Chronotropic and vasodilatory responses to adenosine and B-adrenoceptor activation in mouse hear: effects of adenosine A1 receptor overexpression
No Thumbnail Available
File version
Author(s)
Headrick, JP
Gauthier, NS
Morrison, RR
Matherne, GP
Gauthier, NS
Morrison, RR
Matherne, GP
Griffith University Author(s)
Primary Supervisor
Other Supervisors
Editor(s)
Date
2000
Size
File type(s)
Location
License
Abstract
- Chronotropic and vasodilatory effects of adenosine receptor activation with 2-chloroadenosine (2-ClAdo) and ߭adrenoceptor activation with isoproterenol were studied in wild-type murine hearts and transgenic hearts overexpressing the A1 adenosine receptor. 2. Treatment of wild-type hearts with 2-ClAdo induced bradycardia (pEC50 6.4ᰮ2) and vasodilatation (pEC50 7.9ᰮ1; minimal resistance 2.2ᰮ2 mmHg/mL per min per g). The A1 receptor-mediated bradycardia was 20-fold more sensitive in transgenic hearts (pEC50 7.7ᰮ2), whereas coronary vasoactivity of 2-ClAdo was unaltered (pEC50 7.6ᰮ1). 3. ߭Adrenoceptor stimulation with isoproterenol increased heart rate (pEC50 8.5ᰮ2; maximal rate 594Ჳ b.p.m.) and produced vasodilation (pEC50 8.7ᰮ1; minimal resistance 1.7ᰮ2 mmHg/mL per min per g) in wild-type hearts. Treatment with 10 IU/mL adenosine deaminase increased the magnitude of the tachycardia (maximal rate 653Ჷ b.p.m.) without altering potency (pEC50 8.5ᰮ1). Antagonism of A1 receptors with 10 nmol/L 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695Ჶ b.p.m.) without altering potency (pEC50 8.3ᰮ1). 4. Isoproterenol-mediated vasodilatation was unaltered by transgenic A1 receptor overexpression. Overexpression of A1 receptors significantly reduced the maximal heart rate during ߭adrenoceptor stimulation by 35% (to 381Ჸ b.p.m.) without altering potency (pEC50 8.4ᰮ2). At 10 nmol/L, DPCPX increased the magnitude of the chronotropic response to isoproterenol in transgenic hearts (maximal heart rate 484ᳶ b.p.m.) without altering potency (pEC50 8.3ᰮ2). 5. The data show that transgenic A1 receptor overexpression selectively sensitizes the cardiovascular A1 receptor response and that A1 receptor activation by endogenous adenosine depresses the magnitude, but not potency, of the ߭adrenoceptor-mediated chronotropic response in mouse heart. The A1 receptor-mediated depression of ߭adrenoceptor responsiveness is non-competitive (reduced response magnitude with no change in sensitivity). This indicates that A1 receptor activation non-competitively inhibits effector mechanisms activated by ߭adrenoceptors (e.g. adenylate cyclase) and/or A1 receptors activate unrelated but opposing mechanisms. This inhibitory response may have physiological importance during periods of sympathetic stimulation of cardiac work.
Journal Title
Clinical and Experimental Pharmacology & Physiology
Conference Title
Book Title
Edition
Volume
27
Issue
Thesis Type
Degree Program
School
Patent number
Funder(s)
Grant identifier(s)
Rights Statement
Rights Statement
© 2000 Blackwell Publishing. The definitive version is available at [www.blackwell-synergy.com.]
Item Access Status
Note
Access the data
Related item(s)
Subject
Zoology
Pharmacology and pharmaceutical sciences
Medical physiology
Clinical sciences