PDEs1‐5 activity and expression in tissues of cirrhotic rats reveal a role for aortic PDE3 in NO desensitization

Abstract

Liver cirrhosis is associated with increased nitric oxide (NO) production in the vasculature. We have previously demonstrated that aorta from rats with liver cirrhosis have a reduced relaxant response to NO donors that is corrected by DMPPO, a PDE5-specific inhibitor. Vasodilator responses to DMPPO itself were also reduced in rings from cirrhotic rats. These results supported previous suggestions that upregulation of PDE5 in liver cirrhosis might contribute to renal sodium retention, and consequently modulate vascular reactivity in the context of increased NO production (Tahseldar-Roumieh et al. in Am. J. Physiol. Heart Circ. Physiol. 290, H481-H488, 2006). Here, we investigated the possible alteration in activity and expression of cyclic nucleotide phosphodiesterase PDE1-PDE5 in kidney and vascular tissues in rats 4 weeks after bile duct ligation. The kidney of rats with cirrhosis had increased activity of PDE1 and PDE4 but not PDE5, and increased expression of PDE1A. Unexpectedly and interestingly, there was no change in cirrhotic aorta PDE5, but an increase in PDE3 and PDE4 activity associated with increased expression of PDE3A and PDE3B. Cilostamide, a specific PDE3 inhibitor, corrected the decreased response to an NO donor in isolated aorta from cirrhotic rats, suggesting that the difference in response to NO donors was due to differences in PDE3-induced hydrolysis of cGMP or to cGMP-induced inhibition of PDE3, rather than to differences in PDE5 contribution. In conclusion, these changes in PDE isozymes could greatly contribute to NO desensitization and to the regulation of vascular and renal function in liver cirrhosis.

Angiotensin‐converting enzyme inhibition prevents myocardial infarction‐induced increase in renal cortical cGMP and cAMP phosphodiesterase activities

“…Moreover, cAMP plays a major role in metabolism and homeostasis regulation, being involved in heart failure pathophysiology . Cortical cAMP‐PDE activity was higher than cGMP‐PDE activity in all groups, as previously demonstrated . cAMP‐PDE activity was attributable mainly to PDE4 and PDE2 activities, which is in agreement with previous results showing that PDE4 activity is high in rats cortical tubules and PDE2 in glomeruli .…”

“…In sham, MI, and MI‐PER rats, PDE2 and PDE1, but not PDE5, accounted for most of cGMP‐PDE cortical activity. In previous studies , the contribution of PDE1 was strong as in the present study, although PDE5 also played an important role in cGMP hydrolysis . This strong contribution of PDE1 could account for the interesting antihypertensive activity of a novel sulfonamide compound which has been described, acting as a PDE1 inhibitor .…”

“…After myocardial infarction, renal PDE1, PDE2, and PDE4 activities were increased, compared to controls. Recently, angiotensin II was found to upregulate PDE1 in vascular smooth muscle as well as in cardiac tissue , and increased PDE1 activity was measured in kidneys of cirrhotic rats, characterized by renal sodium retention . Consequently, upregulated PDE1 likely contributes to increase hydrolysis of ANP‐induced cGMP renal pool in our model.…”

“…In rat renal cortex, it is known that PDE1 preferentially hydrolyses cGMP and that cGMP-PDE activity is related to PDE1, PDE2, and PDE5, whereas PDE4, PDE2, and PDE3 contribute to cAMP-PDE activity [31]. Interestingly, we have previously reported the relative contributions of each isozyme in cAMP-and cGMP-PDE activity in Sprague Dawley rat renal cortex [32]. In sham, MI, and MI-PER rats, PDE2 and PDE1, but not PDE5, accounted for most of cGMP-PDE cortical activity.…”

Cilostazol attenuates cholestatic liver injury and its complications in common bile duct ligated rats

“…Such increased enzyme activity rapidly catabolizes the second messenger cGMP (Lee and Humphreys, 1996). In addition, Tahseldar-Roumieh et al (2009) found that, PDE3 activity increased in CBDL rats and it may play a role in the decreased vascular responsiveness to nitroglycrine an Table 1 Scores for degeneration, necrosis, inflammation, fibrosis and number of biliary ducts in sham control rat treated with vehicle; CBDL treated with vehicle; CBDL treated with cilostazol (9 mg/kg/day, by gavage). These parameters were determined by the end of the 1st and 3rd week after CBDL.…”