The herbal formula KH-204 is protective against erectile dysfunction by minimizing oxidative stress and improving lipid profiles in a rat model of erectile dysfunction induced by hypercholesterolaemia

The main findings of the present study were as follows: (1) treatment with KH-204 restored erectile function by improving lipid profiles and decreasing oxidative stress in a rat model of ED induced by HC; (2) treatment with KH-204 activated the protein expression of eNOS and nNOS, leading to an increase in NO bioactivity and an improvement in erectile function; and (3) KH-204 treatment decreased 8-OHdG levels, confirming the antioxidant effect of KH-204. Furthermore, the increase in the expression of eNOS, nNOS, and the muscle/collagen ratio with KH-204 treatment is consistent with the antioxidant effect of KH-204.

Although the precise mechanism underlying HC-associated ED has not been clearly elucidated, several studies have reported distinguishing findings in men and animals with HC. These findings included impairment of endothelium-dependent and endothelium-independent relaxations of the corpus cavernosum, decreased cavernosal endothelial cell content, altered smooth muscle cell function, and increased collagen content [10, 31, 32]. These results are thought to be related to oxidative stress damage by HC in the vascular endothelium and erectile tissue [10–12].

HC has been shown to increase the protein expression of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase and to induce eNOS uncoupling in the penis [33]. Activated NAD(P)H oxidase and eNOS uncoupling are known to lead to the formation of vascular superoxide anions, which induces an imbalance between the formation of superoxide anions and the detoxification of superoxide anions by antioxidant defence systems. In addition, superoxide anions may directly inactivate NO and decrease its bioavailability. NO is the most important neurotransmitter mediating the relaxation of the smooth muscle layer present in the corpus cavernosum [13, 19]. NO is an endothelium-derived relaxation factor and plays an important role in the regulation of the bioavailability of NO. NOS exists in three isoforms: nNOS, eNOS, and inducible NOS. NO is produced by eNOS in the endothelium of the corpus cavernosum and penile artery, and it is secreted form nonadrenergic and noncholinergic nerve endings [20]. NO and superoxide anions can react to form reactive nitrogen species, such as the highly toxic molecule peroxynitrite. Peroxynitirite may cause oxidative damage to DNA, proteins, and lipids, as well as eNOS uncoupling, release of vasoconstrictors, apoptosis, tissue injury, and inflammation [34]. Therefore, oxidative stress promoted by an increase in superoxide anions may impair the expression of eNOS and nNOS [14, 15, 22, 23], reduce eNOS activity and NO production [15–17, 22, 23, 35, 36], increase caveolin-1 expression [21] and its interaction with eNOS [11], and dysregulate cGMP signal transduction pathways [12]. Taken together, these findings suggest that ED occurs in HC.

In our study, the rats in the HFC group showed decreased expression of eNOS and nNOS, increased level of 8-OHdG, and decreased muscle/collagen ratio in the corpus cavernosum compared to the control group. These findings suggest that HC due to a high fat and cholesterol diet induced oxidative stress, leading to vascular endothelial and corporal tissue damage. This damage was detected as decreases in the ICP and ICP/MAP ratio compared to control.

The beneficial effects of KH-204, which are due to its antioxidant properties, have been reported in several studies. Bae, et al. found that KH-204 treatment decreased the expression of Rho kinase and increased the expression of cGMP in androgen-deprived rat bladder and that KH-204 may prevent deleterious molecular changes in the bladder of a rat model of LOH [37]. Furthermore, in a cryptorchidism-induced rat model, KH-204 treatment alleviated elevations in the levels of heat shock protein and germ cell apoptosis by reducing oxidative stress [38]. In our study, KH-204 treatment prevented the decrease in the expression of eNOS and nNOS and the ratio of muscle/collagen in corpus cavernosum induced by HC, strongly indicating that KH-204 had a preventive effect on HC-associated vascular endothelium and corpora tissue impairment. In particular, decreased 8-OHdG, a predominant marker of oxidative damage to DNA, seemed to indicate that the antioxidant activity of KH-204 prevented oxidative injury under oxidative stress conditions.

Currently, a phosphodiesterase type5 inhibitor (PDE5i) is widely used for treatment of ED. PDE5i acts to block the degradative action of cGMP-specific phosphodiesterase type5 on cGMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. The most common cause of ED is thought be related to vascular abnormalities caused by endothelial and erectile tissue dysfunction [3, 4], and we demonstrated that the antioxidant effect of KH-204 led to improved erectile function by reducing endothelial and corporal tissue dysfunction from oxidative stress. Therefore, we suggest that KH-204, unlike PED5i, has the potential to therapeutically improve ED by correcting the fundamental cause of ED.

In this study, the group treated with KH204 showed decreased TC, LDL/VLDL-C, and TG and increased HDL-C levels compared to the HFC group. We did not examine, however, why the lipid profile was improved by KH-204 treatment. Although some reports have described the antiobesity and hypolipidemic effects of Lycium chinense Miller and Rubus coreanus Miquel [24, 25], there is little scholarly evidence available that would explain the improvement in lipid profile seen in our study. Thus, further study should be conducted to elucidate the hypolipidemic mechanisms of this formula.