Screening of Antianginal Drugs

Screening of Antianginal Drugs

1. Definition, rationale & the screening cascade

• Antianginal / anti-ischaemic drug screening is the ordered set of in-vitro, ex-vivo and in-vivo assays used to detect and quantify a candidate molecule's ability to relieve the myocardial oxygen supply–demand imbalance that underlies angina pectoris — either by dilating coronary vessels (increasing supply), by reducing cardiac work (lowering demand), or by conferring direct cytoprotection against ischaemia–reperfusion injury (Vogel V1 Part I, Coronary Drugs pp.165–205).
• The pharmacological target of an antianginal agent is the coronary circulation and the ischaemic myocardium; therefore screening models are built to reproduce, in a graded and reproducible way, one or more of: coronary vasospasm/constriction, fixed coronary stenosis, acute coronary occlusion (regional ischaemia/infarction), or catecholamine-driven demand-ischaemia (Vogel V1 Part I pp.165–205).
• The screening cascade moves from simplest and highest-throughput to most predictive but lowest-throughput (Vogel V1 Part I pp.165–205; Medhi Ch.19 pp.207–216):
  • In-vitro / isolated-organ — isolated coronary artery rings/strips, isolated atria, isolated perfused whole heart (Langendorff / working-heart). Advantages: mechanism-directed, no confounding reflexes, small compound quantities, dose–response construction; limitation: loss of in-vivo neurohumoral and haemodynamic context.
  • In-vivo small-animal — isoprenaline-induced myocardial necrosis, coronary-artery ligation in rat/mouse, ST-segment models. Advantages: intact reflexes, integrated response; moderate throughput.
  • In-vivo large-animal — coronary occlusion / stenosis in anaesthetised or conscious dog and pig, microsphere embolisation, pacing- and treadmill-exercise-induced ischaemia. Highest translational fidelity; used for lead confirmation and haemodynamic profiling.
• Reference (standard) antianginal drugs run in parallel in every assay to validate model sensitivity and to benchmark potency: nitroglycerin (glyceryl trinitrate) and the sydnonimine NO-donors molsidomine / SIN-1 (nitrate class); propranolol (β-blocker, 5 mg/kg s.c. as the coronary-ligation standard); nifedipine, diltiazem, verapamil, amlodipine (calcium-channel blockers); and the K⁺(ATP)-channel opener / nitrate-hybrid nicorandil (a "new antianginal agent") (Vogel V1 Part I pp.165, 172, 181–183, 191; nicorandil vs nitroglycerin comparison p.68/pp.190-92).
• Modern clinically-used comparators such as ranolazine (late-Na⁺-current inhibitor) and nicorandil are validated against the same endpoints, allowing new mechanisms to be positioned relative to established therapy — correlating bench readouts (coronary flow, ST-shift, infarct size) with the clinical antianginal endpoints of exercise tolerance and ST-segment depression. Ranolazine is used chiefly as a clinical mechanistic comparator here; a dedicated ranolazine-specific late-Na⁺-current screening protocol is a self-sourced primary-methods addition (see the Recent Advances layer for its bench assay handle).