Khamira Gaozaban Sada, a Low-Cost Unani Preparation, Alleviates Isoproterenol and L-NAME-Induced Augmented Cardiac...

Cardiac hypertrophy, often a maladaptive response to sustained cardiac workload, can lead to heart failure and increased mortality. Traditional Unani formulation Khamira Gaozaban Sada (KGS) is evaluated for its cardioprotective effects in preclinical models. The objectives are to assess the efficacy of KGS in reducing cardiac workload and preventing pathological remodeling in L-NAME-induced hypertension and isoproterenol (ISO)-induced cardiac hypertrophy models, and to identify its underlying mechanisms and safety profile.

Two doses of KGS (1000 and 2000 mg/kg b.w.) were administered in L-NAME and ISO-induced rat models. Hemodynamic parameters, biochemical markers, histopathological, and echocardiographic assessments were evaluated. Immunohistochemistry for eNOS expression was performed. In vitro, ISO-induced cytotoxicity and calcium overload were assessed in H9C2 cells. CYP inhibition and metabolite docking studies were also conducted.

In the L-NAME model, high-dose KGS reduced SBP and RR intervals and enhanced cardiac eNOS expression, indicating reduced cardiac workload. In the ISO model, high-dose KGS significantly attenuated QTc prolongation, SBP elevation, and biomarker levels and ameliorated myocardial histopathological damage. Echocardiography showed decreased LV mass and wall thickness, confirming reduced cardiac remodeling. In vitro, KGS showed protective effects on H9C2 cells at 200 μg/mL by reducing ISO-induced cytotoxicity and calcium overload. CYP inhibition was minimal. Metabolite profiling identified 19 tentative metabolites; tiliroside and trehalose showed strong docking affinity toward eNOS and β1-adrenergic receptors, respectively.

This study demonstrated that high-dose KGS offers significant cardioprotection by attenuating LNAME- induced hypertension and ISO-induced cardiac hypertrophy through improved eNOS expression, reduced fibrosis, oxidative stress, and intracellular calcium overload. It restored cardiac structure and function, normalized key biochemical markers (Ang-II, NA, Aldosterone, ANP), and enhanced electrical conductance without notable cytotoxicity or CYP enzyme inhibition. LC -MS and docking studies identified bioactive metabolites targeting eNOS and β1 receptors, supporting a multi-target mechanism.

KGS exhibits significant cardioprotective effects by reducing cardiac workload, improving myocardial structure, and attenuating hypertrophic responses. Its low CYP inhibition potential supports its use as an adjuvant therapy for hypertensive and hypertrophic cardiac conditions.