molecules Review Overview of Antagonists Used for Determining the Mechanisms of Action Employed by Potential Vasodilators with Their Suggested Signaling Pathways Yean Chun Loh, Chu Shan Tan, Yung Sing Ch’ng, Mariam Ahmad, Mohd Zaini Asmawi and Mun Fei Yam * School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia; [email protected] (Y.C.L.); [email protected] (C.S.T.); [email protected] (Y.S.C.); [email protected] (M.A.); [email protected] (M.Z.A.) * Correspondence: [email protected]; Tel.: +60-4-653-4586 Academic Editor: Derek J. McPhee Received: 27 January 2016; Accepted: 28 March 2016; Published: 15 April 2016 Abstract: This paper is a review on the types of antagonists and the signaling mechanism pathways that have been used to determine the mechanisms of action employed for vasodilation by test compounds. Thus, we exhaustively reviewed and analyzed reports related to this topic published in PubMed between the years of 2010 till 2015. The aim of this paperis to suggest the most appropriate type of antagonists that correspond to receptors that would be involved during the mechanistic studies, as well as the latest signaling pathways trends that are being studied in order to determine the route(s) that atest compound employs for inducing vasodilation. The methods to perform the mechanism studies were included. Fundamentally, the affinity, specificity and selectivity of the antagonists to their receptors or enzymes were clearly elaborated as well as the solubility and reversibility. All the signaling pathways on the mechanisms of action involved in the vascular tone regulation have been well described in previous review articles. However, the most appropriate antagonists that should be utilized have never been suggested and elaborated before, hence the reason for this review. Keywords: vasodilators; antagonists; signaling pathway; blood vessel; vascular tone 1. Introduction Cardiovascular diseases are known to be the number one killer in the world, compared to other diseases such as disorders of the blood vessels and the heart. Hypertension is one of the main causes of cardiovascular diseases, and appropriately named as the silent killer due to it being an asymptomatic disease. In addition, it leads to a variety concomitant diseases, including stroke, heart diseases, kidney failure, cerebrovascular diseases, and more [1].Typically, hypertension has been categorized into four classes by the seventh report of Joint National Committee, which includes the normal and pre-hypertension stages, hypertension stage 1 and hypertension stage 2 [2]. Although there are many kinds of anti-hypertensive drugs present in the market nowadays, most have low effectiveness and undesired chronic side effects. Therefore, finding novel anti-hypertensive drugs is still a topic of huge interest to current researchers. Hypertension is defined as having persistently high pressure exerted throughout the wall of blood vessels [3]. Blood vessels isolated from living organisms are commonly used for the in vitro studies on anti-hypertensive drugs researches [4]. Blood pressure has always been regulated in a narrow range to convey sufficient perfusion for tissues without causing any harm on the vascular system, especially the endothelium and vascular smooth muscle cells. Therefore, it is necessary to Molecules 2016, 21, 495; doi:10.3390/molecules21040495 www.mdpi.com/journal/molecules Molecules 2016, 21, 495 2 of 35 between enzyme-linked, channel-linked, and G-protein coupled receptors. Plenty of reviews and research articles have discussed the probable signaling mechanism pathways involved in vascular Molecules 2016, 21, 495 2 of 34 tone regulation, providing great references for researchers, yet none of those discussed which of the signaling mechanisms pathway are significant, or suggest the most appropriate antagonists that should be utilized in respect to their corresponding receptors during studies of mechanistic pathways focus on understanding the signaling mechanism pathways involved in vascular tone regulation, includingemployed its way by the of test signaling compounds amplification claimed to bybe producingexerting vasodilative second messengerseffects. Therefore, and thethe interactionaim of betweenthis review enzyme-linked, is to provide channel-linked, a general view on and the G-proteintypes of mechanistic coupled receptors.pathways commonly Plenty of employed reviews and researchby those articles researches have discussedthat are related the to probable this topic signaling and the type mechanism of antagonists pathways used. 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Figure 1.Percentage summary of signaling mechanism pathway studies conducted in research on Figure 1. Percentage summary of signaling mechanism pathway studies conducted in research on blood vessel vasodilation published in PubMed from the year 2010 to 2015, as shown in Table 1. There blood vessel vasodilation published in PubMed from the year 2010 to 2015, as shown in Table1. There were a total of 257 published research articles that performed research related to the vasodilation of were a total of 257 published research articles that performed research related to the vasodilation of