A Comparative Study of Vasorelaxant Effects of ATP, ADP, and Adenosine on the Superior Mesenteric Artery of SHR

Abstract

We investigated superior mesenteric arteries from spontaneously hypertensive rats (SHR) to determine the relaxation responses induced by ATP, ADP, and adenosine and the relationship between the relaxant effects of these compounds and nitric oxide (NO) or cyclooxygenase (COX)-derived prostanoids. In rat superior mesenteric artery, relaxation induced by ATP and ADP but not by adenosine was completely eliminated by endothelial denudation. In the superior mesenteric arteries isolated from SHR [vs. age-matched control Wistar Kyoto rats (WKY)], a) ATP-and ADP-induced relaxations were weaker, whereas adenosine-induced relaxation was similar in both groups, b) ATP-and ADP-induced relaxations were substantially and partly reduced by N G -nitro-L-arginine [a NO synthase (NOS) inhibitor], respectively, c) indomethacin, an inhibitor of COX, increased ATP-and ADP-induced relaxations, d) ADP-induced relaxation was weaker under combined inhibition by NOS and COX, and e) adenosine-induced relaxation was not altered by treatment with these inhibitors. These data indicate that levels of responsiveness to these nucleotides/adenosine vary in the superior mesenteric arteries from SHR and WKY and are differentially modulated by NO and COX-derived prostanoids.Key words adenosine; ADP; ATP; relaxation; spontaneously hypertensive rat Extracellular nucleotides and their metabolites including ATP, ADP, and adenosine play pivotal roles in (patho)-physiological processes, including immune responses, inflammation, cardiac fibrosis, atherosclerosis, hypertension, and diabetes.1-10) They also exert a variety of effects on the vasculature, such as platelet activation and alteration in smooth muscle contraction and relaxation, by activating plasmalemmal receptors (e.g., purinoceptors). 1,2,8,11,12) Purinoceptors are classified into two subtypes, namely P1 and P2, based on their pharmacological properties and molecular cloning characteristics.11,12) Adenosine and its phosphates ATP and ADP are endogenous ligands for P1 and P2 receptors, respectively. Several studies have suggested that the expression and signaling responses of these receptors is altered under disease conditions. 4,11,[13][14][15][16][17] Moreover, these receptors can mediate a variety of responses to several nucleotides, resulting in the existence of multiple receptors with overlapping ligand preferences. 11,18)Therefore, it is difficult to understand the effect of nucleotides on vascular function under pathophysiological conditions. Hypertension is a leading risk factor for cardiovascularassociated morbidity and mortality. An important and contributory element in sustained hypertension is an increase in vascular tone, potentially resulting from concurrently reduced relaxation and augmented contraction induced by various endogenous ligands. [19][20][21][22][23][24][25][26] Hypertension-associated vascular dysfunction is partly regulated by endothelium-derived factors. [21][22][23][24] There is a fine balance between endothelium-derived relaxing and contracting factors, a disturba...

Trimethylamine-<i>N</i>-oxide Specifically Impairs Endothelium-Derived Hyperpolarizing Factor-Type Relaxation in Rat Femoral Artery

“…11) Thus, we further explored the possible role of EDHF-mediated relaxation induced by ACh in both arteries because this has been reported to partly contribute to AChinduced relaxation in arteries. 14,15,19) A novel, intriguing, and potentially important finding made in the present study is the presence of a specific impairment of EDHF-type relaxation in rat femoral arteries but not in rat superior mesenteric arteries. This idea is supported by several pieces of evidence.…”

“…The concentration-relaxation responses of the vascular function in the superior mesenteric arteries and femoral arteries were determined by measuring the isometric force as reported previously. [14][15][16] The superior mesenteric artery and femoral arteries were rapidly isolated from the rats under isoflurane-induced anesthesia and immersed in oxygenated, modified Krebs-Henseleit solution (KHS; composition in mmol/L: NaCl 118.0, KCl 4.7, NaHCO 3 25.0, CaCl 2 1.8, NaH 2 PO 4 1.2, MgSO 4 1.2, and glucose 11.0). Subsequently, the artery was cleaned and cut into rings (length, 2 mm), suspended in a well-oxygenated (95% O 2 , 5% CO 2 ) bath containing KHS at 37°C, and maintained at a resting tension of 1.0 g (superior mesenteric artery) or 0.5 g (femoral artery).…”

“…Isometric tension was recorded using an isometric force-displacement transducer connected to an acquisition system. [14][15][16] To assess the acute effects of TMAO on the relaxation responses, we incubated arterial rings with or without 300 µmol/L TMAO for 60 min before applying phenylephrine (PE) or serotonin (5-HT) to the superior mesenteric artery or femoral artery, respectively. We used TMAO at 300 µmol/L because several reports have demonstrated that this concentration of TMAO deteriorates the functions.…”

“…The arteries also often exhibited endothelial dysfunction under pathophysiological states, including hypertension. 15,16)…”

Reduced Relaxant Response to Adenine in the Superior Mesenteric Artery of Spontaneously Hypertensive Rats

“…9) However, little attention has been given to adenine-mediated vasomotion in hypertension. Therefore, this study examined the vasorelaxant effects of adenine in the superior mesenteric arteries obtained from spontaneously hypertensive rats (SHR), a representative hypertensive animal model, [13][14][15] and its control, Wistar Kyoto (WKY) rats.…”