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Cited by 32Receptor Mechanisms and SignalingCardiac electrophysiology and arrhythmiasPhosphodiesterase function and regulation

α1-Adrenoceptor Subtypes Mediate Negative Inotropy in Myocardium from α1A/C-Knockout and Wild Type Mice

McCloskey, Diana T., Gregg Rokosh, D., O'Connell, Timothy D., Keung, Edmund C., Simpson, Paul C., Baker, Anthony J.·2002·Journal of Molecular and Cellular Cardiology
DOI 10.1006/jmcc.2002.2049
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Abstract

Cardiac alpha(1)-adrenoceptors (AR) have two predominant subtypes (alpha(1A)-AR and alpha(1B)-AR) however, their roles in regulating contraction are unclear. We determined the effects of stimulating alpha(1A)-AR (using the subtype-selective agonist A61603) and alpha(1B)-AR (using a gene knockout mouse lacking alpha(1A)-AR) separately, and together (using phenylephrine) on Ca(2+) transients, intracellular pH, and contraction of mouse cardiac trabeculae. Stimulation of alpha(1)-AR subtypes separately or together caused a triphasic contractile response. After a transient ( approximately 3%) force rise (phase 1), force declined markedly (phase 2), then partially recovered (phase 3). In phase 2, the force decline (% of initial) with combined alpha(1A)-AR plus alpha(1B)-AR stimulation (50+/-3%) was more than with separate subtype stimulation (P<0.01), suggesting alpha(1A)-AR and alpha(1B)-AR mediate additive effects during phase 2. Force decline in phase 2 paralleled decreases of Ca(2+) transients that were reduced more with combined vs. separate subtype stimulation. During phase 3 the final force reduction was similar with stimulation of alpha(1A)-AR (20+/-5%), or alpha(1B)-AR (20+/-3%), or both (26+/-4%) suggesting alpha(1A)-AR and alpha(1B)-AR mediate non-additive effects during phase 3. In contrast, Ca(2+) transients recovered fully in phase 3 suggesting reduced force in phase 3 involved decreased myofilament Ca(2+)-sensitivity. Decreased Ca(2+)-sensitivity was not mediated by changes of intracellular pH since this was not affected by alpha(1)-AR stimulation. In contrast to mouse trabeculae, rat trabeculae demonstrated a positive inotropic response to alpha(1)-AR stimulation. In conclusion, for mouse myocardium in vitro both alpha(1)-adrenoceptor subtypes mediate negative inotropy involving decreased Ca(2+) transients and a decreased Ca(2+) sensitivity that does not involve altered intracellular pH.

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Authors
McCloskey, D. T., Gregg Rokosh, D., O'Connell, T. D., Keung, E. C., Simpson, P. C., & Baker, A. J.
Affiliations
San Francisco VA Medical Center (US)
ORCID
Venue
Journal of Molecular and Cellular Cardiology
Publisher
Elsevier BV
Published
2002-08
Volume
34
Issue
8
Pages
1007-1017
ISSN
0022-2828 (ISSN-L)
DOI
10.1006/jmcc.2002.2049
OpenAlex
W2058756865
Cited by
32
References
50
Citations by year
2020: 1 · 2019: 1 · 2017: 2 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 1
FWCI
1.39
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular and Cellular Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5r01hl054890-05, 5r29hl056257-04, 5f32hl010422-03)
  • National Heart, Lung, and Blood Institute (HL54890, HL10422, HL31113, R01HL031113, HL56257)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
Keywords
alpha1-adrenoceptors, alpha1A-adrenoceptor, alpha1B-adrenoceptor, negative inotropic effect, cardiac contractility, calcium transients, myofilament calcium sensitivity, intracellular pH, cardiac trabeculae, phenylephrine, knockout mice
MeSH terms
Animals, Calcium, Female, Hydrogen-Ion Concentration, Male, Myocardial Contraction, Myocardium, Phenylephrine, Receptors, Adrenergic, alpha-1, Mice, Knockout, Mice, Rats

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