Pharmacological interactions of carvedilol and curcumin nanomicelles in spontaneously hypertensive rats: a bliss and HSA analysis.

Hypertensive target organ damage (TOD), including cardiac fibrosis, vascular remodeling, and low-grade inflammation, is driven by oxidative stress and proinflammatory cytokines. We previously demonstrated that acute carvedilol-curcumin co-administration in a Soluplus® nanomicellar formulation synergistically reduces mean arterial pressure in spontaneously hypertensive rats (SHR). However, the chronic protective effects of this combination on TOD remain unknown. The aim of this study to evaluate whether 8-week co-administration of carvedilol and curcumin in a Soluplus® nanomicellar system exerts synergistic effects on carotid SBP, aortic remodeling, cardiac inflammation, and oxidative stress in SHR and to quantify the drug interaction using the Bliss independence model. SHR received carvedilol (9 mg/kg/day), curcumin (6 mg/kg/day), their combination, or vehicle for 8 weeks. We measured (i) hemodynamics (tail-cuff and carotid SBP, beat-to-beat and short-/medium-term blood pressure variability); (ii) aortic and ventricular fibrosis (histomorphometry); (iii) oxidative stress (protein carbonyls, TBARS); and (iv) cardiac TNF-α, IL-6, and TGF-β (Western blot). We assessed synergy using Bliss independence analysis and the Highest Single Agent (HSA) model. The Bliss analysis revealed antagonistic interactions for cardiac fibrosis and cardiac TBARS, and additive interactions for TGF-β, aortic carbonyls, and aortic TBARS. The HSA analysis revealed that IL-6, TNF-α, and cardiomyocyte size showed additive/independent effects, while aortic fibrosis showed a synergistic interaction (ΔE_HSA =  + 22.22%, p < 0.0001). No synergistic interactions were observed for other parameters. However, the combination still significantly reduced all these parameters compared to vehicle-treated SHR. Chronic co-administration of carvedilol and curcumin in Soluplus® nanomicelles produced a synergistic antifibrotic effect on the aorta, while other parameters showed additive, independent, or antagonistic interactions. The combination preserved the beneficial effects of the monotherapies on oxidative stress and fibrosis, suggesting that the co-administration still provides target organ protection, although not through broad synergistic mechanisms.