Does the Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? – A systematic review

Background

Pharmacogenetic testing to individualize ACE inhibitor therapy remains controversial. We conducted a systematic review to assess the effect modification of the insertion/deletion (I/D) polymorphism of the ACE gene on any outcome in patients treated with ACE inhibitors for cardiovascular and/or renal disease.

Methods

Our systematic review involved searching six electronic databases, then contacting the investigators (and pharmaceutical industry representatives) responsible for the creation of these databases. Two reviewers independently selected relevant randomized, placebo-controlled trials and abstracted from each study details on characteristics and quality.

Results

Eleven studies met our inclusion criteria. Despite repeated efforts to contact authors, only four of the eleven studies provided sufficient data to quantify the effect modification by genotypes. We observed a trend towards better response to ACE inhibitors in Caucasian DD carriers compared to II carriers, in terms of blood pressure, proteinuria, glomerular filtration rate, ACE activity and progression to end-stage renal failure. Pooling of the results was inappropriate, due to heterogeneity in ethnicity, clinical domains and outcomes.

Conclusion

Lack of sufficient genetic data from the reviewed studies precluded drawing any convincing conclusions. Better reporting of genetic data are needed to confirm our preliminary observations concerning better response to ACE inhibitors among Caucasian DD carriers as compared to II carriers.     

Development and use of an ovarian synchronization model to study the effects of endogenous estrogen and nitric oxide on uterine blood flow during ovarian cycles in sheep

The objective of the current study was to develop an ovine animal model for consistent study of uterine blood flow (UBF) changes during synchronized ovarian cycles regardless of season. Sheep were surgically bilaterally instrumented with uterine artery blood flow transducers and 5-7 days later implanted with a vaginal progesterone (P(4))-controlled internal drug-releasing device (CIDR; 0.3 g) for 7 days. On Day 6 of P(4), sheep were given two prostaglandin F(2 alpha) injections (7.5 mg i.m. 4 h apart). At CIDR removal, Experimental Day 0, zero (n = 9), 500 IU (n = 8), or 1000 IU (n = 7) eCG was injected i.m.; UBF was monitored continuously for 55-75 h. Jugular blood was sampled every 8 h to evaluate levels of P(4), estradiol-17 beta (E(2)beta) and luteinizing hormone (LH). The inhibitor of nitric oxide synthase, L-nitro-arginine methyl ester (L-NAME) was infused in a stepwise fashion unilaterally into one uterine artery at 48-50 h after 500 IU eCG and the effects on UBF were examined (n = 7). The zero-eCG group gradually increased UBF from a baseline of 17.4 +/- 3.9 to 80.5 +/- 1.1 ml/min. The 500-IU-eCG group increased UBF between 10 and 15 h from a baseline of 11 +/- 3.3 to 83.3 +/- 1.0 ml/min, whereas UBF for the 1000-IU-eCG group was higher (100.1 +/- 1.7 ml/min) than that seen in either of the other groups. Plasma P(4) fell to baseline within 8 h of CIDR removal, while E(2)beta rose gradually in association with elevations in UBF. LH surges occurred between 32 and 56 h after CIDR removal and the LH surge occurred earlier in the 1000-IU-eCG group than the other two groups (P < 0.01). L-NAME infusion dose dependently reduced maximum levels of UBF ipsilaterally by 54.6% +/- 6.2%, but contralaterally only by 27.4% +/- 8.5%. Regardless of season, either dose of eCG will result in analogous UBF responses. During the follicular phase, elevations in UBF are in part locally controlled by the de novo production of nitric oxide.     

Oligomerization of adenosin‐5′‐O‐ylmethylphosphonate,an isopolar AMP analogue: Evaluation of the route to short oligoadenylates

In an attempt to prepare a library of short oligoadenylate analogues featuring both the enzyme‐stable internucleotide linkage and the 5′‐O‐methylphosphonate moiety and thus obtain a pool of potential RNase L agonists/antagonists, we studied the spontaneous polycondensation of the adenosin‐5′‐O‐ylmethylphosphonic acid (p_cA), an isopolar AMP analogue, and its imidazolide derivatives employing N,N′‐dicyclohexylcarbodiimide under nonaqueous conditions and uranyl ions under aqueous conditions, respectively. The RP LC–MS analyses of the reaction mixtures per se, and those obtained after the periodate treatment, along with analyses and separations by capillary zone electrophoresis, allowed us to characterize major linear and cyclic oligoadenylates obtained. The structure of selected compounds was supported, after their isolation, by NMR spectroscopy. Ab initio calculation of the model structures simulating the AMP‐imidazolide and p_cA‐imidazolide offered the explanation why the latter compound exerted, in contrast to AMP‐imidazolide, a very low stability in aqueous solutions. © 2009 Wiley Periodicals, Inc. Biopolymers 93: 277–289, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com     

Codeine and 6-Acetylcodeine Analgesia in Mice

Summary 1. Acetylation of morphine at the 6-position changes its pharmacology. To see if similar changes are seen with codeine, we examined the analgesic actions of codeine and 6-acetylcodeine.2. Like codeine, 6-acetylcodeine is an effective analgesic systemically, supraspinally and spinally, with a potency approximately a third that of codeine.3. The sensitivity of 6-acetylcodeine analgesia to the mu-selective antagonists β-FNA and naloxonazine confirmed its classification as a mu opioid. However, it differed from the other mu analgesics in other paradigms.4. Antisense mapping revealed the sensitivity of 6-acetylcodeine to probes targeting exons 1 and 2 of the mu opioid receptor gene (Oprm), a profile distinct from either codeine or morphine. Although heroin analgesia also is sensitive to antisense targeting exons 1 and 2, heroin analgesia also is sensitive to the antagonist 3-O-methylnaltrexone, while 6-acetylcodeine analgesia is not.5. Thus, 6-acetylcodeine is an effective mu opioid analgesic with a distinct pharmacological profile.     

Curling during desiccation protects the foliose lichen Lobaria pulmonaria against photoinhibition

This study aims to assess the photoprotective potential of desiccation-induced curling in the light-susceptible old forest lichen Lobaria pulmonaria by using chlorophyll fluorescence imaging. Naturally curled thalli showed less photoinhibition-induced limitations in primary processes of photosynthesis than artificially flattened specimens during exposures to 450 μmol m⁻² s⁻¹ in the laboratory after both 12- (medium dose treatment) and 62-h duration (high dose treatment). Thallus areas shaded by curled lobes during light exposure showed unchanged values of measured chlorophyll fluorescence parameters (F _V/F _M, Φ_{PS II}), whereas non-shaded parts of curled thalli, as well as the mean for the entire flattened thalli, showed photoinhibitory limitation after light treatments. Furthermore, the chlorophyll fluorescence imaging showed that the typical small-scale reticulated ridges on the upper side of L. pulmonaria caused a spatial, small-scale reduction in damage due to minor shading. Severe dry-state photoinhibition readily occurred in flattened and light-treated L. pulmonaria, although the mechanisms for such damage in a desiccated and inactive stage are not well known. Natural curling is one strategy to reduce the chance for serious photoinhibition in desiccated L. pulmonaria thalli during high light exposures.     

ATP and ADP hydrolysis in cell membranes from rat myometrium

Extracellular nucleotides affect female reproductive functions, fertilization, and pregnancy. The aim of this study was to investigate biochemical characteristics of ATP and ADP hydrolysis and identify E-NTPDases in myometrial cell membranes from Wistar albino rats. The apparent K _m values were 506.4?±?62.1 and 638.8?±?31.3?μM, with a calculated V _max (app) of 3,973.0?±?279.5 and 2,853.9?±?79.8?nmol/min/mg for ATP and ADP, respectively. The enzyme activity described here has common properties characteristic for NTPDases: divalent cation dependence; alkaline pH optimum for both substrates, insensitivity to some of classical ATPase inhibitors (ouabain, oligomycine, theophylline, levamisole) and significant inhibition by suramine and high concentration of sodium azides (5?mM). According to similar apparent K_m values for both substrates, the ATP/ADP hydrolysis ratio, and Chevillard competition plot, NTPDase1 is dominant ATP/ADP hydrolyzing enzyme in myometrial cell membranes. RT-PCR analysis revealed expression of three members of ectonucleoside triphosphate diphosphohydrolase family (NTPDase 1, 2, and 8) in rat uterus. These findings may further elucidate the role of NTPDases and ATP in reproductive physiology.     

Time-course of hypothalamic-pituitary-adrenal axis activity and inflammation in juvenile rat brain after cranial irradiation

Recent studies reported that exposure of juvenile rats to cranial irradiation affects hypothalamic-pituitary-adrenal (HPA) axis stability, leading to its activation along with radiation-induced inflammation. In the present study, we hypothesized whether inflammatory reaction in the CNS could be a mediator of HPA axis response to cranial irradiation (CI). Therefore, we analyzed time-course changes of serum corticosterone level, as well IL-1β and TNF-α level in the serum and hypothalamus of juvenile rats after CI. Protein and gene expression of the glucocorticoid receptor (GR) and nuclear factor kappaB (NFκB) were examined in the hippocampus within 24?h postirradiation interval. Cranial irradiation led to rapid induction of both GR and NFκB mRNA and protein in the hippocampus at 1?h. The increment in NFκB protein persisted for 2?h, therefore NFκB/GR protein ratio was turned in favor of NFκB. Central inflammation was characterized by increased IL-1β in the hypothalamus, with maximum levels at 2 and 4?h after irradiation, while both IL-1β and TNF-α were undetectable in the serum. Enhanced hypothalamic IL-1β probably induced the relocation of hippocampal NFκB to the nucleus and decreased NFκB mRNA at 6?h, indicating promotion of inflammation in the key tissue for HPA axis regulation. Concomitant increase of corticosterone level and enhanced GR nuclear translocation in the hippocampus at 6?h might represent a compensatory mechanism for observed inflammation. Our results indicate that acute radiation response is characterized by increased central inflammation and concomitant HPA axis activation, most likely having a role in protection of the organism from overwhelming inflammatory reaction.     

Dormancy development during cold hardening of in vitro cultured Malus domestica Borkh. plants in relation to their frost resistance and cryotolerance

The development of dormancy, frost resistance and cryotolerance of in vitro apple plants (Malus domestica Borkh.), cv. Greensleeves during their exposure to cold hardening was studied. In vitro cultures were cold hardened at 4°C under a short photoperiod up to 25?weeks. The dormancy status, non-structural saccharides, proline, water content and frost resistance were evaluated for optimization of cryopreservation. According to regrowth tests, in vitro cultures exhibited endogenous dormancy after the maximal frost resistance was reached. The highest regeneration ability of shoot tips after cryopreservation by encapsulation–dehydration method coincided with the period of the plant’s dormant state and maximum of frost resistance. All studied saccharides and proline exhibited the maximal values at the beginning of cold hardening and/or the dormancy phase. Contrary to the accumulation of saccharides and proline, water content showed the inverse time behaviour. According to these results, the cold hardening-induced endodormancy, high frost resistance and accumulation of saccharides and proline are the important prerequisites for the successful cryopreservation of shoot tips of in vitro grown apple plants.     

4-Substituted boro-proline dipeptides: Synthesis, characterization, and dipeptidyl peptidase IV, 8, and 9 activities

The boroProline-based dipeptidyl boronic acids were among the first DPP-IV inhibitors identified, and remain the most potent known. We introduced various substitutions at the 4-position of the boroProline ring regioselectively and stereoselectively, and incorporated these aminoboronic acids into a series of 4-substituted boroPro-based dipeptides. Among these dipeptidyl boronic acids, Arg-(4S)-boroHyp (4q) was the most potent inhibitor of DPP-IV, DPP8 and DPP9, while (4S)-Hyp-(4R)-boroHyp (4o) exhibited the most selectivity for DPP-IV over DPP8 and DPP9.