Low [Mg2+]e enhances arterial spontaneous tone via phosphatidylinositol 3-kinase in DOCA-salt hypertension.
Phosphatidylinositol 3-kinase (PI3K) has been implicated in low extracellular Mg2+ concentration ( [Mg2+]e)-induced aortic contraction, and Mg2+ deficiency has been associated with hypertension. Moreover, arterial PI3K activity is increased in hypertensive deoxycorticosterone (DOCA)-salt rats. We hypothesized that low [Mg2+]e activates PI3K, eliciting enhanced vascular contraction, PI3K activity, and norepinephrine (NE)-induced contraction. Spontaneous tone was monitored in endothelium-denuded aortic strips from sham and DOCA-salt rats exposed to low Mg2+ (0.15 mmol/L), high Mg2+ (4.8 mmol/L), or normal (1.17 mmol/L) physiologic salt solution (PSS) in isolated tissue baths. LY294002 (20 micromol/L), a PI3K inhibitor, or vehicle was added (30 minutes), followed by NE (10(-9) to 3 x10(-5) mol/L). Low [Mg2+]e significantly enhanced tone in aortas from DOCA-salt and sham rats compared with normal PSS (DOCA-salt low [Mg2+]e, +51.5 +7.0 vs DOCA-salt normal PSS, +7.1 +1.4 % of initial phenylephrine [PE] contraction). LY294002 and incubation with high Mg2+ PSS decreased tone in aortas from DOCA-salt rats (low [Mg2+]e LY294002, --87.5 +8.8; normal PSS LY294002, -81.7 +13.7; and high [Mg2+]e, -31.2 +10.8 % of initial PE contraction). Low [Mg2+]e leftward-shifted NE-induced aortic contractions in sham and thus matched the shift observed with DOCA (-log EC50 mol/L: sham PSS, -7.7 +0.1; DOCA-salt PSS, -8.2 +0.1; sham low [Mg2+]e, -8.2 +0.1; and DOCA-salt low [Mg2+]e, -8.1 +0.1). Moreover, this shift was inhibited by LY294002. In conclusion, low [Mg2+]e might activate PI3K, leading to enhanced tone and agonist-induced contraction observed in aortas from DOCA-salt hypertensive rats.
Northcott
Carrie A
CA
Department of Pharmacology and To-icology, Michigan State University, B445 Life Science Bldg, East Lansing, MI 48823, USA. taetscar @msu.edu
Watts
Stephanie W
SW
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000503:physiopathology*; D046508:Culture Techniques; D003900:Desoxycorticosterone; D006973:Hypertension / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D008274:Magnesium / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000187:drug effects
D003900:Desoxycorticosterone; D012965:Sodium Chloride; D019869:Phosphatidylinositol 3-Kinases; D008274:Magnesium; D009638:Norepinephrine