title: Increased arterial smooth muscle Ca2+ signaling, vasoconstriction, and myogenic reactivity in Milan hypertensive rats.
abstract: The Milan hypertensive strain (MHS) rats are a genetic model of hypertension with adducin gene polymorphisms linked to enhanced renal tubular Na(+) reabsorption. Recently we demonstrated that Ca(2+) signaling is augmented in freshly isolated mesenteric artery myocytes from MHS rats. This is associated with greatly enhanced expression of Na(+)/Ca(2+) exchanger-1 (NCX1), C-type transient receptor potential (TRPC6) protein, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) compared with arteries from Milan normotensive strain (MNS) rats. Here, we test the hypothesis that the enhanced Ca(2+) signaling in MHS arterial smooth muscle is directly reflected in augmented vasoconstriction [myogenic and phenylephrine (PE)-evoked responses] in isolated mesenteric small arteries. Systolic blood pressure was higher in MHS (145 ± 1 mmHg) than in MNS (112 ± 1 mmHg; P < 0.001; n = 16 each) rats. Pressurized mesenteric resistance arteries from MHS rats had significantly augmented myogenic tone and reactivity and enhanced constriction to low-dose (1-100 nM) PE. Isolated MHS arterial myocytes exhibited approximately twofold increased peak Ca(2+) signals in response to 5 μM PE or ATP in the absence and presence of extracellular Ca(2+). These augmented responses are consistent with increased vasoconstrictor-evoked sarcoplasmic reticulum (SR) Ca(2+) release and increased Ca(2+) entry, respectively. The increased SR Ca(2+) release correlates with a doubling of inositol 1,4,5-trisphosphate receptor type 1 and tripling of SERCA2 expression. Pressurized MHS arteries also exhibited a ∼70% increase in 100 nM ouabain-induced vasoconstriction compared with MNS arteries. These functional alterations reveal that, in a genetic model of hypertension linked to renal dysfunction, multiple mechanisms within the arterial myocytes contribute to enhanced Ca(2+) signaling and myogenic and vasoconstrictor-induced arterial constriction. MHS rats have elevated plasma levels of endogenous ouabain, which may initiate the protein upregulation and enhanced Ca(2+) signaling. These molecular and functional changes provide a mechanism for the increased peripheral vascular resistance (whole body autoregulation) that underlies the sustained hypertension.
authors.affiliation: Dept. of Physiology, Univ. of Maryland School of Medicine, 685 W. Baltimore St. HSF1, Rm. 565, Baltimore, MD 21201, USA.
authors.forename: Cristina I
authors.initials: CI
authors.lastname: Linde
authors.forename: Eiji
authors.initials: E
authors.lastname: Karashima
authors.forename: Hema
authors.initials: H
authors.lastname: Raina
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zulian
authors.forename: Withrow G
authors.initials: WG
authors.lastname: Wier
authors.forename: John M
authors.initials: JM
authors.lastname: Hamlyn
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.forename: Mordecai P
authors.initials: MP
authors.lastname: Blaustein
authors.forename: Vera A
authors.initials: VA
authors.lastname: Golovina
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006977:Hypertension, Renal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017538:Mesenteric Artery, Superior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013030:Spain; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D017673:Sodium Chloride, Dietary; D010042:Ouabain; D002118:Calcium