination events. RESULTS: Our literature search identified 12 180 articles, of which 80 studies with 4805 participants were included in the review. The complexity of lifestyle modification intervention was dismantled by identifying six core components that influenced outcomes. Interventions targeting single or multiple health risk behaviours could have a single or combination of multiple core-components. Interventions (2 RCTS; 4 non-RCTs; 228 participants) targeting alcohol consumption and smoking behaviour were effective but based on limited evidence. Similarly, interventions targeting low physical activity only (16 RCTs; 17 non-RCTs; 1413 participants) or multiple behaviours (low physical activity only, sedentary behaviours and poor diet) (17 RCTs; 24 non-RCTs; 3164 participants) yielded mixed effectiveness in outcomes. Most interventions targeting low physical activity only or multiple behaviours generated positive effects on various outcomes while some interventions led to no change or worsened outcomes, which could be attributed to the presence of a single core-component or a combination of similar core components in interventions. The intervention-level meta-analysis for weight management outcomes showed that none of the interventions were associated with a statistically significant change in outcomes when compared with treatment-as-usual and each other. Interventions with core-components combination of energy deficit diet, aerobic exercise and behaviour change techniques showed the highest weight loss [mean difference (MD) = -3.61, 95% credible interval (CrI) -9.68 to 1.95] and those with core-components combination dietary advice and aerobic exercise showed a weight gain (MD 0.94, 95% CrI -3.93 to 4.91). Similar findings were found with the component network meta-analysis for which additional components were identified. Most studies had a high and moderate risk of bias. Various theories and behaviour change techniques were used in intervention development and adaptation. CONCLUSION: Our systematic review is the first to comprehensively explore lifestyle modification interventions targeting a range of single and multiple health risk behaviours in adults with ID, co-produced with people with lived experience. It has practical implications for future research as it highlights the importance of mixed-methods research in understanding lifestyle modification interventions and the need for population-specific improvements in the field (e.g., tailored interventions, development of evaluation instruments or tools, use of rigorous research methodologies and comprehensive reporting frameworks). Wide dissemination of related knowledge and the involvement of PPI groups, including people with lived experience, will help future researchers design interventions that consider the unique needs, desires and abilities of people with ID.

The effectiveness of prenatal and postnatal home visits by paramedical professionals and women's group meetings in improving maternal and child health outcomes in low and middle-income countries: a systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness of prenatal and postnatal home visits (HVs) and women group meetings (WGMs) by paramedical professionals to improve maternal and child health outcomes in low- and middle-income countries (LMICs). STUDY DESIGN: Systematic review and meta-analysis. METHODS: We conducted a systematic review of trials published till December 2020, as per registered protocol in The International Prospective Register of Systematic Reviews (PROSPERO) (CRD42018091968). Outcomes were neonatal mortality rate (NMR), maternal mortality ratio (MMR), the incidence of low birth weight, and still birth rate (SBR). The Cochrane Pregnancy and Childbirth Group's Trials Register, Cochrane Central Register of Controlled Trials, PubMed, and Excerpta Medica Database (EMBASE) were searched. Pooled results were estimated using random-effects meta-analysis in RevMan version 5.2. RESULTS: Twenty-five trials met the inclusion criteria. HVs were the key intervention in 12, WGMs in 11, and both interventions in 2 trials. The pooled estimates have shown that NMR was significantly reduced by HVs (OR 0.77, confidence interval [CI]: 0.67-0.90, P = 0.0007, I2 = 77%) and WGMs (OR 0.76, CI: 0.65-0.90, P = 0.001, I2 = 71%). SBR was significantly reduced by HVs (OR 0.77, CI: 0.70-0.85; P < 0.001, I2 = 0%). Subgroup analysis of studies in which more than 10% of pregnant women participated in the WGMs showed significant reduction in NMR (OR 0.67, CI 0.58-0.77, P = 0.00001, I2 = 31%) and MMR (OR 0.55, CI 0.36-0.84, P = 0.005, I2 = 27%). Two studies reported improvement in birth weight by HVs. CONCLUSIONS: HVs and WGMs (with >10% pregnant women) by paramedical professionals are effective strategies in reducing the NMR and MMR in LMICs. HVs were also effective in reducing SBR.

High fructose-induced metabolic changes enhance inflammation in human dendritic cells.

Dendritic cells (DCs) are critical antigen-presenting cells which are the initiators and regulators of the immune response. Numerous studies support the idea that dietary sugars influence DC functions. Increased consumption of fructose has been thought to be the leading cause of metabolic disorders. Although evidence supports their association with immune dysfunction, the specific mechanisms are not well understood. Fructose is one of the main dietary sugars in our diet. Therefore, here we compared the effect of fructose and glucose on the functions of human DCs. High levels of D-fructose compared to D-glucose led to activation of DCs in vitro by promoting interleukin (IL)-6 and IL-1ß production. Moreover, fructose exposed DCs also induced interferon (IFN)-γ secretion from T cells. Proinflammatory response of DCs in high fructose environment was found to be independent of the major known metabolic regulators or glycolytic control. Instead, DC activation on acute exposure to fructose was via activation of receptor for advanced glycation end product (RAGE) in response to increased accumulation of advanced glycation end products (AGE). However, chronic exposure of DCs to high fructose environment induced a shift towards glycolysis compared to glucose cultured DCs. Further investigations revealed that the AGEs formed by fructose induced increased levels of inflammatory cytokines in DCs compared to AGEs from glucose. In summary, understanding the link between metabolic changes and fructose-induced DC activation compared to glucose has broad implications for immune dysfunction associated with metabolic disorders.

Glucose uptake stimulatory effect of 4-hydroxypipecolic acid by increased GLUT 4 translocation in skeletal muscle cells.

Peganum harmala Linn, commonly known as 'harmal' belonging to the family Zygophyllaceae, is one of the most important medicinal plants of India. In continuation of our drug development program on Indian medicinal plants we discovered antihyperglycemic activity in 4-hydroxypipecolic acid (4-HPA), isolated from the seed of P. harmala. Effect of 4-HPA on glucose uptake and glucose transporter-4 (GLUT-4) translocation was investigated in L6 skeletal muscle cell lines. Treatment with 4-HPA stimulated both glucose uptake and GLUT4 translocation from intracellular to cell surface in skeletal muscle cells in a concentration-dependent manner, which might be leading to antihyperglycemic effect.

The morphology and genetic characterization of Iheringascaris goai n. sp. (Nematoda: Raphidascarididae) from the intestine of the silver whiting and spotted catfish off the central west coast of India.

In this study a new species of nematode, Iheringascaris goai n. sp., is reported from two fish hosts, including silver whiting, Sillago sihama, and spotted catfish, Arius maculatus, caught off the Central West Coast of India at Goa. The new species can be differentiated morphologically from I. inquies, the most closely related species collected from cohabiting marine fish. The distinguishing characteristics are distinct cuticular striations, a unilateral excretory system, the presence of dentigerous ridges on the inner margin of the lips and the ratio of oesophagus to body length. In males, the ratio of spicules to body length is higher and the number of pre-anal papillae is less in comparison to those in I. inquies. In addition, the tail curves ventrad in males, while in females, the vulva is post-equatorial. The sequence alignment of 18S rDNA and cytochrome c oxidase subunit I with sequences of known species selected from the same superfamily shows a significant difference. The morphological and molecular differences reported here can, therefore, be used to assign the specimen to a new species.

Self retentive partial silicone auricular prosthesis: a case report.

An auricular prosthesis may be required for a number of conditions including congenital abnormalities, malignancy and trauma, which result in disfigurement of the pinna. Whatever the cause of the absence of the pinna, it is a significant loss of a prominent part of the face for the person involved. This article describes a simple and cost effective technique for retention of a silicone partial auricular prosthesis. A Fish-bone shaped substructure (FSS) designed and fabricated using orthodontic wire and autopolymerizing acrylic resin, was embedded into the silicone elastomer of a self-retentive silicone prosthesis. The prosthesis is designed to overcome the disadvantages associated with traditionally fabricated prostheses; namely poor structural strength, inadequate retention, poor adaptation and durability over time.

N-acetycysteine: A potential therapeutic agent in COVID-19 infection.

COVID-19 is an overwhelming pandemic which has shattered the whole world. Lung injury being the main clinical manifestation, it is likely to cause COPD (chronic obstructive pulmonary disease) and ARDS (acute respiratory distress syndrome). The possible cause behind this might be redox imbalance due to viral infection. Elevation in Glutathione (GSH) levels by administration of its promolecule might be effective. N-acetylcysteine is one such drug with potency to scavenge Reactive Oxygen Species, least side effects, and an effective precursor of glutathione. Consequently we hypothesize that N-acetylcysteine along with the conventional treatment may be treated as a potential therapeutic solution in cases of COVID-19 patients.

The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis.

OBJECTIVE: Skeletal muscle insulin signaling is a major determinant of muscle growth and glucose homeostasis. Protein kinase B/Akt plays a prominent role in mediating many of the metabolic effects of insulin. Mice and humans harboring systemic loss-of-function mutations in Akt2, the most abundant Akt isoform in metabolic tissues, are glucose intolerant and insulin resistant. Since the skeletal muscle accounts for a significant amount of postprandial glucose disposal, a popular hypothesis in the diabetes field suggests that a reduction in Akt, specifically in skeletal muscle, leads to systemic glucose intolerance and insulin resistance. Despite this common belief, the specific role of skeletal muscle Akt in muscle growth and insulin sensitivity remains undefined. METHODS: We generated multiple mouse models of skeletal muscle Akt deficiency to evaluate the role of muscle Akt signaling in vivo. The effects of these genetic perturbations on muscle mass, glucose homeostasis and insulin sensitivity were assessed using both in vivo and ex vivo assays. RESULTS: Surprisingly, mice lacking Akt2 alone in skeletal muscle displayed normal skeletal muscle insulin signaling, glucose tolerance, and insulin sensitivity despite a dramatic reduction in phosphorylated Akt. In contrast, deletion of both Akt isoforms (M-AktDKO) prevented downstream signaling and resulted in muscle atrophy. Despite the absence of Akt signaling, in vivo and ex vivo insulin-stimulated glucose uptake were normal in M-AktDKO mice. Similar effects on insulin sensitivity were observed in mice with prolonged deletion (4 weeks) of both skeletal muscle Akt isoforms selectively in adulthood. Conversely, short term deletion (2 weeks) of skeletal muscle specific Akt in adult muscles impaired insulin tolerance paralleling the effect observed by acute pharmacological inhibition of Akt in vitro. Mechanistically, chronic ablation of Akt induced mitochondrial dysfunction and activation of AMPK, which was required for insulin-stimulated glucose uptake in the absence of Akt. CONCLUSIONS: Together, these data indicate that chronic reduction in Akt activity alone in skeletal muscle is not sufficient to induce insulin resistance or prevent glucose uptake in all conditions. Therefore, since insulin-stimulated glucose disposal in skeletal muscle is markedly impaired in insulin-resistant states, we hypothesize that alterations in signaling molecules in addition to skeletal muscle Akt are necessary to perturb glucose tolerance and insulin sensitivity in vivo.

Fructose-induced ROS generation impairs glucose utilization in L6 skeletal muscle cells.

High fructose consumption has implicated in insulin resistance and metabolic syndrome. Fructose is a highly lipogenic sugar that has intense metabolic effects in liver. Recent evidences suggest that fructose exposure to other tissues has substantial and profound metabolic consequences predisposing toward chronic conditions such as type 2 diabetes. Since skeletal muscle is the major site for glucose utilization, in the present study we define the effects of fructose exposure on glucose utilization in skeletal muscle cells. Upon fructose exposure, the L6 skeletal muscle cells displayed diminished glucose uptake, glucose transporter type 4 (GLUT4) translocation, and impaired insulin signaling. The exposure to fructose elevated reactive oxygen species (ROS) production in L6 myotubes, accompanied by activation of the stress/inflammation markers c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2), and degradation of inhibitor of NF-κB (IκBα). We found that fructose caused impairment of glucose utilization and insulin signaling through ROS-mediated activation of JNK and ERK1/2 pathways, which was prevented in the presence of antioxidants. In conclusion, our data demonstrate that exposure to fructose induces cell-autonomous oxidative response through ROS production leading to impaired insulin signaling and attenuated glucose utilization in skeletal muscle cells.

Mesenchymal stem cell surface antigen SB-10 corresponds to activated leukocyte cell adhesion molecule and is involved in osteogenic differentiation.

Bone marrow contains a rare population of mesenchymal stem cells (MSCs) capable of giving rise to multiple mesodermal tissues including bone, cartilage, tendon, muscle, and fat. The cell surface antigen recognized by monoclonal antibody SB-10 is expressed on human MSCs but is lost during their developmental progression into differentiated phenotypes. Here we report on the immunopurification of the SB-10 antigen and its identification as activated leukocyte-cell adhesion molecule (ALCAM). Mass spectrometry establishes that the molecular mass of ALCAM is 80,303 +/- 193 Da and that it possesses 17,763 +/- 237 Da of N-linked oligosaccharide substituents. Molecular cloning of a full-length cDNA from a MSC expression library demonstrates nucleotide sequence identity with ALCAM. We also identified ALCAM homologs in rat, rabbit, and canine MSCs, each of which is over 90% identical to human ALCAM in their peptide sequence. The addition of antibody SB-10 Fab fragments to human MSCs undergoing osteogenic differentiation in vitro accelerated the process, thereby implicating a role for ALCAM during bone morphogenesis and adding ALCAM to the group of cell adhesion molecules involved in osteogenesis. Together, these results provide evidence that ALCAM plays a critical role in the differentiation of mesenchymal tissues in multiple species across the phylogenetic tree.

Human mesenchymal stem cells promote human osteoclast differentiation from CD34+ bone marrow hematopoietic progenitors.

Interactions between osteoclast progenitors and stromal cells derived from mesenchymal stem cells (MSCs) within the bone marrow are important for osteoclast differentiation. In vitro models of osteoclastogenesis are well established in animal species; however, such assays do not necessarily reflect human osteoclastogenesis. We sought to establish a reproducible coculture model of human osteoclastogenesis using highly purified human marrow-derived MSCs (hMSCs) and CD34+ hematopoietic stem cells (HSCs). After 3 weeks, coculture of hMSCs and HSCs resulted in an increase in hematopoietic cell number with formation of multinucleated osteoclast-like cells (Ocls). Coculture of hMSCs with HSCs, transduced with a retroviral vector that expresses enhanced green fluorescent protein, produced enhanced green fluorescent protein+ Ocls, further demonstrating that Ocls arise from HSCs. These Ocls express calcitonin and vitronectin receptors and tartrate-resistant acid phosphatase and possess the ability to resorb bone. Ocl formation in this assay is cell contact dependent and is independent of added exogenous factors. Conditioned medium from the coculture contained high levels of interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF), and macrophage-colony stimulating factor. IL-6 and LIF were present at low levels in cultures of hMSCs but undetectable in cultures of HSCs alone. These data suggest that coculture with HSCs induce hMSCs to secrete cytokines involved in Ocl formation. Addition of neutralizing anti-IL-6, IL-11, LIF, or macrophage-colony stimulating factor antibodies to the coculture inhibited Ocl formation. hMSCs seem to support Ocl formation as undifferentiated progenitor cells, because treatment of hMSCs with dexamethasone, ascorbic acid, and beta-glycerophosphate (to induce osteogenic differentiation) actually inhibited osteoclastogenesis in this coculture model. In conclusion, we have developed a simple and reproducible assay using culture-expanded hMSCs and purified HSCs with which to study the mechanisms of human osteoclastogenesis.

Human astrocytes contain two distinct angiotensin receptor subtypes.

The ability of angiotensin peptides to stimulate prostaglandin release and raise intracellular calcium levels by activating a phosphoinositide-specific phospholipase C was assessed in three human astrocytoma cell lines (CRTG3, STTG1, and WITG2). The addition of angiotensin II to CRTG3 cells resulted in a dose-dependent release of prostaglandin E2 and prostacyclin, the production of inositol 1,4,5-trisphosphate, and the mobilization of intracellular calcium. Angiotensin-(1-7), previously considered to be an inactive metabolite of angiotensin II, was as potent as angiotensin II for prostaglandin release but did not activate phospholipase C or mobilize intracellular calcium. In contrast, angiotensin-(2-8) caused only a slight increase in prostaglandin release, even though it was as effective as angiotensin II in augmenting inositol 1,4,5-trisphosphate production and calcium mobilization. Moreover, neither the release of prostaglandins in response to angiotensin II or angiotensin-(1-7) nor the mobilization of intracellular calcium in response to angiotensin II required extracellular calcium. Angiotensin II and angiotensin-(1-7) caused the release of prostaglandins from all three human astrocytoma cell lines, but changes in the level of intracellular calcium in response to angiotensin II only occurred in CRTG3 cells. Although previous studies have provided evidence for angiotensin receptor subtypes on the basis of selectivity of antagonists or signal transduction mechanisms, these data suggest that human astrocytes contain multiple angiotensin receptor subtypes on the basis of their response to different angiotensin heptapeptides--angiotensin-(1-7) and angiotensin-(2-8).(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Characterization of receptors.

Angiotensin II stimulates prostaglandin release in blood vessels via activation of angiotensin receptors present in endothelium, vascular smooth muscle cells, or both. We evaluated the response of angiotensin II, angiotensin I, and [des-Phe8] angiotensin II [angiotensin-(1-7)] on prostaglandin release in porcine aortic endothelial cells. Incubation of cell monolayers with angiotensin I and angiotensin-(1-7), but not angiotensin II, stimulated the release of prostaglandin E2 and prostaglandin I2 in a dose-dependent manner (10(-10) to 10(-6) M) with an EC50 of approximately 1 nM. In addition, we characterized the angiotensin receptor subtypes mediating prostaglandin synthesis by using subtype-selective antagonists. Angiotensin I-stimulated prostaglandin synthesis was not altered by either of the nonselective classical angiotensin receptor antagonists [Sar1,Thr8]angiotensin II or [Sar1,Ile8]angiotensin II. In contrast, either the angiotensin subtype 1 (AT1) antagonist DuP 753 or the subtype 2 (AT2) antagonist CGP42112A significantly attenuated the prostaglandin release in response to angiotensin I. However, PD123177, another AT2 antagonist, did not inhibit angiotensin I-stimulated prostaglandin release. Angiotensin-(1-7)-induced prostaglandin release was significantly attenuated by [Sar1,Thr8]angiotensin II (10(-6) M) and PD123177 (10(-6) M) but not by [Sar1,Ile8]angiotensin II, DuP 753, or CGP42112A. Higher doses (10(-5) M) of DuP 753 and CGP42112A attenuated the angiotensin-(1-7) response. These data suggest that in porcine aortic endothelial cells, angiotensin I and angiotensin-(1-7) but not angiotensin II are potent stimuli for prostaglandin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes.

We have identified two distinct cellular responses that occur in human astrocytes in the presence of angiotensin (Ang) peptides and are linked to specific receptor subtypes. Ang II and the N-terminal heptapeptide Ang-(1-7) stimulated release of prostaglandin (PG) E2 and PGI2 (measured as the stable metabolite 6-keto-PGF1 alpha). In contrast, only Ang II but not Ang-(1-7) activated phosphoinositide-specific phospholipase C, leading to mobilization of intracellular calcium. The Ang II-induced PGE2 and PGI2 syntheses were attenuated by [Sar1,Ile8]Ang II but not by [Sar1,Thr8]Ang II. Ang-(1-7)-induced PGE2 and PGI2 syntheses were not inhibited by either of these two classical antagonists. DuP 753, a subtype 1-selective Ang receptor antagonist, blocked the Ang II-induced release of PGE2 but not PGI2. In contrast, CGP 42112A, the subtype 2-selective antagonist, totally blocked the Ang II-induced PGI2 release and partially attenuated the PGE2 release. Ang-(1-7)-induced PGE2 and PGI2 release was not altered by DuP 753; however, CGP 42112A totally blocked the effects of Ang-(1-7) on PG stimulation. Calcium mobilization in response to Ang II was blocked by [Sar1,Thr8]Ang II, [Sar1,Ile8]Ang II, and DuP 753 but not by CGP 42112A. These data suggest that human astrocytes contain both Ang receptor subtypes. The subtype 1 Ang receptor participates both in the release of PGs and in the mobilization of calcium, whereas the subtype 2 receptor is coupled to the release of PGs only. In addition, PG release coupled to subtype 2 Ang II receptors occurs through a calcium-independent mechanism and responds uniquely to Ang-(1-7).

Alterations in prostaglandin production in spontaneously hypertensive rat smooth muscle cells.

We have characterized angiotensin binding sites in cultured smooth muscle cells obtained from the aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. In both strains of rats the binding of 125I-angiotensin II (125I-Ang II) in smooth muscle cells was time dependent and reached a maximum at 60 minutes. Scatchard analysis revealed a single binding site in both strains with equilibrium constants (KD) of 5.35 nmol/L in SHR and 3.47 nmol/L in WKY rats. Binding capacities (Bmax) in smooth muscle cells averaged 270 and 150 fmol/mg protein in SHR and WKY rats, respectively. Angiotensin peptides competed for 125I-Ang II binding with an order of potency of Ang II > angiotensin-(1-7) = angiotensin I. In smooth muscle cells of the SHR, basal prostaglandin E2 (PGE2) and prostacyclin (prostaglandin I2 [PGI2]) release were threefold and 15-fold lower than that found in WKY rat smooth muscle cells. Ang II as well as angiotensin-(1-7) stimulated PGE2 and PGI2 release in WKY rat smooth muscle cells. In smooth muscle cells from SHR, Ang II increased the production of both PGE2 and PGI2, whereas angiotensin-(1-7) enhanced only PGE2 but not PGI2 release. There was no significant difference between Ang II-stimulated PGE2 and PGI2 release or angiotensin-(1-7)-stimulated PGE2 production in SHR and WKY rat smooth muscle cells. However, angiotensin-(1-7)-stimulated PGI2 release was significantly lower (p < 0.0005) in SHR compared with WKY smooth muscle cells. Collectively, the data suggest that smooth muscle cells of SHR contain a higher number of angiotensin binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-(1-7): a new hormone of the angiotensin system.

We provide a new foundation for an alternative interpretation of the biochemical physiology of the brain and other tissue angiotensin systems on the basis of research done in our laboratory. This perspective is prompted by the discovery that angiotensin-(1-7) has cellular functions that differ from those established for angiotensin II. Although angiotensin-(1-7) is not an agonist in terms of activating vasoconstriction, stimulating thirst, or promoting aldosterone release, the heptapeptide caused neuronal excitation and vasopressin release with a potency similar to that found with angiotensin II. Furthermore, angiotensin-(1-7) enhances the production of prostanoids by a receptor-mediated event that causes no associated rise in intracellular Ca2+. These actions of angiotensin-(1-7) provide a new understanding of the heterogeneous functions of angiotensin peptides as modulators of a wide range of regulatory functions in mammals.

Negative regulation of atrial natriuretic factor receptor coupled membrane guanylate cyclase by phorbol ester. Potential protein kinase C regulation of cyclic GMP signal in isolated adrenocortical carcinoma cells of rat.

Rat adrenocortical carcinoma cells possess a high density of atrial natriuretic factor (ANF) receptors which are coupled with membrane guanylate cyclase and corticosterone production. Herein we show that pretreatment of these cells with phorbol 12-myristate 13-acetate (PMA), a known activator of protein kinase C, attenuates the ANF-stimulated cyclic GMP accumulation in a dose-dependent manner. The half maximum inhibitory concentration of PMA was 10(-10) M. When these cells were incubated with PMA in the presence of 1-(5-isoquinolinyl-sulfonyl)-2-methyl piperazine, a protein kinase C inhibitor, the PMA-mediated attenuation of ANF-stimulated cyclic GMP formation is blocked. These results suggest that protein kinase C negatively regulates the ANF-receptor coupled membrane guanylate cyclase system in these cells.

Atrial natriuretic factor regulation of cyclic GMP levels and steroidogenesis in isolated fasciculata cells of rat adrenal cortex.

Isolated fasciculata cells of rat adrenal cortex, when incubated with atrial natriuretic factor (ANF), stimulated the levels of cyclic GMP and corticosterone production in a concentration-dependent manner without a rise in the levels of cyclic AMP. The ANF-dependent elevation of cyclic GMP was rapid, with a detectable increment in 30 s. ANF also stimulated the particulate guanylate cyclase. These results not only indicate the coupling of cyclic GMP and corticosterone production with ANF signal, but also demonstrate that, like the ACTH signal, cyclic AMP is not the mediator of ANF-induced adrenocortical steroidogenesis.

The nonpeptide angiotensin II antagonist DuP 753 is a potent stimulus for prostacyclin synthesis.

In an attempt to define the angiotensin II receptor subtype responsible for prostaglandin release, we studied the effects of the nonpeptide, subtype 1 (or B) selective angiotensin II antagonist, DuP 753. Release of prostaglandin E2 produced by angiotensin II from rat C6 glioma, human astrocytoma, or porcine aortic smooth muscle cells in culture was blocked by the addition of the 10(-7) M of DuP 753. In contrast, the release of prostacyclin, as assessed by measurement of the stable metabolite 6-keto PGF1 alpha, was not attenuated by addition of Du P 753. However, DuP 753 either alone or in combination with angiotensin II, produced dose-dependent increases in prostacyclin release with doses as low as 10(-8) M. In the absence of angiotensin II, DuP 753 also increased prostaglandin E2 release at high doses but the magnitude of the potentiation was substantially less than for prostacyclin release (50 to 250% v 400 to 2800% above basal). Thus, we clearly show that angiotensin II stimulates PGE2 release via subtype 1 (or B) angiotensin receptors. Whether the effect of DuP 753 on prostaglandin release is a result of agonistic properties or intrinsic effects unrelated to blockage of angiotensin II receptors remains to be determined. The marked stimulatory effect of DuP 753 release precludes characterization of the receptor subtype that mediates the Ang II-induced release of prostacyclin. Nonetheless, potent stimulation of prostacyclin release by DuP 753, especially in vascular smooth muscle cells, requires reevaluation of the mechanisms that participate in the anti-hypertensive effects of the compound.