New insights into the role of nitric oxide in cardiovascular protection (part 10)
In the presence of PDE3 inhibitor, the EC50 values of PDE4 inhibitors were two- to sixfold their IC50 values on purified vascular PDE4. The presence of functional endothelium decreased EC50 values of PDE4 inhibitors equivalent to their IC50 values on the enzyme . Therefore, PDE3 inhibition and the presence of functional endothelium both enabled the relaxing effect of PDE4 inhibition. This suggests that PDE3 inhibition by endogenous cGMP or by exogenous inhibitor is a prerequisite to the endothelium-dependent relaxing effect of PDE4 inhibitors.
Similarly, studies examined the variation of cyclic nucleotide levels in aorta without endothelium induced by PDE 3 and PDE4 inhibitors, in the presence or the absence of a nitric oxide donor (Figure 3). In control aortae, the PDE3 as well as the PDE4 inhibitor (30 |J.M) significantly increased cAMP levels (1.7- and twofold, respectively) without altering cGMP levels. Furthermore, addition of PDE3 inhibitor (SKF 94120, 5 |iM) together with PDE4 inhibitor (rolipram) potentiated the effect of the PDE4 inhibitor on cAMP content (1.7-fold). In aortae treated with nitric oxide donor (10 |J.M 3-morpholino-sydnonimine-hydrochloride plus 100 U/mL superoxide dismutase), the PDE4 inhibitor markedly increased cAMP levels (sixfold). Simultaneous addition of the PDE3 inhibitor did not produce any larger effect, indicating that PDE4 was probably maximally inhibited. Visit the best pharmacy that thousands of international customers already chose to be their favorite one and see how easy it can be for you to get that Claritin online tablets in the amount required for your treatment spending a lot less money than otherwise.
Figure 3 Effects of phosphodiesterase (PDE) 3 and PDE4 inhibitors on cAMP content in (A) control aorta or (B) aorta treated with 3-morpholino-sydnonimine-hydrochloride plus superoxide dismutase without endothelium. The rings were incubated in the presence of drug vehicle (0.1% dimethylsulphoxide, D), PDE3 inhibitor (30uM SKF 94120, S), PDE4 inhibitor (30uM rolipram, R) or with a combination of 5uM SKF 94120 and 30 uM rolipram (S+R). Results are expressed as the mean of six to 10 experiments (number indicated under the bars) ± SEM. °°P<0.01, °°°P<0.001 compared with preceding bar; *P<0.05, **P<0.01, ***P<0.001 compared with aorta incubated with drug vehicle (first bar). Data taken from reference 15, with permission