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)

The benzimidazol analogue BM14.478 is a phosphodiesterase inhibitor with both vasodilator and positive inotropic properties. Hemodynamic parameters and plasma hormone levels of 8 patients (1 female, 7 male) with chronic congestive heart failure NYHA Classes II-IV (1 patient with coronary artery disease, 7 patients with primary dilated cardiomyopathy) were assessed before and until 6 h after the intravenous application of 1.0 mg BM14.478. There was a significant decrease of mean pulmonary artery pressure (28 +/- 11 vs. 23 +/- 11 mmHg; p less than 0.05), mean right atrial pressure (8.6 +/- 5.2 vs. 5.0 +/- 4.7 mmHg; p less than 0.02), and systemic vascular resistance (1651 +/- 484 vs. 1206 +/- 252 dynes.s.cm-5; p less than 0.05) as early as 10 min after injection of BM14.478. Pulmonary vascular resistance also was reduced (128 +/- 86 vs. 61 +/- 39 dynes.s.cm-5, 30 min after injection; p less than 0.02). Simultaneously there was a significant increase of cardiac index (2.3 +/- 0.7 vs. 3.1 +/- 0.8 l.min-1.m-2, 10 min after injection; p less than 0.02), and stroke volume index (28.8 +/- 11.7 vs. 33.9 +/- 8.5 ml.min-1.m-2; 30 min after injection; p less than 0.05). Although mean heart rate did not change significantly, some patients reacted with a transient increase. There was also a slight but insignificant increase of the double product. No serious side effects were observed. The hemodynamic improvement was followed by a delayed reduction of plasma levels of epinephrine (51 +/- 20 vs. 41 +/- 21 pg/ml; p less than 0.02; 30 min after injection) and atrial natriuretic peptide (229 +/- 283 vs. 121 +/- 168 pg/ml; p less than 0.05; 1 h after injection). Mean levels of plasma norepinephrine, however, did not change significantly and individual responses showed large variations, which could not be predicted by the behavior of the hemodynamic parameters. Three of eight patients (2 of these with elevated baseline filling pressures) even showed a marked increase of plasma norepinephrine levels after BM14.478. Response of plasma renin activity and plasma vasopressin levels to BM14.478 also was heterogeneous. According to the results of this study, acute administration of the phosphodiesterase inhibitor BM14.478 has an immediate beneficial hemodynamic effect in patients with severe congestive heart failure by reducing both preload and afterload, and by increasing cardiac index and stroke volume. However, this improvement of hemodynamic parameters is not necessarily accompanied by a favorable short-term response of plasma hormones, and therefore does not allow any conclusions on survival of these patients.
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PMID:Hemodynamic and neuroendocrine response to acute administration of the phosphodiesterase inhibitor BM14.478 in patients with congestive heart failure. 204 89

The rationale of combining vasodilatation with positive inotropic intervention in the treatment of chronic heart failure has found a new implementation in the "inodilator" drugs. Inodilators are characterized by the properties of exerting positive inotropic effect and inducing systemic vasodilatation. The cellular mechanisms involved in the regulation of contractility of cardiac and vascular muscle and the pathophysiological events occurring in heart failure are briefly discussed, and the pharmacological profile as well as the therapeutic use of these drugs are reviewed. On the basis of the mechanism of action, two groups of inodilators are distinguished, the phosphodiesterase inhibitors and the dopaminergic agents. The increase of [cAMP]i induced by the phosphodiesterase inhibitors is responsible for their vasodilating effect and for the positive inotropic action, but many of them have in addition the ability to enhance the Ca2+ sensitivity of cardiac contractile proteins. The complex organization and the cardinal role of the catecholaminergic receptor system in the control of cardiovascular function and its contribution to the pathophysiological events occurring in heart failure are the rational basis of the therapeutic use of dopaminergic agents. These drugs, acting on DA, beta-, and alpha-receptors, exert not only positive inotropic and vasodilating effects, but also a diuretic action, and can reduce aldosterone and renin secretion, blunt an excessive sympathetic activity, and possibly promote the release of atrial natriuretic peptide. The multireceptor mechanism of dopamine-like drugs, which accounts for their favorable hemodynamic, neurohumoral, and diuretic effects, represents the most promising approach to inodilator therapy.
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PMID:Present and future trends in research and clinical applications of inodilators. 248 38

The intracellular messengers that seem to be involved in renin secretion (RS) from juxtaglomerular cells (JG) are calcium (Ca), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Unlike the majority of secretory systems, an increase in intracellular Ca concentration and calmodulin and protein kinase C activation inhibit RS. The intracellular Ca concentration in JG cells can be modified if: 1) the normal mechanisms of Ca extrusion of these cells is altered; 2) the calcium output is blocked by lanthanum; 3) the function of the voltage-sensitive Ca-channels is modified; 4) uptake or liberation of Ca from endoplasmic reticulum is modified; 5) plasmatic membrane is bypassed with calcium ionophores such as A 23187. 6) JG cells are stimulated by hormones that increase Ca and activate protein kinase C such as angiotensin II, vasopressin or alpha-1 adrenergic agonists; 7) extracellular Ca concentration increases or decreases. RS is stimulated by dibutyryl cAMP, cAMP phosphodiesterase inhibitors and by hormones and agents that activate adenylate cyclase (beta adrenergic agonists, bradykinin, histamine, forskolin and ethylcarboxamide adenosine). On the contrary, RS is inhibited by hormones and agents that inhibit adenylate cyclase such as: alpha-2 adrenergic agonists, neuropeptide Y, angiotensin II and cyclohexyladenosine. Pertussis toxin increases basal RS, blocks the inhibition by agents and hormones which inhibit adenylate cyclase and potentiate the stimulation produced by beta-adrenergic agonists. In JG cells, atrial natriuretic peptide inhibits RS, increases cGMP and decreases cAMP. The increase in cGMP correlates well with the inhibition of RS.
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PMID:[Intracellular messengers in the regulation of renin secretion]. 255 Oct 26

The pathophysiology of the syndrome of congestive heart failure (CHF) includes 2 major components that closely interact. The first one is a reduction in ventricular performance, which is manifested initially during exercise and is later present at rest. The second one involves abnormalities of the peripheral circulation and organs, which become gradually more prominent and lead ultimately to symptoms. The exercise capacity of patients with chronic CHF is limited not only by an inadequate increase in cardiac output and an excessive increase in ventricular filling pressure, but also by a fixed vasodilatory response to exercise. Although the role of increased activity of the sympathetic and renin-angiotensin-aldosterone systems in the derangements of the peripheral circulation has been extensively investigated, the structural abnormalities of the arterial wall have received little emphasis in patients with CHF. Chronic reduction of the cardiac output may lead to endothelium-dependent reduction in arterial diameter and vasomotor response, which may in turn increase systemic vascular resistance and further reduce cardiac output. Therapeutic agents should be characterized by their acute and chronic effects not only on ventricular performance, but also on the peripheral circulation. More specifically, when one is concerned with the effect of a therapeutic intervention on exercise capacity, evaluation of its direct and indirect effects on the skeletal muscle vasculature is particularly important. Accordingly, the effects of phosphodiesterase inhibition on vascular smooth muscle tone and skeletal muscle vasculature are reviewed. In addition, the potential of phosphodiesterase inhibition to reverse structural abnormalities of the arterial wall is discussed.
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PMID:Effects of phosphodiesterase inhibition on skeletal muscle vasculature. 290 94

The peak hemodynamic effect and hormonal response of the phosphodiesterase inhibitor enoximone (MDL 17,043) were compared with those of dobutamine in 10 patients with severe congestive heart failure. Both agents significantly (p less than 0.05) increased cardiac index, stroke volume index and heart rate. Enoximone tended to decrease mean systemic arterial and pulmonary artery wedge pressures (0.05 less than p less than 0.1), whereas dobutamine did not. Both agents decreased systemic vascular resistance (p less than 0.05). The increase in heart rate was greater with dobutamine than with enoximone (p less than 0.05). Plasma renin activity increased significantly with dobutamine (from 11.3 +/- 13.5 to 17.8 +/- 15.0 ng/ml/hour, p less than 0.01) and with enoximone (from 13.6 +/- 18.3 to 16.6 +/- 18.8 ng/ml/hour, 0.05 less than p less than 0.1). Dobutamine suppressed plasma norepinephrine level (p less than 0.05) and enoximone did not. Neither agent affected the plasma vasopressin level. These data demonstrate a similar acute hemodynamic and hormonal profile for both enoximone and dobutamine. Further, dobutamine, like other beta agonists, provokes renin secretion and may do so to a greater extent than enoximone.
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PMID:Comparative hemodynamic and hormonal response of enoximone and dobutamine in severe congestive heart failure. 294 27

Using a renal cortical slice system from sodium loaded (SL) or sodium deficient (SD) rats, this study investigated whether the effect of prostaglandin E2 (PGE2) on renin release (RR) is mediated by tissue cyclic AMP content (TcAMPc) changes, and if it can be modified by dietary sodium manipulation. At 10(-5) M, PGE2 significantly stimulated RR and TcAMPc in both SL and SD groups of slices. PGE2 doses of 10(-9) M and 10(-7) M were ineffective, although RR, but not TcAMPc, was significantly greater in the SD group in response to 10(-7) M PGE2 than RR in the SL group. Addition of the phosphodiesterase inhibitor theophylline (10(-4) M) together with the same three PGE2 doses maintained the stimulatory effect of 10(-5)M PGE2 alone on RR and TcAMPc in both groups of slices, and reversed the effect of 10(-7) M PGE2 alone on RR and TcAMPc in the SD group of slices only. Added by itself, theophylline was ineffective. These data indicate that: PGE2 can stimulate RR by a direct effect on the juxtaglomerular cells; the RR responses to PGE2 and theophylline administration are enhanced in the SD state; and the possibility of cAMP mediation of the effect of PGE2 on RR is discussed.
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PMID:Dietary sodium deficiency potentiates the effect of prostaglandin E2 on in vitro renin release in the rat. 299 26

This study was designed to examine: (a) the effects of adenosine and its analogues on renin release in the absence of tubules, glomeruli, and macula densa, and (b) whether adenosine may be involved in a macula densa-mediated renin release mechanism. Rabbit afferent arterioles (Af) alone and afferent arterioles with macula densa attached (Af + MD) were microdissected and incubated for two consecutive 30-min periods. Hourly renin release rate from a single arteriole (or an arteriole with macula densa) was calculated and expressed as ng AI X h-1 X Af-1 (or Af + MD-1)/h (where AI is angiotensin I). Basal renin release rate from Af was 0.69 +/- 0.09 ng AI X h-1 X Af-1/h (means +/- SEM, n = 16) and remained stable for 60 min. Basal renin release rate from Af + MD was 0.20 +/- 0.04 ng AI X h-1 X Af + MD-1/h (n = 6), which was significantly lower (P less than 0.0025) than that from Af. When adenosine (0.1 microM) was added to Af, renin release decreased from 0.72 +/- 0.16 to 0.24 +/- 0.04 ng AI X h-1 X Af-1/h (P less than 0.025; n = 9). However, when adenosine was added to Af + MD, no significant change in renin release was observed. N6-cyclohexyl adenosine (an A1 adenosine receptor agonist) at 0.1 microM decreased renin release from Af from 0.69 +/- 0.14 to 0.39 +/- 0.12 ng AI X h-1 X Af-1/h (n = 5, P less than 0.05). However, 5'-N-ethylcarboxamide adenosine (an A2 adenosine receptor agonist) either at 0.1 microM or at 10 microM had no effect. Theophylline, at a concentration (10 microM) that does not block phosphodiesterase but does block adenosine receptors, increased renin release from Af + MD from 0.21 +/- 0.03 to 0.46 +/- 0.08 ng AI X h-1 X Af + MD-1/h (P less than 0.05; n = 8). The results are consistent with the hypotheses that adenosine decreases renin release via the activation of A1 adenosine receptors, and that adenosine may be an inhibitory signal from the macula densa to juxtaglomerular cells.
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PMID:Possible role of adenosine in the macula densa mechanism of renin release in rabbits. 299 77

We have examined the effect of a synthetic analogue of human alpha-atrial natriuretic peptide (ANP), APII, on renin release in cultured renal juxtaglomerular cells (JGA cells). Using cell cultures containing 80-90% renal juxtaglomerular cells, we found that ANP (10(-13)-10(-9) M) strongly inhibited renin release from the cells in a dose-dependent fashion (ki, 10 pM) to about 10% of control. Inhibition of renin release by ANP was paralleled by an increase in cellular cGMP levels; while in the presence of the cGMP-phosphodiesterase inhibitor M&B 22948 (1 mM), concentrations of ANP lower by a factor of 100 were required to obtain the same effects on renin release and cGMP levels. The guanylate cyclase inhibitor methylene blue (10 microM), on the other hand, shifted the dose-response curves for renin release and cGMP levels to 100-fold higher concentrations of ANP. Neither the influx of 45Ca into the cells nor the intracellular quin-2 signal, which is a measure for changes of intracellular Ca concentration, was in any way altered by ANP. Our results suggest that ANP inhibits renin release from juxtaglomerular cells by a cGMP-dependent process that does not involve changes in intracellular calcium.
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PMID:Atrial natriuretic peptide inhibits renin release from juxtaglomerular cells by a cGMP-mediated process. 301 9

Using a renal cortical slice preparation obtained from hibernating ground squirrels, this study investigated whether three major intrarenal prostaglandins (PG) and other agents added at a 10(-5) M dose can affect renin release (RR), and if their effect on RR is correlated with changes in tissue cyclic AMP content (tcAMPc). Resting in vitro levels for RR and tcAMPc during hibernation were found to be comparable to those observed in non-hibernating (NH) mammals. Addition of PGE1 significantly stimulated RR while PGE2 and PGF2-alpha were ineffective. None of the three PG's tested altered resting levels of tcAMPC. When added by itself or in conjunction with any of the three PG's, the phosphodiesterase inhibitor theophylline did not modify resting levels of RR and tcAMPc, but it prevented the previous stimulatory effect of PGE1 alone on RR. Addition of lipid-soluble dcAMP, either alone or in conjunction with any of the three PG's, resulted in an increase in tcAMPc in all instances, no change in resting RR regarding PGE2 and PGF2-alpha, and again the prevention of the stimulatory effect of PGE1 alone on RR. These data suggest that: the resting activity of the renin-angiotensin system (RAS) and the adenylate cyclase-cAMP system (AC-cAMP) of the hibernating ground squirrel is comparable to that of NH species; in contrast, the sensitivity of the RAS of the hibernator to PG stimulation is less than that exhibited by the RAS of NH species when comparable in vitro concentrations of three major PG's are used; PGE1 stimulation of RR in the hibernator is independent of changes in tcAMPc; changes in tcAMPc may be inversely related to those in RR in the hibernator; and the known stimulatory effect of PG's on the renal cortical AC-cAMP of NH species is not seen in the hibernating ground squirrel at comparable PG doses.
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PMID:Prostaglandin E1 (PGE1) stimulates in vitro renin release in the hibernating ground squirrel. 301 51

The effect of aminophylline on renin release from human chorion was investigated by perfusing the tissue with various concentrations of the drug. Buffer containing aminophylline (2 X 10(-6) mol/l) doubled the rate of active and total renin secretion, but a more concentrated solution (10(-5) mol/l) released proportionately less active and total renin although the result was statistically significant. Renin secretion was not altered by aminophylline (5 X 10(-5) mol/l). The pattern of renin release was modulated by concentrations of aminophylline which were at least a 100-fold lower than those required to inhibit cyclic adenosine 3',5'-monophosphate phosphodiesterase. However, as the methylxanthines are potent adenosine receptor antagonists, we suggest that in the human chorion adenosine is a mediator of renin release.
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PMID:The effect of aminophylline on renin release from human chorio-decidua. 352 15


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