Cysteinyl leukotriene-dependent [Ca2+]i responses to angiotensin II in cardiomyocytes.
With the use of fura 2 measurements in multiple and single cells, we examined whether cysteinyl leukotrienes (CysLT) mediate angiotensin II (ANG II)-evoked increases in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in neonatal rat cardiomyocytes. ANG II-evoked CysLT release peaked at 1 min. The angiotensin type 1 (AT(1)) antagonist losartan, but not the AT(2) antagonist PD-123319, attenuated the elevations in [Ca(2+)](i) and CysLT levels evoked by ANG II. Vasopressin and endothelin-1 increased [Ca(2+)](i) but not CysLT levels. The 5-lipoxygenase (5-LO) inhibitor AA-861 and the CysLT(1)-selective antagonist MK-571 reduced the maximal [Ca(2+)](i) responses to ANG II but not to vasopressin and endothelin-1. While MK-571 reduced the responses to leukotriene D(4) (LTD(4)), the dual CysLT antagonist BAY-u9773 completely blocked the [Ca(2+)](i) elevation to both LTD(4) and LTC(4). These data confirm that ANG II-evoked increases, but not vasopressin- and endothelin-1-evoked increases, in [Ca(2+)](i) involve generation of the 5-lipoxygenase metabolite CysLT. The inositol (1,4,5)-trisphosphate [Ins(1,4,5)P(3)] antagonist 2-aminoethoxydiphenyl borate attenuated the [Ca(2+)](i) responses to ANG II and LTD(4). Thus AT(1) receptor activation by ANG II is linked to CysLT-mediated Ca(2+) release from Ins(1,4,5)P(3)-sensitive intracellular stores to augment direct ANG II-evoked Ca(2+) mobilization in rat cardiomyocytes.
Liu
Pinggang
P
Department of Pharmacology and the Cardiovascular Risk Factor Reduction Unit, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E5.
Misurski
Derek A
DA
Gopalakrishnan
Venkat
V
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D001127:Arginine Vasopressin / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D003545:Cysteine / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D017997:Leukotriene C4 / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors; D019808:Losartan / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013050:Spectrometry, Fluorescence
D057911:Angiotensin Receptor Antagonists; D016227:Benzoquinones; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007093:Imidazoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011725:Pyridines; D011804:Quinolines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C112381:cysteinyl-leukotriene; D000804:Angiotensin II; D001127:Arginine Vasopressin; C073402:PD 123319; D017997:Leukotriene C4; C059141:verlukast; D017998:Leukotriene D4; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D015544:Inositol 1,4,5-Trisphosphate; D019808:Losartan; D003545:Cysteine; D002118:Calcium; D016257:Fura-2