Screening Methods for Antihypertensive Drugs

Introduction & rationale

• Definition — Antihypertensive drug screening is the staged preclinical battery — in-vitro vascular/enzyme assays → in-vivo induced & genetic hypertension models → blood-pressure read-outs — used to detect, quantify and rank the BP-lowering activity of a candidate molecule before clinical testing.
• Why animal models — the aetiology of human essential hypertension is unknown and multifactorial, so no single model reproduces the human disease; each model instead isolates one mechanistic driver — renal ischaemia, mineralocorticoid excess, sympathetic drive, genetic background or NO deficiency — to interrogate pathophysiology, end-organ damage and treatment.
• Validity ceiling — extrapolation from any experimental model to human hypertension demands caution — rat models "mainly share high blood pressure" but diverge widely in biochemistry, course and prognosis.
• Screening cascade (tiered) — Tier 1 in-vitro/isolated tissue (aortic-ring relaxation, ACE inhibition, Ang-II antagonism, renin inhibition — mechanism-defining, high-throughput, low animal cost) → Tier 2 acute in-vivo functional (pithed rat, acute Goldblatt 2K1C 4-h clip) → Tier 3 chronic established hypertension (1K1C/2K2C, DOCA-salt, Ang-II infusion, L-NAME, genetic SHR/Dahl) — animal cost and translational relevance rise down the cascade.
• Reference standards — validated standard antihypertensives are used to validate the screen (not as its targets): endralazine, nifedipine, urapidil (tail-cuff conscious-rat standards), captopril, enalapril, ramipril (ACE-inhibition standards) and losartan (AT₁-antagonist standard).
• Key endpoints — % reduction in systolic/mean BP vs pre-drug control, duration of effect, ID₅₀/IC₅₀, potency ratio, pA₂/Schild slope (in-vitro antagonism), plasma renin activity (PRA), plasma/tissue angiotensin II, and end-organ measures (cardiac mass, proteinuria, glomerulosclerosis, endothelium-dependent relaxation).