Contractile function and response to agonists in myocytes from failing human heart.
Ventricular myocytes from failing human hearts have a similar maximum contraction amplitude in high Ca2+ to those from non-failing heart at low stimulation rates (0.2 Hz, 32 degrees C), but do not exhibit the same positive frequency-interval relationship. At higher stimulation rates (1 Hz) therefore, the amplitude is depressed in cells from failing hearts compared to controls. Slow relaxation is seen in myocytes from failing ventricle at all stimulation rates, and contraction velocity is also slightly reduced. beta-adrenoceptor desensitization is evident, and increases with severity of disease. There is also a post-receptor defect in myocytes from failing heart since responses to forskolin and cyclic AMP analogues are reduced, and this is accompanied by decreased cyclic AMP levels in myocardium from patients in end-stage disease. Pertussis toxin treatment, which inactivates Gi, reverses most of the alterations in the beta-adrenoceptor pathway. The role of the sympathetic system is indicated by the parallels between myocytes from failing human heart and those from the noradrenaline-treated guinea-pig, which show beta-adrenoceptor desensitization, a post-receptor defect and reduced basal cyclic AMP levels. However, relaxation velocities are not slowed in these guinea-pig myocytes, indicating that basal cyclic AMP does not have a tonic role in speeding relaxation.
Harding
S E
SE
Department of Cardiac Medicine, National Heart and Lung Institute, Dovehouse St., London, U.K.
Davies
C H
CH
Wynne
D G
DG
Poole-Wilson
P A
PA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D046508:Culture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D009638:Norepinephrine