Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity.
 ...
PMID:Pharmacology of bipyridine phosphodiesterase III inhibitors. 160 Sep 69

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute or decompensated heart failure. These agents inhibit the intracellular hydrolysis of cyclic adenosine monophosphate, thereby promoting cyclic adenosine monophosphate--catalyzed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They have a wider therapeutic index than do the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoreceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent on some degree of basal adenylate cyclase activity.
 ...
PMID:Pharmacology of bipyridine phosphodiesterase III inhibitors. 185 89

In vitro effects of three triorganotins--tributyltin (TBT), triethyltin (TET), and trimethyltin (TMT)--on calmodulin (CaM) activity were studied. Stimulation of Ca2(+)-ATPase of rat brain synaptic membranes and phosphodiesterase (PDE) of bovine brain were assayed as indicators of CaM activity. The rat synaptic membranes were prepared and CaM was depleted by washing with 1 mM EGTA. All the three organotins inhibited the basal as well as CaM-stimulated Ca2(+)-ATPase in a concentration-dependent manner, suggesting their interaction with calcium pump. However, CaM-stimulated Ca2(+)-ATPase was more sensitive than the basal enzyme. The order of potency of the three organotin compounds was TBT greater than TET greater than TMT. The IC50 values of Ca2(+)-ATPase (basal) were 0.63, 35, and approximately 800 microM, respectively, whereas the values for CaM-stimulated Ca2(+)-ATPase were 0.05, 0.8, and 18 microM for TBT, TET, and TMT, respectively. CaM-deficient PDE did not show any sensitivity to these three organotin compounds, while TBT and TET significantly decreased the CaM-stimulated PDE activity. TMT, which was the least effective inhibitor of Ca2+ pump, did not alter PDE activity. Further, the inhibition of CaM-stimulated Ca2(+)-ATPase activity by these organotins could be reversed by excess addition of CaM. These results suggest that the organotins interact with CaM activity, as evidenced by their potent effect on CaM-dependent Ca2(+)-ATPase and PDE activities.
 ...
PMID:Differential effects of triorganotins on calmodulin activity. 215 84

Cardiac phosphodiesterase III (PDE) inhibitors derived from pyridinone, imidazolone, pyridazinone and related structures form a new class of positive inotropic vasodilator agents (e.g. milrinone) that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. Drugs such as milrinone have a wider therapeutic index than the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of PDE inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity. Individual PDE inhibitors differ in terms of both chronotropic and extracardiac properties. The reasons for this are not yet fully understood.
 ...
PMID:Pharmacology of positive inotropic phosphodiesterase III inhibitors. 255 11

Seminalplasmin, a strongly basic protein isolated from bull semen, was found to antagonize with high potency and extraordinary specificity the function of calmodulin. Calmodulin antagonism is the result of an interaction between the two proteins, which is mainly determined by electrostatic forces. The stimulation of Ca2+-transporting ATPase and phosphodiesterase by calmodulin was half-maximally inhibited at approx. 0.1 microM-seminalplasmin. However, the basal activity of calmodulin-dependent enzymes was not significantly altered by seminalplasmin over the concentration range investigated.
 ...
PMID:Seminalplasmin. An endogenous calmodulin antagonist. 299 94

The two presumed calmodulin antagonists calmidazolium and compound 48/80 were compared for their effects on several calmodulin-dependent and calmodulin-independent enzyme systems. Compound 48/80 and calmidazolium were found to be about equipotent in antagonizing the calmodulin-dependent fraction of brain phosphodiesterase and erythrocyte Ca2+-transporting ATPase. Compound 48/80 combines high potency with high specificity in that: (1) the basal, calmodulin-independent, activity of calmodulin-regulated enzymes was not suppressed; (2) calmodulin-independent enzyme activities, such as Ca2+-transporting ATPases of sarcoplasmic reticulum, Mg2+-dependent ATPases of different tissues and Na+/K+-transporting ATPase of cardiac sarcolemma, were far less altered, or not altered at all, by compound 48/80 as compared with calmidazolium; and (3) antagonism of proteolysis-induced stimulation as opposed to calmodulin-induced activation of erythrocyte Ca2+-transporting ATPase required a 32 times higher concentration of compound 48/80. In all these aspects compound 48/80 was found to be a superior antagonist to calmidazolium since inhibition of calmodulin-independent events by the other agent occurred at considerably lower concentrations. Therefore compound 48/80 is proposed to be a much more specific and useful tool for studying the participation of calmodulin in biological processes than the presently used agents.
 ...
PMID:Comparison of the calmodulin antagonists compound 48/80 and calmidazolium. 614 89

It has been clearly established that ischemic heart disease, hypertension and ageing affect diastolic function before any change is observed in contractile function. Though an increasingly recognised clinical entity, cardiac failure with normal systolic function still does not have any specific treatment. Phosphodiesterase inhibitors which increase AMPc, in addition to their inotropic and vasodilator effects, accelerate relaxation. Major and isolated abnormalities of relaxation have been demonstrated in vitro in non necrosed tissues of both the dilated and hypertrophic forms of advanced cardiomyopathy. The myocardium seems unable to restore rapidly the low cytosolic calcium concentrations required for the deactivation of the contractile proteins. The underlying mechanisms are probably very complex but a deficit in AMPc production has been demonstrated in very advanced stages of cardiomyopathy. In ischemia, however, the abnormalities of relaxation seem to be directly related to a defect in free energy production inhibiting the sarcoplasmic reticulum calcium pump. If abnormalities of relaxation due to ischemia and those due essentially to a passive mechanism are excluded, phosphodiesterase inhibitors would seem to have pharmacological effects likely to improve diastolic function. Clinical studies confirm the beneficial effects of Milrinone and Enoximone on relaxation and the rapid phase of diastolic filling, both in acute and chronic studies. However, it has not yet been clearly established whether improved diastolic function is due to a direct action on the myocardium or an indirect action due to improved conditions of load. In order to determine the specific effects of phosphodiesterase inhibitors on diastolic function, further research is required.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Effects of phosphodiesterase inhibitors on diastolic function]. 821 93

Type 2 diabetic men commonly experience erectile dysfunction for which phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) are often recommended. By preventing degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle, these inhibitors also enhance arterial vasorelaxant effects of nitric oxide donors (which stimulate cGMP synthesis). In the present work, we confirmed this enhancing effect after co-administration of sildenafil with nitroprusside to freshly-isolated rat tail arterial tissues. However, in the same tissues we also observed that sildenafil does not enhance but rather attenuates vasorelaxant effects of three commonly-used antidiabetic drugs, i.e. the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone. Indeed, sildenafil completely blocked vasorelaxant effects of low concentrations of these drugs. In addition, we found that this same novel anti-vasorelaxant interaction of sildenafil with these agents was abolished by either 1) omitting extracellular glucose or 2) inhibiting specific smooth muscle glycolytic pathways; pathways known to preferentially utilize extracellular glucose to fuel certain adenosine triphosphate (ATP)-dependent ion transporters: e.g. ATP-sensitive K channels, sarcoplasmic reticulum Ca-ATPase, plasma membrane Ca-ATPase and Na/K-ATPase. Accordingly, we suspect that altered activity of one or more of these ion transporters mediates the observed attenuating (anti-vasorelaxant) interaction of sildenafil with the antidiabetic drugs. The present results are relevant because hypertension is so common and difficult to control in Type 2 diabetes. The present data suggest that sildenafil might interfere with the known antihypertensive potential of metformin and the thiazolidinediones. However, they do not suggest that it will interact with them to cause life-threatening episodes of severe hypotension, as can occur when it is co-administered with nitrates.
...
PMID:Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents. 2600 78

Calcium ions play a critical role in neuronal cell death. Pigment epithelium-derived factor (PEDF) is a promising neuroprotective protein for photoreceptor cells but the mechanisms mediating its effects against retinal degeneration are still not well characterized. We addressed this question in the rd1 degenerating mouse retina that bears a mutation in the Pde6b gene encoding one subunit of the phosphodiesterase enzyme. Loss of phosphodiesterase activity in rod photoreceptor cells increases cyclic guanosine monophosphate (cGMP) levels leading to a rise in intracellular calcium. Short-term treatments with recombinant human PEDF protein decreased intracellular calcium in photoreceptors in vivo. Taking advantage of calcium pump blockers, we defined that PEDF signaling acts on PMCA calcium pumps to lower intracellular calcium. PEDF restrained cell death pathways activated by high calcium levels and engaging calpains, BAX and AIF. The neurotrophic effects were mediated by the PEDF receptor (PEDF-R), encoded by the PNPLA2 gene. Finally, peptides containing the neurotrophic domain of PEDF targeted these same cell death pathways in vivo. The findings reveal rescue from death of degenerating photoreceptor cells by a PEDF-mediated preservation of intracellular calcium homeostasis.
 ...
PMID:Pigment epithelium-derived factor hinders photoreceptor cell death by reducing intracellular calcium in the degenerating retina. 2975 30