Endothelial nitric oxide attenuates Na⁺/Ca²⁺ exchanger‐mediated vasoconstriction in rat aorta

Abstract

Background and purpose: The Na þ /Ca 2 þ exchanger (NCX) may be an important modulator of Ca 2 þ entry and exit. The present study investigated whether NCX was affected by prostacyclin and nitric oxide (NO) released from the vascular endothelium, as NCX contains phosphorylation sites for PKA and PKG. Experimental approach: Rat aortic rings were set up in organ baths. Tension was measured across the ring with a force transducer. Key results: Lowering extracellular [Na þ ] ([Na þ ] o ) to 1.18 mM induced vasoconstriction in rat endothelium-denuded aortic rings. This effect was blocked by the NCX inhibitor KB-R7943 (2-2-[4-(4-nitrobenzyloxy)phenyl] ethyl isothiourea methanesulphonate; 1 mM). In endothelium-intact aortic rings, decreasing [Na þ ] o did not constrict the aortic rings significantly, but after treatment with the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 1 mM) or the NOS inhibitor L-NAME (N o -nitro-L-arginine methyl ester; 50 mM), a vasoconstriction that was similar in size to that in endothelium-denuded preparations was evident. The vasorelaxation induced by the NO donor sodium nitroprusside sodium nitroprusside dihydrate (30 nM) was the same in the endothelium-denuded aortic rings preconstricted with either low Na þ (1.18 mM), the thromboxane A2 agonist U46619 (9,11-dideoxy-9a, 11a-methanoepoxy prostaglandin F 2a ; 0.1 mM) or high K þ (80 mM). Conclusions and implications:The results suggest that the endothelium inhibits NCX operation via guanylate cyclase/NO. This is stronger than for other constrictors such as phenylephrine and may relate to concomitant NCX-stimulated NO release from the endothelium. This finding may be important where NCX operates in reverse mode, such as during ischaemia, and highlights a new mechanism whereby the endothelium modulates Ca 2 þ homoeostasis in vascular smooth muscle.

Mechanism of glucose-6-phosphate dehydrogenase-mediated regulation of coronary artery contractility

“…Our results show that decreasing extracellular Na ϩ , which forces the NCX to operate in the reverse mode, is sufficient to substantially increase G6PD activity and CA contraction. Reverse-mode Na ϩ /Ca 2ϩ exchange also augments depolarization-induced CA contractions, supporting the idea that it is important for generation of smooth muscle tone (28,39).…”

Intravascular pressure augments cerebral arterial constriction by inducing voltage-insensitive Ca2+waves

“…Arteries were then re‐pressurized and returned to a standard ryanodine–PSS. In a subgroup of these experiments, investigators modified the elevated K + –ryanodine–PSS by replacing NaCl with LiCl (120 or 60 m m ) or NMDG‐Cl (60 m m ) to diminish Na + /Ca 2+ exchanger activity (Raina et al 2008; Zhao & Majewski, 2008).…”

A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity

“…Endothelium-dependent vasorelaxation was performed as previously described (58,59). Female C57BL/6 mouse aortas were dissected and aortic rings were mounted in a myograph apparatus (DMT620M, DMT-USA).…”

“…Then, graded concentrations of acetylcholine (10 -9 -10 -5 moles/liter) were added cumulatively to test endothelium-dependent vasorelaxation. Results were reported as a percentage of PE contraction as previously described (59).…”