**3. Pathological role of NO**

NO is essential in the maintenance of vascular homeostasis including smooth muscle relaxation, inhibition of platelet aggregation, attenuation of vascular smooth muscle cell (VSMC) proliferation, neurotransmission, and immune defense [12]. Therefore, the impaired NO pathway has been implicated in endothelial dysfunction and pathogenesis of a number of diseases featuring inflammatory reaction. These include arthritis, myocarditis, colitis, and nephritis. Altered NO synthesis has been noted in selected pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases [13, 14]. In general, physiological NO actions on target tissues are brief, reversible, and dependent on the downstream cGMP-dependent signaling events. Conversely, the pathological actions noted with excessively and sustained NO production involved NO interaction with superoxide to generate peroxynitrite, a highly reactive free radical which exhibits the toxic actions of potent oxidants. Peroxynitrite, independent of the cGMP signaling events, has been implicated in oxidative injury noted in a number of disease models [15–17]. In addition to its free radical actions, peroxynitrite inactivates prostacyclin synthase to reduce prostacyclin levels, leading to vascular dysfunction [18].

ADMA, a risk factor for cardiovascular diseases, inhibits NOS to reduce biosynthesis of NO, resulting in impaired blood flow, accelerated atherogenesis, and suppressed angiogenesis [19]. ADMA is involved in the development of endothelial dysfunction. In essential hypertension patients, the L-arginine and ADMA levels are elevated and inversely related to endothelial function [20, 21]. Endothelial function depends on the integrity of eNOS and the availability and vascular signaling of

**75**

*Therapeutic Applications and Mechanisms of YC-1: A Soluble Guanylate Cyclase Stimulator*

NO. In clinical settings, endothelial dysfunction is important because it may develop hypertension and atherosclerosis and therefore is a predictor in ensuing cardiovascular diseases [22]. In hyperhomocysteinemia, an increase in ADMA has been linked to impaired vascular endothelial function. Elevated homocysteine levels exert inhibitory effects on the expression or activation of dimethylarginine dimethylaminohydrolase (DDAH) [23–27]. Two isoforms of DDAH, DDAH-1 and DDAH-2, were identified in tissues expressing nNOS and eNOS, respectively [28]. Both DDAH isoforms are expressed widely in different organs, with higher content found in the liver and kidney [29]. Similarly, endothelial dysfunction has also been found in hypercholesterolemia. Several studies indicated that hypercholesterolemia may cause a decline in DDAH activity and an increase in the ADMA level [30, 31]. Böger et al. also found that exposure of cultured endothelial cells to oxidized low-density lipoprotein (oxLDL) cholesterol resulted in ADMA accumulation in the culture medium [31]. Oxidized LDL could cause endothelial dysfunction in complex mechanisms including reduction of eNOS expression [31], to trigger endothelial apoptosis [32] and to inhibit vascular endothelial growth factor (VEGF)-induced endothelial proliferation [33]. Furthermore, oxLDL impairs NO-induced stimulation of cGMP accumulation [34]. Patients with cardiac syndrome X (CSX) have higher levels of ADMA and increased mean common carotid intima-media thickness that are ascribed to ADMA effects on NO bioavailability resulting in endothelial dysfunction and subsequently impede microvascular circulation, which are the leading mechanisms in the development of CSX [10, 35, 36]. ADMA also plays important roles in endothelial dysfunction in subjects with chronic kidney failure [9, 37, 38]. ADMA is metabolized to L-citrulline *via* the action of DDAH-1, which is highly expressed in the kidney [29]. There is a strong association between impairment of renal function and elevation of ADMA content [9, 39]. Microangiopathy-related cerebral damage (MARCD) is a cerebrovascular disease caused by arteriosclerosis in deep white matter, which includes lacunar infarction and white matter hyperintensity [40]. Arteriosclerosis in deep white matter resulting from acute and chronic ischemia is probably responsible for the development of MARCD [41]. Several potential risk factors for arteriosclerosis have been evaluated in patients with MARCD [42, 43]. NO is involved not only in regulating cerebral blood flow but also in preventing arteriosclerosis by inhibiting fibrosis and proliferation of smooth muscle cells in the arterial wall [44]. In fact, NOS inhibitors and functional single-nucleotide polymorphisms in the eNOS gene have been shown to be correlated with MARCD [44, 45]. Excessive NO production could also be a problem in the progression of the disease such as glaucoma. Increased NO generated by iNOS in astrocytes and microglia in the optic nerve head of patients with glaucoma may contribute to the optic neuropathy associated with this disease. The pharmacological use of an inhibitor of iNOS, aminoguanidine, significantly

*DOI: http://dx.doi.org/10.5772/intechopen.84572*

prevents the loss of retinal ganglion cells [46].

NO-independent manner have been developed.

**4. Novel compounds for NO-independent sGC/cGMP activation**

in clinical practice for more than a century. However, formation of harmful intermediate, peroxynitrite, and the long-term treatment with NO donors resulting in drug resistance limit the clinical applications of NO donor compounds. To overcome these obstacles, the novel agents for triggering sGC/cGMP cascade in

Organic NO donors such as nitrite and nitroglycerin are successful examples

A series of 1-(substituted benzyl)-3-(substituted aryl)-condensed pyrazole derivatives were synthesized and identified as class novel antiplatelet agents [47, 48]. As one of the most promising analogues, 1-benzyl-3-(5′-hydroxymethyl-2′-furyl)

#### *Therapeutic Applications and Mechanisms of YC-1: A Soluble Guanylate Cyclase Stimulator DOI: http://dx.doi.org/10.5772/intechopen.84572*

NO. In clinical settings, endothelial dysfunction is important because it may develop hypertension and atherosclerosis and therefore is a predictor in ensuing cardiovascular diseases [22]. In hyperhomocysteinemia, an increase in ADMA has been linked to impaired vascular endothelial function. Elevated homocysteine levels exert inhibitory effects on the expression or activation of dimethylarginine dimethylaminohydrolase (DDAH) [23–27]. Two isoforms of DDAH, DDAH-1 and DDAH-2, were identified in tissues expressing nNOS and eNOS, respectively [28]. Both DDAH isoforms are expressed widely in different organs, with higher content found in the liver and kidney [29]. Similarly, endothelial dysfunction has also been found in hypercholesterolemia. Several studies indicated that hypercholesterolemia may cause a decline in DDAH activity and an increase in the ADMA level [30, 31]. Böger et al. also found that exposure of cultured endothelial cells to oxidized low-density lipoprotein (oxLDL) cholesterol resulted in ADMA accumulation in the culture medium [31]. Oxidized LDL could cause endothelial dysfunction in complex mechanisms including reduction of eNOS expression [31], to trigger endothelial apoptosis [32] and to inhibit vascular endothelial growth factor (VEGF)-induced endothelial proliferation [33]. Furthermore, oxLDL impairs NO-induced stimulation of cGMP accumulation [34]. Patients with cardiac syndrome X (CSX) have higher levels of ADMA and increased mean common carotid intima-media thickness that are ascribed to ADMA effects on NO bioavailability resulting in endothelial dysfunction and subsequently impede microvascular circulation, which are the leading mechanisms in the development of CSX [10, 35, 36]. ADMA also plays important roles in endothelial dysfunction in subjects with chronic kidney failure [9, 37, 38]. ADMA is metabolized to L-citrulline *via* the action of DDAH-1, which is highly expressed in the kidney [29]. There is a strong association between impairment of renal function and elevation of ADMA content [9, 39]. Microangiopathy-related cerebral damage (MARCD) is a cerebrovascular disease caused by arteriosclerosis in deep white matter, which includes lacunar infarction and white matter hyperintensity [40]. Arteriosclerosis in deep white matter resulting from acute and chronic ischemia is probably responsible for the development of MARCD [41]. Several potential risk factors for arteriosclerosis have been evaluated in patients with MARCD [42, 43]. NO is involved not only in regulating cerebral blood flow but also in preventing arteriosclerosis by inhibiting fibrosis and proliferation of smooth muscle cells in the arterial wall [44]. In fact, NOS inhibitors and functional single-nucleotide polymorphisms in the eNOS gene have been shown to be correlated with MARCD [44, 45]. Excessive NO production could also be a problem in the progression of the disease such as glaucoma. Increased NO generated by iNOS in astrocytes and microglia in the optic nerve head of patients with glaucoma may contribute to the optic neuropathy associated with this disease. The pharmacological use of an inhibitor of iNOS, aminoguanidine, significantly prevents the loss of retinal ganglion cells [46].
