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β 3 ‐Adrenoceptors modulate left ventricular relaxation in the rat heart via the NO‐cGMP‐PKG pathway
Author(s) -
Angelone T.,
Filice E.,
Quintieri A. M.,
Imbrogno S.,
Recchia A.,
Pulerà E.,
Mannarino C.,
Pellegrino D.,
Cerra M. C.
Publication year - 2008
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2008.01838.x
Subject(s) - lusitropy , nadolol , medicine , pertussis toxin , nitric oxide , endocrinology , chemistry , agonist , nitric oxide synthase , isoprenaline , gi alpha subunit , receptor , g protein , biology , stimulation , diastole , propranolol , blood pressure
Aims: Using a model of isolated and Langendorff‐perfused rat heart we analysed whether activation of β 3 ‐adrenergic receptors (β 3 ‐ARs) influences ventricular lusitropic performance. We also focused on the NOS/NO/cGMP/PKG cascade as the signal transduction mechanism. Methods: Hearts were treated with increasing concentrations (from 10 −12 to 10 −6 m ) of BRL 37344 , a selective β 3 ‐AR agonist, and cardiac performance was evaluated by analysing both lusitropic parameters and coronary motility. Cardiac preparations were also perfused with BRL 37344 in the presence of either isoproterenol (ISO) or nadolol, or pertussis toxin (PTx), or selective inhibitors of the NOS/NO/cGMP/PKG pathway. Results: BRL 37344 caused a significant concentration‐dependent reduction in (LVd P /d t ) min , a decrease in half time relaxation significant starting from 10 −12 m , and an increase in (LVd P /d t ) max /(LVd P /d t ) min ratio ( T /− t ). BRL 37344 abolished the ISO‐mediated positive lusitropism. β 3 ‐AR‐dependent effects on relaxation were insensitive to β 1 /β 2 ‐AR inhibition by nadolol (100 n m ), and were abolished by G i/o protein inhibition by PTx (0.01 n m ). NO scavenging by haemoglobin (10 μ m ), and nitric oxide synthase (NOS) inhibition by NG‐monomethyl‐ l ‐arginine (10 μ m ) revealed the involvement of NO signalling in BRL 37344 response. Pre‐treatment with inhibitors of either soluble guanylate cyclase (ODQ; 10 μ m ) or PKG (KT 5823 ; 100 n m ) abolished β 3 ‐AR‐dependent negative lusitropism. In contrast, anantin (10 n m ), an inhibitor of particulate guanylate cyclase, did not modify the effect of BRL 37344 on relaxation. Conclusion: Taken together, our findings provide functional evidence for β 3 ‐AR modulation of ventricular relaxation in the rat heart which involves PTx‐sensitive inhibitory Gi protein and occurs via an NO‐cGMP‐PKG cascade. Whether the effects of β 3 ‐AR stimulation on lusitropism are beneficial or detrimental remains to be established.