Many studies have shown that alterations in the gut microbiota are associated with hypertension. Our study aimed to observe the characteristics of the gut microbiota in hypertension and to further explore whether drug molecules can play a therapeutic role in hypertension by interfering with the gut microbiota. We evaluated the differences in the composition of the gut microbiota in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Meanwhile, three first-line cardiovascular disease (CVD) drugs, losartan, atorvastatin, and aspirin, were used to treat the SHR in order to observe their effects on the gut microbiota in SHR. The 16S rDNA results showed that the diversity and richness of the gut microbiota in SHR were significantly reduced compared with that of the WKY, the Firmicutes/Bacteroidetes ratio was increased, the abundances of Bifidobacterium and short chain fatty acids (SCFAs)-producing bacteria decreased, and the abundance of lactate-producing bacteria increased. In addition to lowering the blood pressure, losartan increased the abundances of Alistipes, Bacteroides, and Butyricimonas in SHR, reduced the abundances of Ruminococcaceae, Streptococcus, and Turicibacter, reduced the Firmicutes/Bacteroidetes ratio, and rebalanced the gut microbiota. Losartan also increased the abundances of Bifidobacterium and SCFAs-producing bacteria and reduced the abundance of lactate-producing bacteria. However, atorvastatin and aspirin had no significant effect on the gut microbiota in SHR. The above results showed that losartan could change the characteristics of the gut microbiota in hypertension and rebalance the gut microbiota, which may be related to lowering the blood pressure. Atorvastatin and aspirin have no significant influence on the gut microbiota in SHR.

Inhomogeneity is a key factor that significantly influences the dissolution behavior of amorphous solid dispersion (ASD). However, the underlying mechanisms of the effects of inhomogeneous phase on the dissolution characteristics as well as the bioavailability of ASDs are still unclear. In this study, two types of felodipine/PVPVA based ASDs with 30 wt % drug loading but different homogeneity were prepared: homogeneous "30 wt % ASD" prepared by spray drying, as well as inhomogeneous "30 wt % PM" prepared by physically mixing the sprayed dried 70 wt % ASD with PVPVA. We aimed to investigate (1) drug−polymer interaction mechanism and "apparent" interaction strength within the two ASDs and (2) dissolution mechanism as well as in vivo performance of the two ASDs. DSC thermogram revealing a single T g in 30 wt % ASD confirmed its homogeneous phase. 1 H NMR, FT-IR, and DVS studies collectively proved that strong hydrogen bonding interactions formed between felodipine and PVPVA in ASDs. Moreover, homogeneous "30 wt % ASD" has more numbers of interacting drug−polymer pairs, and thus exhibits stronger "apparent" interaction strength comparing with that of inhomogeneous "30 wt % PM". Unexpectedly,in the in vitro dissolution studies, inhomogeneous "30 wt % PM" showed much faster dissolution and also generated drug concentration ∼4.4 times higher than that of homogeneous "30 wt % ASD". However, drug precipitate recrystallized much slower in homogeneous "30 wt % ASD", presumably because much more polymer coprecipitated with amorphous drug in this system, which helps inhibiting drug crystallization. Surprisingly, homogeneous "30 wt % ASD" showed a significantly higher bioavailability in the in vivo pharmacokinetic studies, with the maximum plasma concentrations (C max ) and the area under the curve (AUC) values of about 2.7 and 2.3 times higher than those of inhomogeneous "30 wt % PM". The above findings indicated that the amorphous state of drug precipitate contributes significantly to increase bioavailability of ASDs, while traditional in vitro dissolution studies, for instance, if we only compare the dissolved drug in solution or the capability of an ASD to generate supersaturation, are inadequate to predict in vivo performance of ASDs. In conclusion, the phase behavior of ASDs directly impact the formation of drug−polymer interaction, which controls not only drug supersaturation in solution but also drug crystallization in precipitate, and ultimately affect the in vivo performance of ASDs.

Hypertension in adolescents is associated with adverse cardiac and vascular events. In addition to lowering blood pressure, it is not clear whether pharmacological therapy in early life can improve vascular remodeling. This study aimed to evaluate the effects of long-term administration of losartan, aspirin, and atorvastatin on vascular remodeling in juvenile spontaneously hypertensive rats (SHRs). Losartan, aspirin, and atorvastatin were administered via gavage at doses of 20, 10, and 10 mg/kg/day, respectively, on SHRs aged 6–22 weeks. Paraffin sections of the blood vessels were stained with hematoxylin-eosin (H&E) and Sirius Red to evaluate the changes in the vascular structure and the accumulation of different types of collagen. The plasma levels of renin, angiotensin II (Ang II), aldosterone (ALD), endothelin-1 (ET-1), interleukin-6 (IL-6), and neutrophil elastase (NE) were determined using ELISA kits. After the 16-week treatment with losartan, aspirin, and atorvastatin, the wall thickness of the thoracic aorta and carotid artery decreased. The integrity of the elastic fibers in the tunica media was maintained in an orderly manner, and collagen deposition in the adventitia was retarded. The plasma levels of renin, ALD, ET-1, IL-6, and NE in the SHRs also decreased. These findings suggest that losartan, aspirin, and atorvastatin could improve vascular remodeling beyond their antihypertensive, anti-inflammatory, and lipid-lowering effects. Many aspects of the protection provided by pharmacological therapy are important for the prevention of cardiovascular diseases in adults and older adults.