Vasorelaxant

Atrial Natriuretic Factor. Atrial natriuretic factor (ANF) has natriuretic, vasorelaxant, and diuretic properties (142). It was originally discovered in atrial tissue, from which extracts were made and subsequendy injected systematically. The responses evoked from the atrial extracts estabhshed the heart as an endocrine organ. 

Wang R, Wang ZZ, Wu L (1997) Carbon monoxide-induced vasorelaxation and the underlying mechanisms. BrJ Pharmacol 121 927-934... 

S1P3 Ubiquitous Gj/o. Gq, G12/13 Heart rate J, vascular development, NO-dependent vasorelaxation... 

Mitochondria KATP channels Cardiac KATP channel opening has a role in myocardial preconditioning, a paradoxical form of cardioprotection wherein brief ischemic episodes can protect the heart from subsequent lethal ischemic injury. Openers including BMS-180448 and BMS-191095 have been reported to possess preferential cardioprotective effects over vasorelaxant effects by activating mitochondria KAXP channels. 

The vasorelaxant activity, which was assessed as the inhibition of calcium-induced contraction of K-depolarised rat aorta has a IC50 of 3368 tiM compared with 5.6 nM for SR 33557. 

L-type calcium channels (voltage-gated calcium channels L-subtype) Similarity to Diltiazem and a second ligand. ZINC db ( 50 K commercially available subset screened but most filtered to achieve desired PK profile using VolSurf). SHOP similarity, and feature-presence filtering down to 36 compounds 7 hits 18 tested, active in a vasorelaxant assay and some had novel structures. [67]... 

The plant is strongly aromatic on account of an essential oil which comprises cis-a-ocimene (25.11%), 3,7-dimethyl-l,6-octadien-3 ol (16.85%), and trans-nerolidol (13.89%), hence the use of the plant in aromatherapy. A methanolic extract of bark of Litsea cubeba (Lour.) Pers. and its fractions (0.01 mg/mL) from bark inhibit NO and PGE2 production in LPS-activated RAW 264.7 macrophages without significant cytotoxicity at less than 0.01 mg/mL concentration. The methanol extract decreased the enzymatic activity of myeloperoxidase (0.05 mg/mL). These findings suggest that L. cubeba is beneficial for inflammatory conditions and may contain compound(s) with anti-inflammatory properties (63). Can we expect the vasorelaxant laurotetanine (64) isolated from the plant to exert such activity ... 

Chen WY, Ko FN, Wu YC, Lu ST, Teng CM. Vasorelaxing effect in rat thoracic aorta caused by laurotetanine isolated from Litsea cubeba Persoon. J Pharm Pharmacol 1994 46 380-382. 

The group of Caliendo and coworkers has described a multistep synthesis of benzoxazine libraries, in the context of a search for compounds with vasorelaxant activity related to cromakalim [454]. As highlighted in Scheme 6.264, all of the required synthetic manipulations were carried out under microwave irradiation conditions. In all cases, a reduction in reaction time as compared to the corresponding thermal protocols was reported. 

FIGURE 8.11 II S mediated vasorelaxation. Rat aorta segments suspended in an organ bath containing the miniature PHSS and equilibrated with 40pM 02 are stimulated to constrict with lOOnM phenylephrine (PE). Subsequent addition of H2S causes an immediate relaxation event that gradually recovers as the H2S is oxidized or removed by the gas perfusion stream. Repeated additions of H2S at physiologically relevant concentrations demonstrate a predictable kinetic response. 

W. Zhao and R. Wang, H2S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am. J. Physiol. Heart Circ. Physiol. 283, H474-H480 (2002). 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

TBTC1 produced a dose-dependent inhibition of ANP on vascular smooth muscle responses with an effect on norepinephrine, nitroprusside and atrial natriuretic peptide in isolated aortic rings of rats. The inhibition of vasorelaxation was accompanied by a parallel inhibition of ANP-induced cGMP generation29. 

Fig. 4.1. Cellular model illustrating cell types in vascular wall involved in vasorelaxation induced by SERMs. Putative targets of SERMs are indicated within cyan tags. SERMs directly affect L-type VDCC, BK fil subunit in smooth muscle cells, and ER in endothelial cells. L-type VDCC L-type voltage-dependent calcium channel BK calcium-activated large conductance K+ channel PKG protein kinase G eNOS endothelial nitric oxide synthase GC soluble guanylate cyclase cGMP cyclic GM P V electrochemical membrane potential ER estrogen receptor. See text for further details...

Christopher TA, Lopez BL, Stillwagon JC, Gao F, Gao E, Ma XL, Ohlstein EH, Yue TL (2002) Idoxifene causes endothelium-dependent, nitric oxide-mediated vasorelaxation in male rats. Eur J Pharmacol 446(1-3) 139-143... 

Idoxifene causes endothelium-dependent, nitric oxide-mediated vasorelaxation in male rats. Eur J Pharmacol 446 139-143... 

Scheme 2.1 Simplified mechanism whereby organic nitrates (RONO2) effect vasorelaxation. Thiols (R -SH) interact with organic nitrates to give nitrite (NO2-), which is converted successively to nitrous acid (HONO) and NO. NO then reacts with a thiol (R11 —SH) to give a nitrosothiol...

Despite these positive findings, results from inhibitor studies are controversial. Thus, sulphobromophthalein, a known inhibitor of glutathione-S-transferase [42] has been reported both to inhibit [43] and not to inhibit [44—47] vasorelaxation by GTN, while other findings [48] favored involvement of the enzyme in GTN metabolism of cultured smooth muscle cells. 

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