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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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)
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PMID:[Effects of phosphodiesterase inhibitors on diastolic function]. 821 93

We have compared the haemodynamic effects of the imidazole derivative phosphodiesterase inhibitors enoximone and piroximone in patients with low cardiac output after cardiac surgery. Ten patients (group E) received enoximone and 10 patients (group P) received piroximone, both at a loading dose of 0.5 mg kg-1 followed by an infusion of 5 micrograms kg-1 min-1. In both groups the main changes with time were increases in cardiac index (maximum 24.5% in group E, 25.8% in group P) and decreases in systemic vascular resistance (maximum 26.8% in group E and 24.8% in group P). There were moderate increases in heart rate (maximum 11.3% in group E and 13% in group P) but a greater percentage decrease in mean arterial pressure in group E (maximum 11.9% vs 7.9%) with time. One patient in group E developed hypertension during the loading dose. Two patients in group E and two in group P developed hypotension during the loading dose. One patient in group E developed ventricular extrasystoles which may have been related to the drug being studied.
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PMID:Comparison of the haemodynamic effects of enoximone and piroximone in patients after cardiac surgery. 828 May 56

1. Thyroid hormone (L-thyroxine, 10(-10) mol/l) incubated in vitro with human erythrocyte membranes induced the release of a soluble calmodulin-like material, the 3':5'-cyclic nucleotide phosphodiesterase-stimulating activity of which was at least six-fold greater than its concentration measured by a specific calmodulin radioimmunoassay. 2. The material had the characteristics of calmodulin in that it stimulated both phosphodiesterase and erythrocyte Ca(2+)-ATPase activities, cross-reacted with and was neutralized by anti-calmodulin antibody, was adsorbed by phenothiazine-Sepharose and was heat-stable. Control supernatant from the incubation of membranes in the absence of thyroxine contained calmodulin, the bioactivity of which was not enhanced beyond that predicted from radioimmunoassay. Subsequent addition of thyroxine did not increase calmodulin bioactivity. Calmodulin-agarose removed calmodulin-enhancing activity from the supernatant. 3. Thus, the enhancing factor(s) appears to interact directly with calmodulin. These observations indicate that thyroid hormone promotes the release from human erythrocyte membranes of a soluble factor (or factors) which binds to calmodulin and significantly increases its bioactivity. This enhancing activity is similar to that of a calmodulin activator described in a rat model of hypertension (S.-L. Huang et al., J Clin Invest 1988; 82: 276-81).
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PMID:Thyroid hormone stimulates release of calmodulin-enhancing activity from human erythrocyte membranes in vitro. 838 86

We investigated the influence of beta-adrenergic receptor activation on the control of gap junctional conductance (gj) in the heart of cardiomyopathic hamsters (11 months old). We measured gj in isolated ventricular cell pairs using two voltage-clamp circuits. Administration of isoproterenol (10(-6) mol/L) to the bath had no effect on gj in myopathic cell pairs but increased gj by 45 +/- 3% (+/- SE) in normal hamsters. Moreover, forskolin (10(-7) mol/L), an activator of adenyl cyclase, did not change gj in myopathic cells but enhanced gj by 23 +/- 2.8% in controls. Similar results were obtained with isobutylmethylxanthine (10(-6) mol/L), a phosphodiesterase inhibitor. Dibutyryl-cAMP (10(-6) mol/L), however, increased gj of cardiomyopathic cell pairs by 58 +/- 2.1% within 2 minutes and enhanced gj in controls by 50 +/- 3.6%. The effect of dibutyryl-cAMP on gj of myopathic cells was suppressed by intracellular dialysis of an inhibitor of protein kinase A. These observations indicate that the regulation of gj by the beta-adrenergic receptor-G protein-adenyl cyclase signaling system is greatly impaired in the failing heart but the ability of cAMP to increase gj is still preserved.
Hypertension 1996 Feb
PMID:Impaired regulation of cell communication by beta-adrenergic receptor activation in the failing heart. 856 50

Several endogenous factors generated within the vessel wall have been implicated in contributing to the vascular remodeling process associated with hypertension and atherosclerosis. Furthermore, substances generated by smooth muscle cells (SMCs) are known to regulate SMC proliferation in an autocrine fashion. Adenosine is a vasodilator synthesized by SMCs, and exogenous adenosine inhibits SMC proliferation. However, whether adenosine produced endogenously has antimitogenic effects is not known. Hence, we evaluated the effects of SMC-derived adenosine on 2.5% fetal calf serum-induced proliferation of rat aortic SMCs. SMC proliferation was assayed by measurement of DNA synthesis ([3H]thymidine incorporation) and cell counting. To determine the effects of endogenous adenosine on SMC proliferation, we stimulated growth-arrested SMCs with 2.5% fetal calf serum in the presence and absence of modulators of adenosine levels, including (1) erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA; inhibits adenosine deaminase), (2) dipyridamole (blocks adenosine transport and inhibits phosphodiesterase), (3) dipyridamole plus EHNA, and (4) adenosine with or without EHNA. [3H]Thymidine incorporation and cell number were measured after 24 and 96 hours, respectively. EHNA and dipyridamole inhibited both FCS-induced DNA synthesis and cell proliferation in a concentration-dependent manner. Furthermore, extracellular (in medium) adenosine levels were significantly increased when cultured cells were treated with EHNA, and the inhibitory effects of dipyridamole as well as exogenous adenosine were enhanced in the presence of EHNA. Additionally, the inhibitory effects of dipyridamole and EHNA on DNA synthesis were significantly reduced in the presence of KF17837, an A2 adenosine receptor antagonist. These results indicate that SMC-derived adenosine can inhibit SMC proliferation. Hence, it is possible that a defect in localized adenosine synthesis within the vessel wall could contribute to vascular thickening and neointima formation.
Hypertension 1996 Mar
PMID:Smooth muscle cell-derived adenosine inhibits cell growth. 861 38

We investigated the effects of adrenomedullin on nitric oxide synthesis by measuring the production of nitrite, a stable metabolite of nitric oxide, in cultured rat vascular smooth muscle cells. Incubation of cultures with interleukin-1beta (10 ng/mL) for 24 hours caused a significant increase in nitrite generation. The interleukin-1beta-induced nitrite production by vascular smooth muscle cells was significantly increased by adrenomedullin in a dose-dependent manner (10(-10) to 10(-6) mol/L). This effect of adrenomedullin was significantly inhibited in the presence of Ng-monomethyl-L-arginine. The adrenomedullin-induced nitrite production by interleukin-1beta-stimulated cells was accompanied by increased inducible nitric oxide synthase mRNA accumulation. In the presence of the phosphodiesterase inhibitor isobutylmethylxanthine, interleukin-1beta-induced nitrite accumulation was further increased, but the effect of adrenomedullin was not additive or synergistic. Adrenomedullin dose dependently increased intracellular cAMP levels of vascular smooth muscle cells. These results indicate that adrenomedullin augments nitric oxide synthesis in interleukin-1beta-stimulated vascular smooth muscle cells, at least partially through a cAMP-dependent pathway.
Hypertension 1996 Jun
PMID:Adrenomedullin increases inducible nitric oxide synthase in rat vascular smooth muscle cells stimulated with interleukin-1. 864 30

Cicletanine [particularly the levorotatory (-)enantiomer] inhibits calcium/calmodulin cyclic GMP phosphodiesterase (PDE) in vascular smooth muscle (VSM) and potentiates the vasorelaxant actions of the guanylate cyclase activators sodium nitroprusside (SNP) and atriopeptin II, but the possible interference with vasopressor mechanisms remains to be determined. We tested racemic (+/-) cicletanine for its ability to modify the vascular responses to vasocontractant agents in pithed rats. The most significant results were obtained with angiotensin II (AII). Therefore, the dose of AII that increased the carotid artery blood pressure (BP) 50 mm Hg was twice as high in cicletanine-pretreated (50 mg/kg orally, p.o.) as that in vehicle-pretreated animals (ED50 = 0.48 +/- 0.012 vs. 0.25 +/- 0.007 microgram/kg, p < 0.05). The displacement by cicletanine represented 47.2% of that obtained with losartan (40 micrograms/kg, intravenously, i.v.). Similar results were obtained with (-)-cicletanine (p.o. or i.v.), but not with (+)-cicletanine. In isolated rat aorta, the contraction induced by AII was reduced by (-)-cicletanine in a noncompetitive manner (the percent reduction was independent of the AII concentration). (-)-Cicletanine reduces the vascular reactivity to AII, which plays a key role in several forms of hypertension. These findings are compatible with an action of (-)-cicletanine at any of the numerous steps that couple the occupation of AII receptors to the final contractile response, such as calcium/calmodulin cyclic GMP PDE.
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PMID:Reduction by (-)-cicletanine of the vascular reactivity to angiotensin II in rats. 889 83

In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular smooth muscle cell growth. Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 mumol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L; an inhibitor of both extracellular and intracellular phosphodiesterase), alpha, beta-methyleneadenosine 5'-diphosphate (AMP-CP, 100 mumol/L; an ecto-5'-nucleotidase inhibitor), and 1,3-dipropyl-8-p-sulfophenyl-xanthine (DPSPX, 100 mumol/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5'-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10(-4) mol/L) and 8-bromo-cAMP (10(-4) mol/L) on fetal calf serum-induced DNA synthesis ([3H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A2 adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5'-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.
Hypertension 1996 Nov
PMID:Cyclic AMP-adenosine pathway inhibits vascular smooth muscle cell growth. 890 21

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

Understanding the mechanism of action and the pharmacokinetic properties of vasodilatory drugs facilitates optimal use in clinical practice. It should be kept in mind that a drug belongs to a class but is a distinct entity, sometimes derived from a prototype to achieve a specific effect. The most common pharmacokinetic drug improvement is the development of a drug with a half-life sufficiently long to allow an adequate once-daily dosage. Developing a controlled release preparation can increase the apparent half-life of a drug. Altering the molecular structure may also increase the half-life of a prototype drug. Another desirable improvement is increasing the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site. This is especially important for vasodilatory drugs which may be administered over decades for the treatment of hypertension, which usually does not interfere with subjective well-being. Compliance is greatly increased with once-daily dosing. Vasodilatory agents cause relaxation by either a decrease in cytoplasmic calcium, an increase in nitric oxide (NO) or by inhibiting myosin light chain kinase. They are divided into 9 classes: calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin-II receptor antagonists, alpha-adrenergic and imidazole receptor antagonists, beta 1-adrenergic agonist, phosphodiesterase inhibitors, eicosanoids and NO donors. Despite chemical differences, the pharmacokinetic properties of calcium antagonists are similar. Absorption from the gastrointestinal tract is high, with all substances undergoing considerable first-pass metabolism by the liver, resulting in low bioavailability and pronounced individual variation in pharmacokinetics. Renal impairment has little effect on pharmacokinetics since renal elimination of these agents is minimal. Except for the newer drugs of the dihydropyridine type, amlodipine, felodipine, isradipine, nilvadipine, nisoldipine and nitrendipine, the half-life of calcium antagonists is short. Maintaining an effective drug concentration for the remainder of these agents requires multiple daily dosing, in some cases even with controlled release formulations. However, a coat-core preparation of nifedipine has been developed to allow once-daily administration. Adverse effects are directly correlated to the potency of the individual calcium antagonists. Treatment with the potassium channel opener minoxidil is reserved for patients with moderately severe to severe hypertension which is refractory to other treatment. Diazoxide and hydralazine are chiefly used to treat severe hypertensive emergencies, primary pulmonary and malignant hypertension and in severe preeclampsia. ACE inhibitors prevent conversion of angiotensin-I to angiotensin-II and are most effective when renin production is increased. Since ACE is identical to kininase-II, which inactivates the potent endogenous vasodilator bradykinin, ACE inhibition causes a reduction in bradykinin degradation. ACE inhibitors exert cardioprotective and cardioreparative effects by preventing and reversing cardiac fibrosis and ventricular hypertrophy in animal models. The predominant elimination pathway of most ACE inhibitors is via renal excretion. Therefore, renal impairment is associated with reduced elimination and a dosage reduction of 25 to 50% is recommended in patients with moderate to severe renal impairment. Separating angiotensin-II inhibition from bradykinin potentiation has been the goal in developing angiotensin-II receptor antagonists. The incidence of adverse effects of such an agent, losartan, is comparable to that encountered with placebo treatment, and the troublesome cough associated with ACE inhibitors is absent.
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PMID:Clinical pharmacokinetics of vasodilators. Part I. 964 8


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