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Endothelium removal augments endothelium-independent vasodilatation in rat mesenteric vascular bed.

ABSTRACT: BACKGROUND AND PURPOSE: The vascular endothelium regulates vascular tone by releasing various endothelium-derived vasoactive substances to counteract excess vascular response. We investigated whether the vascular endothelium regulates vasodilatation via released endothelium-derived contracting factors (EDCFs), by examining the effect of endothelium removal on responses to periarterial nerve stimulation (PNS) and various vasodilator agents. EXPERIMENTAL APPROACH: The rat mesenteric vascular bed was perfused with Krebs solution. Vasodilator responses to PNS and 5 min perfusion of vasodilator agents in preparations with endothelium were compared with those in the same preparations without endothelium. The endothelium was removed by 30 s perfusion with sodium deoxycholate. KEY RESULTS: Endothelium removal significantly augmented vasodilator responses to PNS and calcitonin gene-related peptide (CGRP), isoprenaline (beta-adrenoceptor agonist), SNP and 8-bromo-cGMP (8-Br-cGMP; cGMP analogue) but not BAY41-2272 (soluble guanylate cyclase activator). The augmentation of SNP-induced vasodilatation after denudation was much greater than that of CGRP- or isoprenaline-induced vasodilatation. In the preparations with an intact endothelium, L-NAME (nitric oxide synthase inhibitor) significantly augmented vasodilator responses to PNS and CGRP, isoprenaline, SNP and 8-Br-cGMP, but not BAY41-2272. Indomethacin (cyclooxygenase inhibitor) and seratrodast (thromboxane A(2) receptor antagonist), but not phosphoramidon (endothelin-1-converting enzyme inhibitor) or BQ-123 (selective endothelin type A receptor antagonists), significantly augmented vasodilator responses to PNS and CGRP, isoprenaline, SNP and BAY41-2272. CONCLUSION AND IMPLICATION: These results suggest that the endothelium in rat mesenteric arteries regulates and maintains vascular tone via counteracting not only vasoconstriction through releasing endothelium-derived relaxing factors, but also vasodilatation, in part by releasing an EDCF, thromboxane A(2).

SUBMITTER: Iwatani Y

PROVIDER: S-EPMC2438989 | biostudies-other | 2008 May

REPOSITORIES: biostudies-other

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Project description:D-pinitol is a cyclitol present in several edible plant species and extensively investigated for the treatment of metabolic diseases in humans, as food supplement, and demonstrated protective effects in the cardiovascular system. For these reasons, the present work aimed at investigating the mechanisms involved in the vascular effects of D-pinitol in mouse mesenteric artery. Mesenteric arteries from male C57BL/6 mice were mounted in a wire myograph. Nitrite was measured by the 2,3-diaminonaphthalene (DAN) method. Protein expression and phosphorylation were measured by Western blot. The systolic blood pressure (SBP) was measured by tail-cuff plethysmography. D-pinitol induced a concentration-dependent vasodilatation in endothelium-intact, but not in endothelium-denuded arteries. N?-Nitro-L-arginine methyl ester (300 ?M) abolished the effect of D-pinitol, while 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 ?M) shifted the concentration-response curve to the right. KN-93 (1 ?M) blunted the vasodilator effect of D-pinitol, but H-89 (0.1 ?M) did not change it. 1-[2-(Trifluoromethyl) phenyl]imidazole (300 ?M), indomethacin (10 ?M), celecoxib (5 ?M), wortmannin (1 ?M), ruthenium red (10 ?M), tiron (10 ?M), MnTMPyP (30 ?M), MPP (0.1 ?M), PHTPP (0.1 ?M), and atropine (1 ?M) did not change the effect of D-pinitol. D-pinitol increased the concentration of nitrite, which was inhibited by L-NAME and calmidazolium (10 ?M). D-pinitol increased the phosphorylation level of eNOS activation site at Ser1177 and reduced the phosphorylation level of its inactivation site at Thr495. In normotensive mice, the intraperitoneal administration of D-pinitol (10 mg/kg) induced a significant reduction of the SBP after 30 min. The present results led us to conclude that D-pinitol has an endothelium- and NO-dependent vasodilator effect in mouse mesenteric artery through a mechanism dependent on the activation of eNOS by the calcium-calmodulin complex, which can explain its hypotensive effect in mice.

Project description:Background and purposeVasodilatation may contribute to the neuroprotective and vascular anti-remodelling effect of the tissue transglutaminase 2 (TG2) inhibitor cystamine. Here, we hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and/or inhibition of Rho kinase underlies cystamine vasodilatation.Experimental approachWe used rat mesenteric small arteries and RT-PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca(2+) ([Ca(2+)]i ), K(+) currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain, in our experiments.Key resultsRT-PCR and immunoblotting revealed expression of TG2 in mesenteric small arteries. Cystamine concentration-dependently inhibited responses to phenylephrine, 5-HT and U46619 and for extracellular potassium. Selective inhibitors of TG2, LDN 27129 and T101, also inhibited phenylephrine contraction. An inhibitor of PLC suppressed cystamine relaxation. Cystamine relaxed and reduced [Ca(2+)]i in phenylephrine-contracted arteries. In potassium-contracted arteries, cystamine induced less relaxation without changing [Ca(2+)]i , and these relaxations were blocked by mitochondrial complex inhibitors. Blockers of Kv 7 channels, XE991 and linopirdine, inhibited cystamine relaxation and increases in voltage-dependent smooth muscle currents. Cystamine and the Rho kinase inhibitor Y27632 reduced basal MYPT1-Thr(855) phosphorylation, but only Y27632 reduced phenylephrine-induced increases in MYPT1-Thr(855) and myosin regulatory light chain phosphorylation.Conclusions and implicationsCystamine induced vasodilatation by inhibition of receptor-coupled TG2, leading to opening of Kv channels and reduction of intracellular calcium, and by activation of a pathway sensitive to inhibitors of the mitochondrial complexes I and III. Both pathways may contribute to the antihypertensive and neuroprotective effect of cystamine.

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Endothelium removal augments endothelium-independent vasodilatation in rat mesenteric vascular bed.

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