The main findings of this study were that long-term treatment with EA delayed hypertension development, and this restored NO in the plasma of SHR. In this study, eNOS expression was also significantly increased by EA in mesenteric artery of SHR, whereas nNOS expression was significantly attenuated.
GV20 alone, or in combination with other acupuncture points, is used for the treatment of hypertension and pre-hypertension patients [9
]. Scalp acupuncture decreases superoxide dismutase activity, reducing the oxidative stress reaction [12
]. Kim et al. [7
] reported that EA treatment on Tsu-san-li (ST36) controlled the NOS system in the stomach and cheek pouch tissues, which were on the stomach meridian, but did not control that in liver tissue, a non-stomach meridian organ in the two-kidney, one-clip renal hypertension hamster model. While examining the distribution of NO in the skin acupuncture points of rats, Chen et al. [13
] showed that l
-arginine-derived NO synthesis appears to mediate noradrenergic function on skin sympathetic nerve activation, which contributes to the skin electrical resistance of acupuncture points and meridians. The hypotensive action of NO induced by EA stimulation remains an unexplained but reproducible observation.
NO is a potent vasodilator that is necessary to maintain BP homeostasis. Similarly Briones et al. [14
] also reported that nNOS expression is greater in mesenteric arteries of SHR than in those of WKY. In contrast, Forte et al. [15
] reported that basal NO synthesis by endothelial cells is reduced in patients with untreated essential hypertension. Furthermore, Hatta et al. [16
] reported that antihypertensive therapy increases the reduced basal NO levels in SHR and DOCA-salt rats. Mokuno et al. [17
] have shown that NO production induced by mechanical stimulation was markedly reduced in 5-week-old SHR at the pre-hypertensive stage, and this impairment of nitric oxide production preceded the onset of hypertension in SHR. These reports support our findings that basal release of NO is reduced in SHR during hypertension.
The vascular generation of oxygen species was increased in development of hypertension [18
] and eNO was rapidly inactivated in the presence of superoxide anions [19
]. Neuronal NO metabolism by superoxide anions in mesenteric arteries from young SHR is also elevated [20
]. Vaziri et al. [21
] also reported that antioxidant therapy ameliorated hypertension and mitigated the upregulation of NOS in vascular and renal tissues. Furthermore, the increased oxidative stress and degradation of NO from eNOS has been described in SHR [22
]. Together, these data suggest that anti-hypertensive treatment restores decreases in NO release by high BP and enhances NOS bioavailability in the aorta.
In hypertension, where intraluminal pressure, shear stress and oxidative stress are increased, augmented nNOS-derived NO may offset decreased eNOS-derived NO, thereby acting as an adaptive mechanism [25
mice showed elevated BP in conscious states [26
], confirming that NO derived from eNOS plays an important role in regulating BP as a vasodilator. But nNOS knockout mice, however, have enlarged stomachs and defects in the inhibitory junction potential involved in gastrointestinal motility, but not hypertension [27
]. In mice lacking functional eNOS(−/−)
, acute injection of a non-selective NOS inhibitor, Nw-nitro-l
-NNA), decreased mean BP [26
], suggesting that NO derived from isoforms other than eNOS increases BP in the absence of eNOS activity [29
]. These results support that the eNOS activation could affect to BPã without abnormally overactivated-nNOS activation inã SHR. Our result shows EA treatments for 3 weeks prefer enhancing eNOS activity to nNOS activity compensated eNOS deactivation.
The autonomic nervous system is involved in the development of hypertension, and chronic imbalance of the autonomic nervous system is a prevalent, potent risk factor for adverse cardiovascular events [30
]. Both increased sympathetic nerve firing rates and reduced neuronal norepinephrine re-uptake contribute to sympathetic activation in hypertension [31
]. Acupuncture stimulation seems to reduce sympathetic nervous system activation via activation of the cholinergic system or opioid receptors in the rostral ventrolateral medulla [4
]. NO in the central nervous system plays a very important role in the control of sympathetic outflow and regulation of cardiovascular activities, and EA stimulation can restore the NOS system in the central nervous system of stress-induced hypertension [33
] and SHR [34
] models. Microinjection of nNOS antisense oligos into the gracile nucleus produces a depressor and inhibitory cardiovascular response to EA stimulation [1
]. Therefore, along with the cited findings, sympatho-inhibition and vasodilation may be induced by EA stimulation in various hypertension models.
It would be interesting to compare this result with clinical therapeutic effects of previous clinical trials. According to previous trials, acupuncture is more effective than sham only when given in addition to medication [11
] and acupuncture alone is not better than sham [36
]. These results can imply both acupuncture and sham acupuncture are effective for lowering BP. The result of our study shows that the suppressive effect of EA on BP seems to be an immediate one, without any cumulative effects. It would be useful to investigate the immediate effects of acupuncture for lowering BP in the future clinical settings.
In conclusion, our results support the concept that EA could attenuate the BP elevation of SHR, along with enhancing NO/NOS activity in the mesenteric artery in SHR. However, future studies are necessary to investigate the underlying NOS mechanisms of the peripheral autonomic nervous system in blood vessels.