Key result
Human cardiac PDEIII was potently inhibited by amrinone, enoximone, and cGMP, whereas human kidney PDEIII was strongly inhibited by rolipram, indicating organ-specific subclasses.
The intracellular distribution and pharmacological sensitivity of PDEIII subclasses in human hearts differ significantly from human kidneys and animal models, being uniquely cGMP-sensitive.
Caution advised extrapolating PDEIII data across organs or species; extends subclass distinctions but leaves open clinical translation.
We observed the intracellular localization of low-Km cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDEIII) subclasses in human heart in comparison to that in human kidney by using comparable potencies of specific inhibitors. PDEIII was observed in not only soluble fraction but particulate fraction in human heart and kidney. Both soluble and particulate PDEIII from human heart selectively hydrolyzed cAMP with similar Km values of 0.36 and 0.40 microM, respectively. They were potently inhibited by amrinone, enoximone, and cyclic guanosine monophosphate (cGMP), but were weakly inhibited by rolipram with much the same IC50 values. Although several animals having soluble and particulate PDEIII possess two pharmacologically distinct subclasses of PDEIII, human heart has only one form, cGMP-sensitive PDEIII. In contrast to cardiac PDEIII, both soluble and particulate PDEIII from human kidney were not readily inhibited by amrinone, enoximone, and cGMP, but rather strongly inhibited by rolipram. Human kidney contains only cGMP-less sensitive form of PDEIII in soluble and particulate fractions. These results suggest that the intracellular distribution of PDEIII subclasses in human hearts are significantly different from those in the hearts of other animal species, and subclasses of PDEIII in humans hearts could not be distinguished by intracellular localization but by organ specificity.
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Masuoka et al. (1990) studied this question. Amrinone and enoximone vs. Rolipram was evaluated on Inhibition of PDEIII subclasses. Human cardiac PDEIII was potently inhibited by amrinone, enoximone, and cGMP, whereas human kidney PDEIII was strongly inhibited by rolipram, indicating organ-specific subclasses.
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