Three Rs

This report critically evaluates the principal animal models used in antihypertensive drug development and the systematic factors underlying the persistent gap between preclinical efficacy and clinical outcomes. Three model systems are examined, the spontaneously hypertensive rat (SHR), the Dahl salt-sensitive rat, and renovascular (two-kidney and one-kidney one-clip) models, assessing their experimental utility, translational limitations, and ethical implications against human essential hypertension. Although each has yielded foundational mechanistic insight and supported major drug classes, their collective predictive validity is constrained by genetic homogeneity, the absence of common comorbidities (obesity, type 2 diabetes, chronic kidney disease), a pronounced bias toward male-only cohorts, short experimental timeframes, and interspecies divergence in key signalling pathways. Inconsistent experimental design, particularly blood-pressure measurement method and under-reporting of animal sex, further erodes reproducibility and cross-study synthesis. The report situates these issues within the global research landscape, highlighting geographic and ancestry-related blind spots that limit relevance to under-represented populations, and within the Three Rs and current UK/EU regulatory and data-protection frameworks. Emerging bridging strategies, CRISPR-Cas9 models incorporating human-relevant blood-pressure QTLs, iPSC-derived vascular constructs and vessel-on-chip systems, and multi-omics integration with human cohort data are evaluated as routes to reducing translational attrition. It concludes that closing the translational gap requires not only better models but mandatory sex-disaggregated design, rigorous transparent reporting, validated comorbid models, and reform of regulatory and ethical review, an institutional challenge as much as a scientific one.