Abstract

In myocardial ischemia, arrhythmias due to excessive norepinephrine (NE) release cause high morbidity and mortality. Thus, reduction of NE release from cardiac sympathetic nerve endings (SNE) in myocardial ischemia is a critical goal. We will study how endogenous modulators regulate cardiac sympathetic neurotransmission in normal and ischemic conditions.
In Aim 1, we will investigate the transductional mechanisms by which histamine H3-receptors (H3R) attenuate Ca2+- dependent NE exocytosis and carrier-mediated NE release, associated with short-term and protracted ischemia/reperfusion (I/R), respectively. This will be studied in H3R-transfected cells and in SNE from guinea-pig hearts expressing native H3R. For NE exocytosis and short-term I/R we will assess how H3R activation limits Ca2+ entry through N-type Ca2+-channels, and the roles of PKC and PLAa in implementing this. For carrier-mediated NE release and protracted I/R, we will investigate the coupling of H3R activation to Na+/H+ exchanger (NHE) inhibition, and will assess the interaction between H3R and angiotensin ATI receptors at the NHE level in SNE. Mouse hearts lacking H3R will be studied. The contribution of endogenous histamine to the cardioprotective effects of H3R activation will be determined in ischemic hearts from mast-cell-deficient mice. Among the transductional signals involved in the H3R-mediated reduction of NHE activity and carrier- mediated NE release, PKC and calmodulin will be investigated.
In Aim 2, we will determine by which mechanisms tissue plasminogen activator promotes NE release in normal and ischemic hearts. Mice with genetic deletions of various components of the fibrinolytic cascade will be used. These studies will elucidate the mechanisms for endogenous control of NE release. Since reduction of NE release is protective in myocardial ischemia, identification and characterization of the factors controlling NE release will help in the development of novel therapeutic strategies in cardiovascular diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034215-33
Application #
7437297
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wang, Lan-Hsiang
Project Start
1985-09-10
Project End
2010-04-30
Budget Start
2008-07-01
Budget End
2010-04-30
Support Year
33
Fiscal Year
2008
Total Cost
$546,652
Indirect Cost

  Institution

Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Marino, Alice; Sakamoto, Takuya; Robador, Pablo A et al. (2017) S1P receptor 1-Mediated Anti-Renin-Angiotensin System Cardioprotection: Pivotal Role of Mast Cell Aldehyde Dehydrogenase Type 2. J Pharmacol Exp Ther 362:230-242
Marino, Alice; Martelli, Alma; Citi, Valentina et al. (2016) The novel H2 S donor 4-carboxy-phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium. Br J Pharmacol 173:3222-3234
Aldi, Silvia; Marino, Alice; Tomita, Kengo et al. (2015) E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role. FASEB J 29:61-9
Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo et al. (2014) Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ?-dependent aldehyde dehydrogenase type-2 activation. J Pharmacol Exp Ther 349:508-17
Hu, Zhaoyang; Crump, Shawn M; Anand, Marie et al. (2014) Kcne3 deletion initiates extracardiac arrhythmogenesis in mice. FASEB J 28:935-45
Aldi, Silvia; Robador, Pablo A; Tomita, Kengo et al. (2014) IgE receptor-mediated mast-cell renin release. Am J Pathol 184:376-81
Chan, Noel Yan-Ki; Robador, Pablo A; Levi, Roberto (2012) Natriuretic peptide-induced catecholamine release from cardiac sympathetic neurons: inhibition by histamine H3 and H4 receptor activation. J Pharmacol Exp Ther 343:568-77
Robador, Pablo A; Seyedi, Nahid; Chan, Noel Yan-Ki et al. (2012) Aldehyde dehydrogenase type 2 activation by adenosine and histamine inhibits ischemic norepinephrine release in cardiac sympathetic neurons: mediation by protein kinase C?. J Pharmacol Exp Ther 343:97-105
Hashikawa-Hobara, Narumi; Chan, Noel Yan-Ki; Levi, Roberto (2012) Histamine 3 receptor activation reduces the expression of neuronal angiotensin II type 1 receptors in the heart. J Pharmacol Exp Ther 340:185-91
Chan, Noel Yan-Ki; Seyedi, Nahid; Takano, Kenichi et al. (2012) An unsuspected property of natriuretic peptides: promotion of calcium-dependent catecholamine release via protein kinase G-mediated phosphodiesterase type 3 inhibition. Circulation 125:298-307

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