MECHANISMS OF B1 AND B2 ADRENERGIC ACTIONS IN CANINE HEART CELLS

肾上腺素能受体（β -肾上腺素能受体）介导的心肌调节

The beta-adrenergic receptor (betaAR) mediated modulation of myocardial performance is a major component of cardiovascular reserve function. While there are several different types of betaAR, those in the myocardium are primarily beta1AR.However, now strong evidence suggests that both beta1AR and beta2AR subtypes coexist in the hearts of various mammalian species, and that stimulation of both aAR subtypes play a significant role in the regulation of cardiac performance. Because the reduced contractile response to betaAR stimulation in both aged and failing hearts is accompanied by a substantial loss of beta1AR, with no loss of beta2AR, the potential role of beta2AR activation for improving cardiac performance has received considerable attention. Recently, we demonstrated that both beta1AR and beta2AR functionally coexist in cardiac myocytes and that beta2AR stimulation augments L-type Ca2+ current (ICa), cytosolic Ca2+ (Cai) transient, and contraction. However, the actions of beta2AR stimulation on cardiac Ca2+ metabolism and contractility are largely dissociated from cAMP production and phospholamban phosphorylation in rat heart myocytes. Pertussis toxin (PTX) pretreatment specifically potentiates the beta2AR stimulated increases in Cai transient, contraction and ICa.In the present study,we found that while beta2AR stimulation by zinterol does induce an positive inotropic effect and increases in ICa and Cai transient, it has no effect on cellular cAMP production or on phospholamban phosphorylation in canine myocytes. These results strongly suggest that cAMP signalling pathway may not be involved in canine cardiac beta2AR stimulation. Furthermore, while the augmentation of ICa induced by beta1AR agonist, NE, is completely blocked by a specific peptide inhibitor of cAMP-dependent protein kinase (PKI, 50 muM in pipette filling solution), beta2AR stimulated increase in ICa by zinterol persists in the presence of PKI. In addition, a G protein inhibitor, GDPbetaS (5 mM), included in pipette filling solution completely abolished the actions of beta2AR as well as beta1AR stimulation on ICa. Taken together, we conclude that while the effect of beta1AR stimulation on ICa is due exclusively to cAMP-dependent protein phosphorylation, the effect of beta2AR stimulation on ICa may be mediated by non-cAMP-dependent G protein(s)-coupled signalling pathway(s) in canine ventricular myocytes.