4 4. NO Insufﬁciency Is the Root Cause of CVD CVD is a group of disorders including congestive heart failure (CHF) and ischemic heart disease that are becoming the leading cause of morbidity and mortality in the world [33, 34]. CVD can result from a quantitative or functional NO deﬁciency that can limit NO-dependent signal transduc- tion pathways to the detriment of normal cellular function. NO formation by endothelial NO synthase (eNOS) plays an important role in the regulation of vasomotor tone in the pulmonary and systemic vascular beds [35–37]. However, NO generation by eNOS may be rapidly depleted in ischemic conditions, since eNOS is dependent upon the availability of oxygen [38, 39]. Loss of endogenous NO activity has a num- ber of detrimental actions, most notably, vasoconstriction, increased activity and adherence of platelets, and accumu- lation of inﬂammatory cells at sites of endothelial damage. Endothelial damage is associated with most forms of CVD. NO possesses a number of physiological properties that make it a potent cardioprotective-signaling molecule [40]. First, NO is a potent vasodilator [41], which allows for regulation of blood ﬂow and essential perfusion of tissue as needed. Secondly, NO reversibly inhibits mitochondrial respiration [42]. The inhibition of mitochondrial respiration during an ischemia-reperfusion event such as heart attack or stroke counterintuitively leads to a decrease in mitochondrial- driven injury by extending the zone of adequate tissue cellular oxygenation away from vessels [43]. Thirdly, NO is a potent inhibitor of neutrophil adherence to vascular endothelium [44]. Neutrophil adherence is an important event initiating further leukocyte activation and superoxide radical generation, which in turn leads to injury to the endothelium and perivascular myocardium in the ischemic heart [45]. Fourth, NO also prevents platelet aggregation [46], which together with the antineutrophil actions of NO attenuates capillary plugging [47]. Finally NO inhibits apop- tosis directly or indirectly by inhibiting caspase-3-like acti- vation via a cGMP-dependent mechanisms and/or through protein S-nitrosylation [48, 49]. Without suﬃcient NO production, the body loses its ability to regulate and control normal vascular function. Therefore, strategies designed to enhance NO production and reduce reactive oxygen species production will likely limit injury and improve recovery from CVD or perhaps even prevent onset and progression of CVD. 5. Therapeutic Effects and Nitric Oxide Bioactivity of TCM Traditional herbal medicines used for thousands of years in Asia and other regions have been proven eﬀective in certain cardiovascular disorders. Some of the herbal medicines have profound NO bioactivity primarily due to the nitrate- nitrite-NO reduction pathway [32]. They contain very large amounts of nitrate/nitrite in the extracts given to patients [32]. The described beneﬁts of these ancient medications may be attributed to their inherent nitrate/nitrite content combined with their robust nitrate/nitrite reductase activity to generate NO independent of the L-arginine-NO pathway Evidence-Based Complementary and Alternative Medicine [14, 26, 32, 50]. The ﬁrst use of nitrate for treatment of pa- tients with symptoms that appears to be angina was des- cribed in an 8th century Chinese manuscript uncovered at the Buddhist grotto of Dunhuang [51]. The patients were instructed to take Xiao Shi Xiong Huang San, hold it under the tongue for a time, and then swallow the saliva. The sig- niﬁcance of the instructions is that under the tongue, even in a healthy mouth, nitrate-reducing bacteria convert some of the nitrate into nitrite. Therefore, if the patient follows the physician’s instructions fully, he or she will be taking nitrite, known to be eﬀective in alleviating pain resulting from angina. Chinese physicians in traditional medicine have more recently tested the therapeutic eﬀects of Xiao Shi Xio- ng Huang San (the Nitrum and Realgar Powder), one of the Dunhuang prescriptions, on angina pectoris caused by coro- nary heart disease. Compared to nitroglycerin, Xiao Shi Xiong Huang San showed much higher eﬃcacy and improve- ment in a clinical trial of 61 patients [52]. Recently, the research results demonstrate that certain TCM increased NO release in rat vascular endothelial cells under hypoxia [53]. Puriﬁed ginsenoside Rg1 enhanced the production of NO from IFN-gamma-activated-macrophage cells RAW 264-7 [54]. Mu-Fang-Ji-Tang (TJ-36), a traditional Chinese her- bal medicine, is made from four natural traditional Chi- nese drugs: Panax ginseng radix, Cinnamomum cassia, Sinomenum acutum, and Gypsum ﬁbrosum, which is said to have been used for more than 1800 years to treat heart failure in China. Recent studies have shown that Mu-Fang-Ji- Tang (TJ-36) had protective eﬀects against myocardial injury in a murine model of congestive heart failure induced by viral myocarditis [55]. Our studies have provided convincing evi- dence that many of these TCM contain signiﬁcant amounts of nitrate and nitrite and also active nitrite reductase activity in certain herbs known to have protective or therapeutic beneﬁts to patients with CVD (Table 1), such as the Danshen Root (radix salviae miltiorrhizae), Sanchi (radix notogin- seng), and Hongshen (radix ginseng) [32]. These herbs, with speciﬁc indications for cardiovascular disease can generate NO from nitrite, and relax blood vessels. The therapeutic beneﬁts of these herbal medicines are providing an alterna- tive source of NO to patients that may be unable to make NO from L-arginine owing to endothelial dysfunction. There is an endogenous nitrite reductase activity in animal tissues, such as the liver and aorta, but this inherent biological capacity is low (around 1 pmoL/mg protein). The reductase activity in some of these herbal medicines may exceed that detected in the animal tissues [32]. It is estimated that the increased reductase activity may occur by orders of magni- tude, almost 1000 times higher than endogenous production of NO. This would equate to 300 nmoles per day of NO from a single herbal preparation. The average NO production in the human body (70 kg) is 1.68 mmoL NO per day (based on an NO production rate of 1 μmoL/kg/h). By supplying the exogenous nitrate/nitrite and reductase activities, herbal medicines oﬀer an alternative therapeutic strategy to combat or treat any condition related to NO insuﬃciency including heart disease and hypertension. Maintaining NO homeosta- sis requires the repletion of nitrite and nitrate through which the ability to generate NO can be restored to compensate