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I (Handbook of Experimental Pharmacology) [Thomas Unger, Bernward A. Schölkens] To call attention to its many functions is one of the purposes of this book. This new edition of the volume on Angiotensin attempts to provide an updated.
Table of contents
- Angiotensin Vol. II
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- Solubilisation of angiotensin II receptors in rabbit aortae membranes | Nature
- Original Research ARTICLE
- Product Description
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Angiotensin Vol. II
Eve E. Slater, MD ; Debora D. Merrill ; Harry A. Guess, MD ; et al Peter J. Roylance, MB ; Warren D.
Get free access to newly published articles Create a personal account or sign in to: Register for email alerts with links to free full-text articles Access PDFs of free articles Manage your interests Save searches and receive search alerts. Get free access to newly published articles. Create a personal account to register for email alerts with links to free full-text articles. In the present study, carried out in zebrafish, both captopril and losartan appeared to cause vasodilation; however, none of the responses at any time point were statistically significant using six animals per treatment group.
Despite this uncertainty, when the effect size was compared across different species, we observed that both losartan and captopril induced effect magnitude ranges in zebrafish in line with those observed in rat, dog, and human studies. It is possible to hypothesize that a zebrafish model with induced vasoconstriction would likely facilitate the statistically significant detection of drug-induced vasodilation using a similar, small number of animals.
At the same time, the overall observed pattern of response emerging from the meta-analysis may be partially explained by the structural boundaries that limit the maximum effect size of aorta diameter.
Solubilisation of angiotensin II receptors in rabbit aortae membranes | Nature
The detection of this type of effect size using standard statistics would require a higher statistical power than the one used in our experiment or alternatively the use of a model with proven extremely low interindividual variability with respect to the endpoint under investigation.
Beyond vessel diameter, the modulation of the RAS system by losartan and captopril exposure also produced consistent interspecies responses for heart rate, blood flow, and stroke volume. The only two cases where the zebrafish data and that from other models differed stemmed from the effect of captopril on blood flow and stroke volume, which displayed a moderate decrease instead of the neutral or positive effect observed in mammals. It is currently unclear whether these discrepancies are biologically meaningful, and additional studies should be carried out in the future to clarify this point.
From an evolutionary standpoint, it is known that the RAS system is conserved in fish. Already in , Nishimura and Ogawa, after reviewing the available evidence concerning the conservation of the RAS system in nonmammals, concluded that the components of the RAS system appeared to be evolutionary conserved in fish but raised doubts about the functional conservation of those components, such as their involvement in the sodium retaining processes observed in mammals Nishimura and Ogawa, Subsequent studies have confirmed the evolutionary conservation of the RAS components in teleost fish Fournier et al.
Several studies investigating the effects of RAS pharmacological modulation in fish models have generated conflicting results, which have led some authors to hypothesize a low conservation of the sartan binding site on the AT1 receptor Fuentes and Eddy, ; Russell et al. Kitambi et al. In the same study, exposure of zebrafish larvae to the ACE inhibitor enalapril maleate induced vasodilation of intraocular blood vessels but not blood vessels in the trunk.
On the other hand, many similarities between zebrafish and mammalian RAS-mediated functions also emerge from other studies. Rider et al.
Kumai et al. Our results were also generated using noninvasive in vivo imaging techniques measuring multiple endpoints simultaneously and suggest high similarity between zebrafish and mammalian cardiovascular responses mediated by AT1 receptor antagonism. ACE inhibition generated comparable responses only for the endpoint vasodilation and heart rate but not for stroke volume and blood flow, confirming, to some extent, the elusive nature of ACE functional conservation between teleost fish and mammals.
The comparison of the effect concentrations ranges of the different compounds tested in the present study brought to light an obvious difference between the three drugs. Whereas propranolol exerted cardiovascular effects in zebrafish in the micromolar range, losartan and captopril acted in the millimolar range. This gap is also observable in human C max values but to a much smaller extent i.
First, it is possible that the three drugs have different uptake and PK profile in the zebrafish. For example, the low LogKow of captopril 0. This implies that water test concentrations may not be the most appropriate unit of comparison and that internal concentrations should be used whenever possible to inform comparative evaluations. On the other side, it is plausible that drug-specific pharmacodynamics contributed to the observed difference in water effect concentrations because of the different role played by beta-adrenergic receptors and renin—angiotensin system in the mediation of cardiovascular functions.
Finally, in addition to the evolutionary considerations discussed above, it cannot be excluded that the renin—angiotensin system of zebrafish at 7 dpf may not be fully mature from a molecular and functional perspective; however, to our knowledge, no data are currently available to evaluate the plausibility of this hypothesis. Our meta-analysis revealed some striking similarities between zebrafish and mammalian responses to three common cardiovascular drugs: propranolol, losartan, and captopril.
Original Research ARTICLE
Our data suggest that, albeit based on data from a limited number of drugs, the cardiovascular effects of both beta-adrenergic receptor and angiotensin II type 1 receptor antagonism can be reliably demonstrated in larval zebrafish. In contrast, treatment to induce ACE inhibition led to results that were only partially in agreement with the known mammalian responses. This uncertainty would suggest that this specific mechanism of action should be considered outside the domain of applicability of the zebrafish model for drug testing, until more robust evidence becomes available.
As already demonstrated previously by Parker et al. Nonetheless, it is important to highlight certain shortcomings of our study that may have affected, in some cases, the degree of reliability of the overall results.
The first and most obvious limitation is the relatively low statistical power of the experiments, carried out using six animals per treatment group. The selection of this design was driven both by previous experiments Parker et al. Of note, however, is that this limitation applies not only to our study but also to several papers from which we extracted the mammalian data used in our meta-analysis. As far as zebrafish tests are concerned, the data we generated can be used to set the statistical power of future experiments and achieve an optimal design e.
In some cases, the sensitivity of the experiment could be increased by testing a cardiovascular disease model or by employing genetically engineered zebrafish strains that express fluorescent tags in specific cells. The latter approach may offer a powerful multiscale perspective on drug action and facilitate the interpretation of apical phenotypic processes. A second important limitation of our zebrafish test was the lack of data concerning the internal concentration of the drug in the animal. The routine quantification of drug internal concentrations in zebrafish larvae remains technically challenging e.
There are examples where the authors successfully performed such analysis e.
Previous studies have demonstrated the importance of internal exposure dynamics to interpret drug-mediated effects in adult fish Margiotta-Casaluci et al. It is highly plausible that this aspect is also critically important when larval stages are used. Considering that the routine quantification of drug internal concentrations in zebrafish larvae may remain unrealistic for many laboratories, coordinated efforts aimed at developing PBPK model for the larval life stages may offer a good compromise that would enhance the translational value of the zebrafish model.
The key novel aspect of our work is application of a meta-analysis approach for the quantitative assessment of preclinical model translational potential. This approach, combined with a suitable data visualization strategy, revealed patterns of response that would likely remain undetected by employing more traditional methods of qualitative comparative analysis, including the consideration of a few selected papers as a term of comparison, for example, the use of only statistically significant results i.
The method we used in our study allowed us to zoom out from single studies in an unbiased manner and revealed a surprising overlap of effect magnitudes across species, as well as unexpected intraspecies discrepancies. It also provides a fully transparent platform to evaluate data reproducibility and, in turn, support decision-making. We propose that expanding the meta-analysis of interspecies responses to other target—phenotype combinations in the future will help to precisely define the domain of applicability of zebrafish and increase the confidence in its application.
Achieving this goal may help to fully unlock the 3Rs potential of the zebrafish model, which may play a key role in the design of future testing strategies, representing an important and crucial bridge between high throughput in vitro and low throughput, high content mammalian in vivo testing. All datasets generated for this study are included in the manuscript and the supplementary files. This study was carried out in accordance with the recommendations of the United Kingdom Animals Scientific Procedures Act regarding the use of animals in scientific procedures.
MW and LM-C performed the in vivo studies. LM-C extracted and analyzed both zebrafish and mammalian data and performed the quality assessment of the dataset. SO and MW contributed with essential materials and equipment. LM-C prepared the figures. All the authors reviewed the manuscript. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publications.
MW was and SO is an employee of AstraZeneca, a biopharmaceutical company specialized in the discovery, development, manufacturing, and marketing of prescription medicines including propranolol used here. Abraham, H. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases. Drug Saf. Altimiras, J. Is the short-term modulation of heart rate in teleost fish physiologically significant?
Assessment by spectral analysis techniques. PubMed Abstract Google Scholar. Asnani, A. The zebrafish as a tool to identify novel therapies for human cardiovascular disease. Model Mech.