Screening of Antianginal Drugs

Introduction & screening cascade

• Definition — Antianginal / anti-ischaemic drug screening is the ordered set of in-vitro, ex-vivo and in-vivo assays that detect and quantify a candidate's ability to correct the myocardial oxygen supply–demand imbalance underlying angina — by dilating coronary vessels (supply), reducing cardiac work (demand), or conferring cytoprotection against ischaemia–reperfusion injury.
• Target — Models are built to reproduce, in a graded reproducible way, one or more of: coronary vasospasm/constriction, fixed coronary stenosis, acute coronary occlusion (regional ischaemia/infarction), or catecholamine-driven demand-ischaemia.
• Screening cascade — Runs from simplest/highest-throughput to most predictive/lowest-throughput:
  • In-vitro / isolated-organ — coronary rings/strips, isolated atria, isolated perfused heart (Langendorff/working-heart); mechanism-directed, no confounding reflexes, small compound quantities, dose–response construction; loses in-vivo neurohumoral context.
  • In-vivo small-animal — isoprenaline necrosis, coronary ligation in rat/mouse, ST-segment models; intact reflexes, integrated response, moderate throughput.
  • In-vivo large-animal — coronary occlusion/stenosis in dog/pig, microsphere embolisation, pacing- and treadmill-induced ischaemia; highest translational fidelity for lead confirmation.
• Reference standards — Run in parallel in every assay to validate model sensitivity and benchmark potency: nitroglycerin and the NO-donors molsidomine/SIN-1; propranolol (β-blocker, 5 mg/kg s.c. coronary-ligation standard); the CCBs nifedipine, diltiazem, verapamil, amlodipine; and the K(ATP)-opener / nitrate-hybrid nicorandil; ranolazine and nicorandil position new mechanisms against established therapy.