Hypertensive cardiac disease remains a major cause of death worldwide because its typically complex etiology renders current treatments ineffective. Primary causative factors include environmental stressors, genetic predisposition and metabolic morbidities such as obesity and diabetes. These factors all trigger a systemic pathological production of agonists of G-protein-coupled receptors (GPCRs). When produced in excess, GPCR agonists transactivate many metalloproteinases, which relay agonist signaling. Here we review evidence supporting a global therapeutic concept for treatment of hypertensive cardiac disease with complex or unknown etiology by targeting common mediators of multiple GPCRs such as metalloproteinases and their downstream effectors.