Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The mechanism of vasorelaxation for phosphodiesterase III inhibitors is mediated by increase of cAMP whereas for nitrovasodilators, cGMP. The purpose of this study was to test the hypothesis that the phosphodiesterase III inhibitor milrinone and nitroglycerin (NTG) may have greater than additive effects in human arteries. 2. Internal mammary artery segments (IMA, n = 90) taken from 23 patients were studied in organ chambers. The effect of milrinone (3 microM), NTG (10 nM), or the combination was tested in IMA rings precontracted with potassium (K+, 25 mM) or U46619 (10 nM). Concentration-contraction curves for K+ or U46619 were established in other rings treated with milrinone (70 microM), NTG (0.1 microM), or the combination for 10 min. 3. In K(+)-induced contraction, the combination produced more relaxation (45.4%) than did either milrinone (7.9%, P < 0.05) or NTG (3.8%, P < 0.05) alone. This relaxation was significantly more than the theoretical overadditive effect (P < 0.05). Similar results were seen in U46619-induced contraction (94.1% by the combination vs 70.7% by milrinone, P < 0.05, or 36.1% by NTG, P < 0.05). Pretreatment with the combination depressed contraction to a higher extend compared with milrinone alone (P < 0.05) for the K(+)-induced contraction and to NTG alone (P < 0.05) in U46619-induced contraction. Treatment with the combination also shifted EC50 rightward and this shift was significantly more than that caused by treatment with NTG alone (P < 0.05). 4. We conclude that there is a greater than additive vasorelaxant effect of PDE III inhibitors and nitrovasodilators in human conduit arteries. This effect may be beneficial to patients undergoing coronary artery bypass grafting and to other patients requiring these vasodilators. Reduced doses of the vasodilators in concentration may be sufficient to produce vasodilatation similar to that produced by either of them alone at higher concentrations.
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PMID:Potential greater than additive vasorelaxant actions of milrinone and nitroglycerin on human conduit arteries. 883 35

1. In rat aortic rings precontracted by phenylephrine, H7 (10(-5)M) and staurosporine (10(-7)M), which inhibit PKA, PKG and PKC, and H-89 (10(-6)M), which inhibits PKA and PKG, potentiated relaxations induced by nitroglycerin. Forskolin-induced relaxations were not affected by H7 (10(-5)M). 2. Nitroglycerin-induced relaxations were not affected by calphostin-C (10(-7)M), which inhibits PKC, H-89 (10(-7)M), which inhibits PKA, and staurosporine (2 x 10(-9)M), which inhibits PKC. 3. Iberiotoxin (3 x 10(-8)M), an inhibitor of large conductance Kca channels, partly inhibited the relaxation induced by nitroglycerin and completely inhibited the potentiating effect of H7 on nitroglycerin-induced relaxations. 4. The potentiating effect of zaprinast (10(-5)M), an inhibitor of cGMP-phosphodiesterase, on nitroglycerin-induced relaxation was not affected by iberiotoxin. In the presence of methylene blue (10(-5)M), an inhibitor of guanylate cyclase, the residual relaxing response to nitroglycerin was not affected by H7, but it was inhibited by iberiotoxin. 5. These results suggest that the potentiation of nitroglycerin-induced relaxation by H7, staurosporine and H-89 may be due to inhibition of PKG.
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PMID:The potentiation of nitroglycerin-induced relaxation by PKG inhibition in rat aortic rings. 885 8

Maxadilan is a peptide from the salivary gland of the sand fly Lutzomyia longipalpis, a vector for leishmaniasis. Cutaneous injection of femtomolar quantities of maxadilan produces long-lasting erythema, making it the most potent vasodilator known. Isolated rabbit thoracic and abdominal aorta, carotid artery, and iliac artery demonstrated dose-dependent arterial relaxation in response to maxadilan with a mean effective concentration (EC50) of 2.7 +/- 1.5, 2.1 +/- 0.5, 2.6 +/- 0.4, and 1.9 +/- 0.5 nM, respectively. Maxadilan proved to be at least sevenfold more potent than nitroglycerin in each arterial bed (EC50 = 25 +/- 12, 32 +/- 9, 37 +/- 10, and 22 +/- 13 nM, respectively; P < 0.05 for each vs. maxadilan). Arterial relaxation to maxadilan was independent of endothelium and was equipotent in the thoracic and abdominal aorta, carotid artery, and iliac artery. Arterial relaxation to maxadilan was not inhibited by K(+)-channel antagonists, methylene blue, quinacrine, or ouabain. Maxadilan-mediated arterial relaxation was found to be adenosine 3',5'-cyclic monophosphate (cAMP) dependent, as it was potentiated by the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine and theophylline, and it was inhibited by the protein kinase A inhibitor H-89. Consistent with this observation, incubation of thoracic aorta with maxadilan (0.1 microM) produced a time-dependent increase in arterial cAMP content coincident with arterial relaxation. Using rabbit aortic smooth muscle cells, we also observed a time-dependent reduction in intracellular calcium in response to maxadilan. Thus these data indicate that maxadilan, a peptide from the sand fly salivary gland, is a potent vasodilator that reduces intracellular calcium through a cAMP-dependent mechanism.
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PMID:Vasodilatory properties of recombinant maxadilan. 885 26

Systemic hypertension is a constant feature of chronic renal failure, mediated by renin and exacerbated by salt and fluid loading. Vascular atherosclerosis appears to accelerate in patients on long-term dialysis. Therefore, it is important to control hypertension and keep appropriate renal blood flow during living renal transplantation surgery. Amrinone, a phosphodiesterase inhibitor, produces vasodilation in arterial smooth muscle as well as venodilation in the capacitance bed. By increasing myocardial contractility it increases inotropic effect. Amrinone has potent inodilator effects because of its dual mechanism of action. The current study is aimed to compare hemodynamic effects between amrinone (3-5 mg.kg-1.min-1) (AMR group, n = 4) and nitroglycerin (0.3-1.0 mg.kg-1.min-1) (NTG group, n = 5), combined with dopamine (3-5 mg.kg-1.min-1) in nine patients undergoing living renal transplantation. Increase in cardiac index in AMR group was significantly larger than that in NTG group. Values of systemic and pulmonary vascular resistance in AMR group were significantly smaller than those in NTG group. No significant difference was found in renal function in the post-operative period.
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PMID:[Hemodynamic effects of amrinone combined with dopamine in patients undergoing living renal transplantation]. 902 89

Intracavernous pharmacotherapy of erectile dysfunction has been established for over 10 years, with prostaglandin E1 (PGE1) being the standard substance with the lowest rate of side effects. Recent investigations deal with the identification of intracellular mechanisms of smooth muscle relaxation in cavernous tissue as the most important aspect of penile erection. Nitric oxide and specific phosphodiesterase-isoenzymes seem to play a central role. This resulted in clinical studies with the intracavernous injected nitric oxide-donor linsidomine (SIN 1) and the orally given phosphodiesterase-inhibitor sildenafil. Furthermore new ways of pharmaco-application are tested, e.g. transdermal treatment with nitroglycerin, minoxidil or papaverine, as well as intraurethral injection of prostaglandin E1.
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PMID:[Pharmacological therapy in erectile dysfunction--current standards and new viewpoint]. 919 Jul 65

The effects of intravenous infusions of 1, 3 and 10 microg/kg/min of the phosphodiesterase 5 inhibitor, E4021, at 30-min intervals on coronary artery diameter were studied in 8 conscious pigs monitored with a pair of piezoelectric crystals. The highest dose increased the diameter by 2.9 +/-0.5% (P <0.01 vs vehicle) of the baseline diameter, with a significant decrease in mean pulmonary arterial pressure. However, there were no changes in mean aortic pressure and heart rate. Additionally, E4021 significantly prolonged the duration of the diameter increase induced by nitroglycerin. Thus, phosphodiesterase 5 inhibition causes coronary artery diameter increase and produces an amplifying effect with nitroglycerin.
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PMID:Coronary artery diameter increase induced by a phosphodiesterase 5 inhibitor, E4021, in conscious pigs. 963 65

This study describes the phosphodiesterase inhibitory potency and cardiovascular actions of WIN 65579 (1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyrridyl)-1H-pyrazolo[3,4-d]p yrimidin-4-one), a potent, new cGMP phosphodiesterase 5 inhibitor. WIN 65579 is a competitive inhibitor of phosphodiesterase 5, with IC50 values of 2-3 nM for phosphodiesterase 5 from human or canine vascular sources. WIN 65579 has low affinity for phosphodiesterases 1, 2 and 3 (IC50 > 3-10 microM), and is somewhat selective for phosphodiesterase 4 (IC50 approximately 100 nM). WIN 65579 is an endothelial-dependent relaxant of rat aortic smooth muscle (EC50 = 60 nM) and lowers mean arterial blood pressure in conscious spontaneous hypertensive rats following intravenous or oral dosing. WIN 65579 also increases plasma cGMP levels, and reinstates vascular responsiveness to nitroglycerin in conscious rats that are nitroglycerin-tolerant. These data show that WIN 65579 is one of the more potent phosphodiesterase 5 inhibitors, and that WIN 65579 possesses cardiovascular activities consistent with vascular phosphodiesterase 5 inhibition in vivo.
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PMID:Cardiovascular activity of WIN 65579, a novel inhibitor of cyclic GMP phosphodiesterase 5. 967 Nov 6

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.
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PMID:Clinical pharmacokinetics of vasodilators. Part II. 967 32

The effect of genistein, a tyrosine kinase inhibitor, on nitroglycerin-induced relaxation was examined in rat aortic rings contracted by phenylephrine. In rat aortic rings, genistein (10(-5) M and 3x10(-5) M), a tyrosine kinase inhibitor, but not daidzein, an analogue of genistein, increased relaxation induced by nitroglycerin in a concentration-dependent manner. Iberiotoxin, an inhibitor of Ca2+ -activated K+ channels, inhibited the relaxation induced by nitroglycerin, but it did not affect the effect of genistein. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, did not affect the relaxation induced by nitroglycerin. Theophylline, an inhibitor of cyclic AMP-dependent phosphodiesterase, increased the relaxation induced by nitroglycerin, and genistein (10(-5) M) failed to affect the relaxation induced by nitroglycerin in the presence of theophylline. Genistein also inhibited the activity of cyclic AMP-dependent phosphodiesterase. In addition, 6-[4-(4'-pyridyl)amino phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, an inhibitor of cyclic GMP-inhibitable cyclic AMP phosphodiesterase, inhibited the relaxation induced by nitroglycerin. These results suggest that, in the rat aortic rings, genistein inhibits cyclic AMP-dependent phosphodiesterase activities, resulting in the increase of the relaxation induced by nitroglycerin.
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PMID:Increased nitroglycerin-induced relaxation by genistein in rat aortic rings. 1045 30

Maintenance of adequate oxygen balance to all tissues is one of the primary objectives when dealing with patients undergoing cardiac surgery. Cardiac output is one of the major components of oxygen delivery so that its maintenance is an important consideration. Due to pre-operative cardiac lesion and myocardial dysfunction secondary to the events related to cardiac surgery and cardiopulmonary by-pass, circulatory support by pharmacological or mechanical means is frequently required after surgery. Therefore, inotropes and vasodilators are used to improve the myocardial performance after cardiac surgery. Epinephrine, dopamine and dobutamine are commonly used inotropes. Dopexamine and phosphodiesterase inhibitors such as amrinone, milrinone and enoximone are some of the newer agents that have been introduced in clinical practice. Amongst the vasodilators, sodium nitroprusside and nitroglycerin are commonly used. Alpha adrenergic blockers such as phentolamine and phenoxybenzamine and calcium channel blockers such as diltiazem are some other vasodilators that can be used. Many units still regard epinephrine as an inotrope of choice and use its predominant beta agonist effect in the dose range of 0.02 to 0.04 mg/kg/minute. Some prefer dobutamine and others a combination of inotrope and vasodilator or an inodilator. Phosphodiesterase inhibitors can be useful in certain situations such as pre-existing ventricular dysfunction or when stunning of the myocardium is suspected with down regulation of beta receptors. Dopamine is useful in the renal vasodilating dose to improve renal perfusion and improve output. There is no ideal inotrope at present and each one has its own drawbacks. The clinician must learn to use the inotropes (especially the newer ones) based on his own clinical experience.
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PMID:Pharmacologic support of circulation in patients undergoing cardiac surgery. 1063 2


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