Pharmacologic activity of phosphodiesterases and their inhibitors Romeo T. CRISTINA, Cristina DEHELEAN, Eugenia DUMITRESCU, Alina NETOTEA, A drian GURBAN 1 Faculty of Veterinary Medicine Timisoara, Department of Veterinary Pharmacology 2 University of Medicine and Pharmacy "Victor Babes", Pharmacy Dept., Timisoara, Corresponding author: Prof. R.T. Cristina, 119, Calea Aradului, 300645, Timisoara, RO. e-mail: [email protected]

The phosphodiesterases PDE,s implication in the Faculty of Veterinary Medicine The PDE inhibitors Timisoara (PDE) enzyme systems work ANNUAL SCIENTIFIC SESSION The phosphodiesterase inhibitors have stimulatory Actualities in animals breeding and pathology Phosphodiesterases (PDE) are enzymes that cAMP is a 2 order messenger , who translates the effects on the growth of microtubules in many cell types. hydrolyze the cyclic nucleotides adenosine 3’,5’- external stimuli into cell internal stimuli, and who is It seems that the cAMP-dependent phosphorylation of cyclic monophosphate (cAMP) and guanosine degraded into AMP ( adenosine 5’-monophosphate ) by the tubulin or of the proteins associated with the 6 – 7 May 2010 3’,5’-cyclic monophosphate (cGMP), in their an cAMP-dependent PDE. An increase in free microtubules stimulates the polymerization of the inactive form (5’nucleotide) and, therefore they intracellular calcium can result from either increased microtubules play an essential role in the cellular enzyme flux of calcium into the cell through calcium channels Conclusions systems. or by release of calcium from internal stores (e.g., PDE Specific Selective Specific activity A phosphodiesterase inhibitor is a drug that blocks one or sarcoplasmic reticulum; SR). type activity inhibitors The cyclic nucleotide phosphodiesterases (PDE) It is implicated in the level adjustment of the cGMP in more of the five subtypes of the enzyme activated by the vascular smooth muscle cells, it is considered as degrading the phosphodiester bond in the second The free calcium binds to a special calcium binding Vinpocetine Ca 2+ / important in the control of the action of some phosphodiesterase (PDE), therefore preventing the PDE1 Nimodipine messenger molecules cAMP and cGMP (fig.1). protein called calmodulin . calmodulin, vasoconstrictor which growing the intracellular inactivation of the intracellular second messengers’ cyclic calcium concentration. EHNA (erythro-9-(2- adenosine monophosphate (cAMP) and cyclic guanosine They regulate the localization, duration, and Calcium-calmodulin activates myosin light chain hydroxy-3-nonyl) adenine) monophosphate (cGMP) by respective PDE subtype (s). amplitude of cyclic nucleotide signalling within sub kinase (MLCK), an enzyme that is capable of EHNA May act in synergy to mediate diverse cellular domains. phosphorylating myosin light chains (MLC) in the analogues: pharmacological responses including anti-viral, anti- stimulated by As is purified, this PDE partially lose his activity. This NH 2 PDE2 BAY 60-7550 tumour and anti-arrhythmic effects. It has been O cGMP (9-(6-Phenyl-2- presence of ATP. PDP successfully used with the proper controls as a tool suggests the existence of a specific PDE activation N oxohex-3-yl)-2-(3,4- N N dimethoxybenzyl)-purin- to probe PDE2 functions. NH 6one factor , which is removed by the purification processes. Myosin light chains are 20-kD regulatory subunits N Oxindole O This protein factor is calmodulin (CaM). O N N O N found on the myosin heads. MLC phosphorylation Anagrelide O N NH 2 leads to cross-bridge formation between the myosin Enoximone, Milrinone, The PDE inhibition, change the intracellular response to cAMP and cGMP cAMP and

Spatial structureSpatial of Used clinically for short-term treatment of cardiac cGMP Inamrinone heads and the actin filaments, and hence smooth PDE3 failure, these drugs mimic sympathetic stimulation extra cellular data signals by affecting the mediated inhibited, (formerly O OH and increase cardiac output. O P P O OH amrinone) Fig. 1. O muscle contraction (figure 2). processes of the cyclic nucleotides. Cilostazol - O OH Inhibitors have proven potential as anti-inflammatory The PDE enzymes are classified into 11 families, Mesembrine, The PDE selective inhibition has various therapeutic (Sceletium tortuosum drugs, especially in inflammatory pulmonary diseases cAMP cGMP such as asthma, COPD, and rhinitis. They suppress namely PDE1-PDE11, in mammals. AMPc - alkaloid) applications. The smooth muscle from the most organs, the release of cytokines and other inflammatory PDE4 dependent/ Rolipram, signals, and inhibit the production of reactive oxygen α The enzyme systems effectors that are known are: specific Ibudilast, except the intestine, shrinks under the influence of a - Piclamilast, species. PDE4 inhibitors may have antidepressive - calmodulin system (CaM), Luteolin, effects and have also recently been proposed for use adrenergic stimulation. - protein kinase; as antipsychotics Selectively inhibit PDE5, which is cGMP-specific and The contraction is produced under the action of the MLCK - AC-cAMP system Sildenafil, responsible for the degradation of cGMP in the Tadalafil, corpus cavernosum . These phosphodiesterase (myosin light chain kinase ) which is dependent by the - GC-cGMP system and PDE5 cGMP Vardenafil, inhibitors are used primarily as remedies for erectile Udenafil dysfunction, as well as having some other medical CaM. At the smooth muscle stimulation a PA accumulation - PI system (phosphatidyl-inositol) Avanafil applications such as treatment of pulmonary hypertension. occurs. PDE6 Ca2+/ Dipyridamole After activation by rhodopsin, the GDP of the PDE – phosphodiesterase cGMP- Zaprinast heterotrimer is exchanged for GTP and the Gαt-GTP The agonists that causes the contraction of the smooth AMPc – cyclic adenosine monophosphate signalling diffuses and binds to a membrane-associated ATP – adenosine triphosphate muscle ( α-adrenomimetics , M cholinomimetics , histamine cGM – cyclic guanosine monophosphate HPC1 photoreceptorspecific cGMP PDE. GT – guanosine triphosphate or serotonin 5HT) leads to the PI increased division: AC – adenilate cyclase Non selective inhibitors GC – guanylate cyclase Methylated I – inositol Drugs have the potential to enhance circulation xanthines and The relationship between the PI and the citosol Ca2 + can PI (IP) – phosphatidyl-inositol and may have applicability in treatment of derivatives: PIP2 – phosphatidyl-inositol 4, 5-biphosphate diabetes, fibrotic disorders, peripheral nerve Caffeine, be seen from two perspectives: the PI hydrolysis from the IP3 – inositol 1, 4, 5-triphosphate damage, and microvascular injuries or as DAG – diacilglicerol intracellular Aminophylline, bronchodilators. Methylated xanthines act as both membranes leads to the opening of some doors for the CaM – calmodulin Y7 PDE cAMP activity, IBMX (3-isobutyl-1- competitive nonselective phosphodiesterase TXA2 – thromboxanes PKA- , methylxanthine), inhibitors, inhibit TNF-alpha and leukotriene Ca2 +, the PI changes can lead to the formation of a NO – nitrogen monoxide Paraxanthine, synthesis, and reduce inflammation and innate EDRF – the endothelial relaxing factor Pentoxifylline, second intracellular chemical messenger, which release PA – the phosphatidic acid immunity and nonselective adenosine receptor Theobromine AA – the arahidonic acid antagonists. the Ca2 + from the deposits PG – prostanoide Theophylline, VOC – the voltage-dependent channels ROC – the receptor-dependent channels MLCK – the light chain kinase of the myosin Legend RE – endoplasmic reticulum CaP – calponine CaD – caldesmone Copyright © PCI2 – prostacillin Romeo T. Cristina