Tissue and substrate specificity of inhibition by alkoxy-aryl-lactams of platelet and arterial smooth muscle cyclic nucleotide phosphodiesterases relationship to pharmacological activity (original) (raw)
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Classification of Phosphodiesterases and the Therapeutic Effects of their Inhibitors (Review
—Phosphodiesterase (PDE) is an enzyme that catalyses the hydrolysis of phosphodiester bonds. The enzyme is also takes responsibility for the hydrolysis of cyclic 3',5'adenosine monophosphate (cAMP) and 3',5'cyclic guanosine monophosphate (cGMP). The PDE enzymes in mammals are classified into 11 families, namely PDE1-PDE11. The classification is on the basis of amino acid sequences, substrate specificities, regulatory properties, pharmacological properties, tissue distribution. Various PDE of the same family are related with regards to functionality but differs in their specificities for substrates. Some are hydrolases with selective preferences for cAMP (PDE4, 7 and 8), while the selective preference for some others is for cGMP (PDE5, 6 and 9). Some have the ability to hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10 and 11). cAMP, and cGMP both has important roles in the regulation of inotropic mechanisms in the human myocardium. However, cAMP greatly affects other tissues, and different phosphodiesterase isoenzymes are found in many other tissues. Drugs with inhibitory effects on phosphodiesterase (thus reducing the breakdown of cAMP) have a therapeutic action on the heart, lung, and vasculature as well as on platelet function and inflammatory mechanisms. Inhibitors like these are commonly used as "biochemical tools" to study of role which cyclic nucleotides plays in the cell, but they also may be useful to investigate the structural and functional activities of PDE. As therapeutic agents, they can also be utilized in controlling the pathophysiological changes of responses generated by the cyclic nucleotides in the central nervous system (CNS), cardio-vascular, lung, digestive tract and respectively. PDE enzymes are often targets for inhibition by pharmacological processes due to their unique tissue distribution, structural and functional properties and the inflammatory process. The effect of many of these drugs is evident in more than one isoenzyme, and many tissues possess more than one isoenzyme. As a result, phosphodiesterase inhibitors (PDEI) can have a multiplicity of effects. For example, theophylline has effects on the lung, as well as cardiac and vascular effects; amrinone affects cardiac, vascular and platelet functions. The PDE inhibition, change the intracellular response to extra cellular signals by affecting the processes by the the cyclic nucleotides.
Molecular Pharmacology, 2002
Vascular smooth muscle cells (VSMC) in situ function to control contraction and are said to express a contractile phenotype. However, during development or in response to vascular damage, VSMC proliferate and express a more synthetic phenotype. A survey of literature values for contractile and synthetic VSMC phosphodiesterase (PDE) 3 and PDE4 activities identified a marked difference in the PDE3 and PDE4 activities of these cells. In this study, a comparison of PDE3 and PDE4 activities in contractile and synthetic VSMC demonstrates that ABBREVIATIONS: VSMC, vascular smooth muscle cells; PDE, phosphodiesterase; HBSS, Hanks' balanced salt solution; Ro 20-1724; 4-[(3butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone; IBMX, 3-isobutyl-1-methylxanthine; PCR, polymerase chain reaction; bp, base pair(s); DAPI, 4Ј,6Ј-diamidino-2-phenylindole dihydrochloride, hydrate.
Pharmacologic activity of phosphodiesterases and their inhibitors
The paper is an up dated bibliographical synthesis, as an incipient scientific research, of several important scientific works, which had appeared in the latest year's scientific publications, referring to the Phosphodiesterase group (PDE) and its inhibitors, in the processes of installing, evolution and functional behaviour in humans and animals. The relative lack of information and knowledge in the up mentioned field, and the new specific products introduced in the last ten years in Romania, motivate the presentation of the PDE families and its inhibitors and also, a scholastic explanation of the PDE implications upon the specific enzymatic systems. In the paper the mechanisms for most important PDE groups are described, focusing the intimate processes installing, evolution and the role of the PDE's inhibitors, acting as therapeutic agents and physiological modifiers of PDE generated answers in mammalian's tissues and organs.
Anesthesia & Analgesia, 2006
Little is known about of the comparative cardiac lusitropic and coronary vasoactive effects of type III phosphodiesterase inhibitors independent of their systemic circulatory effects. We hypothesized that phosphodiesterase inhibitors have dissimilar concentration-dependent effects on cardiac function and metabolism and that their coronary vasodilatory effects are solely dependent on flow autoregulation secondary to positive inotropic effects. Our aim was to compare the dose-response electrophysiologic, mechanical, vasodilatory, and metabolic properties of three clinically available phosphodiesterase inhibitors in isolated Langendorff perfused guinea pig hearts. We found that, over a range from 10 Ϫ7 to 10 Ϫ4 M, amrinone, enoximone, and milrinone each produced maximal concentration-dependent positive chronotropic (12%, 18%, 26%), inotropic (16%, 26%, 26%), and lusitropic (14%, 21%, 19%) effects. At clinical concentrations, all phosphodiesterase inhibitors increased heart rate, but only milrinone significantly enhanced contractility and relaxation (11%). Each phosphodiesterase inhibitor similarly increased contractility at its highest concentration; this was accompanied by an increase in oxygen consumption, which was matched by comparable increases in coronary flow and oxygen delivery. Coronary flow reserve was preserved at the highest concentration of each drug, indicating that an increased metabolic rate was responsible for the increase in coronary flow by each drug at each concentration. Over the concentrations examined, we conclude that each of the phosphodiesterase inhibitors does not directly promote coronary vasodilation and that milrinone has the most prominent effects on contractility and relaxation at clinically relevant concentrations.
Cardiovascular and other pharmacological approaches of phosphodiesterase enzyme inhibitors
2013
REVIEW ARTICLE ABSTRACT ARTICLE INFORMATION A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE) selectively in the brain. PDE3 inhibitors can be thought of as a backdoor approach to cardiac stimulation, whereas β-agonists go through the front door to produce the same cardiac effects. PDE3 was identified as a potential therapeutic target in cardiovascular disease and asthma, and indeed, PDE3 inhibitors have subsequently been shown to relax vascular and airway smooth muscle, inhibit platelet aggregation and induce lipolysis. It was recognised that papaverine and pentoxifylline mediated vasorelaxation by a number of mechanisms including non-selective PDE inhibition and these drugs can be considered as forerunners to the clinically successful PDE5 inhibitors used today for the treatment of erectile dysfunction. Phosphodiesterase inhibitors (PDIs) have important vascular and myocardial protective effects and thus have...
Ischemia-dependent efficacy of phosphodiesterase inhibition☆
The Annals of Thoracic Surgery, 1994
To evaluate the inotropic efficacy of phosphodiesterase inhibition in hearts with and without ischemic injury, 27 sheep were evaluated sonomicrometrically during incremental volume loading on right heart bypass. Contractility was assessed with the preload recruitable stroke work relationship. Active relaxation rate was estimated using the time constant of isovolumic pressure decay (tau). For nonischemic assessment, groups 1 and 2 (n = 6 each) underwent 45 minutes of vented perfusion after which milrinone was administered to group 1; group 2 served as nonischemic controls. There was no detectable increase in preload recruitable stroke work or decrement in tau after milrinone administration. Groups 3 and 4 underwent 15 minutes of 37°C ischemia (aortic crossclamping) followed by 30 minutes of vented reperfusion.
Characterisation of cyclic nucleotide phosphodiesterases from rat mesenteric artery
European Journal of Pharmacology: Molecular Pharmacology, 1991
Four cyclic nucleotidc phosphodic,,wrasc activities (PDEs) could be rc~olvcd from rat mcscntcric artc~ by DEAE-Scphaccl chromatography: a cal.x~odulin-achvatcd fraction, a cyclic GMP-inhibitcd fraction, a cyclic AMP-specific rolipram-sensitivc fraction and a cyclic GMP-spccific fraction containing PDE 1, IlL IV and V. Cardiotonic drugs (CI 930 and LY 195115) sclecti~,cly inhibited PDE Ilk rolipram and zaprinast sclcctivcly inhibited PDE IV and PDE V, rcspc~.t,¢cly. These rc~,uhs show that the ,';at mesentcric artery contains the samc PDEs as previously found in the aorta, arid ~;i,l~gct, t that these PDEs may be implicated in the regulation of arterial contraction.