114P University of Oxford
BPS 75th Anniversary Meeting December 2006

 

Regional differences of the influence of rolipram on the effects of (-)-adrenaline via β1-adrenoceptors in murine heart

Alejandro Galindo-Tovar, Catharine A Goddard, William C Colledge and Alberto J Kaumann. Department of Physiology, Development & Neuroscience and Department of Biochemistry, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.

 

Catecholamines cause cardiostimulation through murine β1 -adrenoceptors (β1 -AR) but not through β2 -AR (Oostendorp & Kaumann, 2000; Heubach et al., 2002), conceivably due to avid hydrolysis of cAMP by phosphodiesterases (PDE). The isoenzymes PDE3 and PDE4 catalyse more than 90% of total cAMP in rat cardiomyocytes (Mongillo et al., 2004). We investigated the effects of PDE3 inhibition with cilostamide (300 nM) and PDE4 inhibition with rolipram (1 μM) on the (-)-adrenaline-evoked cardiostimulation mediated through β1 -AR and β2 -AR. Experiments were carried out on cardiac tissues from mixed 129Sv-C57Bl/6 mice of either sex. The effects of the PDE inhibitors were investigated on sinoatrial beating rate, and force of paced left atrium and right ventricular wall. The tissues were pretreated 60 min with 5 μM phenoxybenzamine, followed by washout. Cilostamide and rolipram increased sinoatrial rate by 34±8 bpm and 9±9 bpm in the absence of the β1 -AR antagonist CGP20712 and by 42±9 bpm and 25±4 bpm in its presence respectively. Rolipram but not cilostamide increased left atrial force by 0.9±0.4 mN and 0.2±0.1 mN in the absence and presence of CGP20712 respectively. Cilostamide and rolipram did not change ventricular force. Rolipram potentiated the left atrial effects of (-)-adrenaline both in the absence and presence of CGP20712, and enhanced the maximum ventricular response to (-)-adrenaline (P<0.03). Rolipram did not potentiate the sinoatrial effects of (-)-adrenaline. Cilostamide did not modify the effects of (-)-adrenaline in the 3 cardiac regions. CGP20712 shifted the concentration-effect curves to (-)-adrenaline to the left without revealing CGP20712-resistant effects of (-)-adrenaline.

 

Table 1. Potencies (-logEC50M) of (-)-adrenaline. Data are mean ± s.e.m.

 

 

n Control

n CGP 20712 (300 nM)

Right Atrium

Basal

4

7.2

±

0.2

6

4.8

±

0.1

(beats.min-1)

Rolipram

3

7.3

±

0.2

8

4.9

±

0 .1

 

Cilostamide

4

7.4

±

0.1

4

4.7

±

0.1

Left Atrium

Basal

5

7.2

±

0.1

8

4.2

±

0.2

(contractile

Rolipram

4

8.5

±

0.1 P<0.001

8

5.0

±

0.2 P<0.01

force)

Cilostamide

4

7.7

±

0.2

4

4.6

±

0.1

Ventricle

Basal

4

6.1

±

0.3

8 Unsurmountable blockade

(Contractile

Rolipram

3

6.3

±

0.3

8 Unsurmountable blockade

force)

Cilostamide

4

6.4

±

0.4

Not determined

P values with respect to the corresponding basals of the control and CGP20712 groups.

PDE4 limits the cardiostimulant effects of (-)-adrenaline, mediated through β1 -AR, in left atrium and to a smaller extent in ventricle but not in sinoatrial node. Inhibition of PDE4 failed to reveal β2 -AR-mediated effects of (-)-adrenaline.

 

Heubach, J. et al. (2002). Br. J. Pharmacol., 136, 217-229.
Mongillo, M. et al. (2004). Circ. Res., 95, 67-75.
Oostendorp, J. & Kaumann, A.J. (2000). Arch. Pharmacol ., 361, 134-145.