Localization of a “postreceptor” defect in human dilated cardiomyopathy

In the human failing heart, subsensitivity to β-adrenoceptor agonists and phosphodiesterase inhibitors occurs. 1,2 Besides a down-regulation of β adrenoceptors, a second “postreceptor” defect has been suggested. There are 3 possibilities for postreceptor defects: a decrease in the stimulatory guanine-nucleotide-binding regulatory protein (G s), an increase in the inhibitory guanine-nucleotide-binding regulatory protein (G i) or a decrease in the catalytic subunit of the cardiac adenylate cyclase. Recent reports have suggested the localization of these defects. Karliner and Scheinman 3 suggested a defect of G S, since in myocardial biopsies from patients with varying degrees of heart failure, the guanine nucleotide-stimulated adenylate cyclase activity was depressed. However, an increase of a 40 kDa pertussis toxin substrate (presumably identical with G i) in explanted failing hearts has also been reported. 4 In patients with heart failure, Erne et al 5 observed diminished effects of isoproterenol on contraction velocity, but an unchanged response to forskolin. They 5 argued that postreceptor defects might not occur in the human failing heart. These conclusions were noted by Reithmann and Werdan, 6 who also reported a diminished cyclic adenosine monophosphate formation by forskolin in cultured rat heart cells treated with norepinephrine. They 6 argued, however, that a postreceptor defect might be involved.