title: Mechanism of increased alpha-adrenoceptor-mediated contraction in small resistance arteries of rats with heart failure.
abstract: 1. Alterations in a(1)-adrenoceptor signalling that result in enhanced contraction in resistance arteries in heart failure are not well characterized. To clarify whether this enhanced constriction is due to Ca(2+)-dependent or -independent effects, we measured the phenylephrine-induced changes in [Ca(2+)](i) in the presence of a Rho kinase inhibitor or an inositol 1,4,5-trisphosphate (IP(3)) receptor inhibitor. 2. Heart failure was induced in rats by ligation of the left coronary artery. Changes in the internal diameter of pressurized small femoral arteries were examined using videomicroscopy. Phenylephrine concentration-response curves, constructed in the presence of the Rho kinase inhibitor Y27632 (0.3 micromol/L) or the IP(3) receptor inhibitor xestospongin C (0.3 micromol/L), were compared in heart failure rats and sham-operated (control) rats; fura-2 Ca(2+) signals were measured in the arteries of both groups. 3. The heart : bodyweight ratio, lung : bodyweight ratio, left ventricular end-diastolic pressure and plasma B-type natriuretic peptide were significantly higher in heart failure rats compared with control rats. Phenylephrine-induced contractile responses and increases in [Ca(2+)](i) were significantly greater in arteries from heart failure rats compared with arteries from control rats. At 0.3 micromol/L, Y27632 selectively inhibited phenylephrine-induced constrictions of heart failure arteries, but had no effect on the increase in [Ca(2+)](i). 4. Immunohistochemical staining for Rho kinase was greater in heart failure rats compared with control rats. 5. The degree of inhibition of both the phenylephrine-induced constriction and the increase in [Ca(2+)](i) by xestospongin C (0.3 micromol/L) was greater in arteries from heart failure rats than in those from control rats. 6. The increased contractile response to phenylephrine in arteries of heart failure rats results from IP(3)-dependent increases in [Ca(2+)](i) and from an enhanced Ca(2+) sensitivity via a Rho kinase-dependent mechanism.
authors.affiliation: Department of Internal Medicine, Division of Coronary Heart Disease, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Koida
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Ohyanagi
authors.forename: Atsunori
authors.initials: A
authors.lastname: Ueda
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Mori
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Iwasaka
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006331:Heart Diseases / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
chemical_list: D000316:Adrenergic alpha-Agonists; D000577:Amides; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D009125:Muscle Relaxants, Central; D010080:Oxazoles; D011725:Pyridines; D011942:Receptors, Adrenergic, alpha; D014665:Vasodilator Agents; C108644:xestospongin A; C108830:Y 27632; D010656:Phenylephrine; D009568:Nitrendipine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002118:Calcium