Cyclic AMP levels in ventricular myocytes from noradrenaline-treated guinea-pigs.
Chronic activation of the sympathetic nervous system in human heart failure is believed to cause cardiac beta-adrenoceptor desensitisation. We have investigated the relationship between beta-adrenoceptor desensitisation and cyclic AMP levels in cardiac myocytes isolated from the ventricle of guinea-pigs chronically infused with noradrenaline hydrochloride for 7 days. Functional beta-adrenoceptor desensitisation was confirmed by a significant decrease in the maximum isoprenaline-stimulated contraction amplitude and an increased EC50 for isoprenaline. In the absence of beta-adrenoceptor stimulation, basal cyclic AMP levels were significantly depressed in populations of myocytes from noradrenaline-treated animals compared to sham-operated controls, and this was not accounted for by myocyte hypertrophy or necrosis. Similarly, there was a significant decrease in cyclic AMP levels at maximally inotropic isoprenaline concentrations. Threshold and maximum inotropic concentrations of the phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine (IBMX), restored isoprenaline-stimulated cyclic AMP levels in noradrenaline-treated guinea-pig cardiac myocytes, although we have previously reported no increase in maximum inotropic effect of isoprenaline with these compounds.
Wynne
D G
DG
National Heart and Lung Institute, Imperial College, London, UK.
Del Monte
F
F
Harding
S E
SE
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine