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Twenty years ago it was demonstrated that angiotensin II (Ang II) acts on the brain, which results in an elevation of blood pressure. Ten years later, reninlike activity was discovered in the brain of the rat and dog, which gave rise to the concept of an endogenous brain renin-angiotensin system. In the periphery, the kidney, liver, and lungs work in unison to produce Ang II. Evidence for brain renin, substrate, converting enzyme, and angiotensins is reviewed. New data indicate that the enzyme system for the synthesis of Ang II within the brain may in fact be contained in the cell. All the components for a renin-angiotensin system have now been found in neuroblastoma/glioma cell lines and Ang II is present in primary cell culture of rat brain neurons. The significance of angiotensin in the brain for hypertension is that it may be a stimulus for vasopressin release and sympathetic activation, which can maintain high blood pressure. In the spontaneously hypertensive rat, there is evidence of increased brain angiotensin. Also, experiments with angiotensin-converting enzyme inhibitors show that blockade of brain angiotensin production leads to a long-lasting lowering of blood pressure. The activity of the inhibitors in part appears to be directly on the brain.
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We conclude that rtPA used in vitro at a therapeutic concentration has the capacity to generate significant quantities of kinins from human plasma. This kinin-forming activity depends on the activation of the fibrinolytic pathway. These data suggest that angioedema associated with rtPA treatment of ischemic stroke results directly from plasmin-mediated release of BK.
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The treatment and control groups were comparable in patient age, concurrent therapy and type and site of infarction. At 1 month, for all patients, mean total work performed was 34.9 +/- 20.9 kJ in the enalapril group (n = 169) versus 28.5 +/- 20.6 kJ in the placebo group (n = 158) (difference = 18.4%, p < 0.01). This between-group difference in favor of enalapril was greatest in patients > 70 years old (difference = 41.4%, p < 0.01, n = 105) and those with clinical evidence of heart failure (difference = 33.0%, p < 0.01, n = 122). At 6 months for all patients, mean total work performed was 35.4 +/- 23.8 kJ in the enalapril group versus 34.0 +/- 23.9 kJ in the placebo group (difference = 4.1%, NS).
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Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.
1. In order to determine whether the renin-angiotensin system is involved in myocardial ischaemia-reperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT1) antagonist, EXP3174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion. 2. EXP3174 (0.1 mg kg-1, i.v. followed by 0.02 mg kg-1 h-1 for 5.5 h) and enalaprilate (0.3 mg kg-1, i.v. followed by 0.06 mg kg-1 h-1 for 5.5 h) were used in doses inducing a similar level of inhibition (87 +/- 4 and 91 +/- 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3. Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4. Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT1 antagonist. 5. The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size. 6. These results indicate that activation of the renin-angiotensin system does not contribute to myocyte death in this canine ischaemia/reperfusion model.
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The short term effects of the novel diuretic MK 447 were examined in both normotensive and hypertensive (ACTH treated) conscious sheep. The drug had profound diuretic, natriuretic and kaliuretic effects in both groups. Plasma sodium was unchanged but plasma potassium fell and haematocrit increased. Plasma renin concentration increased with MK 447 in the normotensive but not the hypertensive sheep. In the normotensive sheep cardiac output fell, peripheral resistance increased and blood pressure was unchanged. In the hypertensive ACTH treated sheep cardiac output and blood pressure fell but resistance was unchanged.
The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10(-4) M, which reduced mRNAs for transforming growth factor (TGF)-β1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-β1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10(-4) M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-β1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential.
Distribution between well-stirred compartments is the classical paradigm in pharmacokinetics. Also in capillary-issue exchange modeling a barrier-limited approach is mostly adopted. As a consequence of tissue binding, however, drug distribution cannot be regarded as instantaneous even at the cellular level and the distribution process consists of at least two components: transmembrane exchange and cytoplasmic transport. Two concepts have been proposed for the cytoplasmic distribution process of hydrophobic or amphipathic molecules, (i) slowing of diffusion due to instantaneous binding to immobile cellular structures and (ii) slow binding after instantaneous distribution throughout the cytosol. The purpose of this study was to develop a general approach for comparing both models using a stochastic model of intra- and extravascular drug distribution. Criteria for model discrimination are developed using the first three central moments (mean, variance, and skewness) of the cellular residence time and organ transit time distribution, respectively. After matching the models for the relative dispersion the remaining differences in relative skewness are predicted, discussing the relative roles of membrane permeability, cellular binding and cytoplasmic transport. It is shown under which conditions the models are indistinguishable on the basis of venous organ outflow concentration-time curves. The relative dispersion of cellular residence times is introduced as a model-independent measure of cytoplasmic equilibration kinetics, which indicates whether diffusion through the cytoplasm is rate limiting. If differences in outflow curve shapes (their relative skewness) cannot be detected, independent information on binding and/or diffusion kinetics is necessary to avoid model misspecification. The method is applied to previously published hepatic outflow data of enalaprilat, triiodothyronine, and diclofenac. It provides a general framework for the modeling of cellular pharmacokinetics.
Haemodynamic comparison of three vasodilation regimens [intravenous (i.v.) hydralazine and isosorbide dinitrate (ISDN) combined, i.v. doxazosin, and i.v. enalaprilat] was undertaken in 36 patients with acute left ventricular (LV) failure due to recent myocardial infarction. Each regimen achieved similar reductions in pulmonary artery occluded pressure (PAOP, preload) and systemic arterial pressures (afterload), with increased cardiac and stroke volume (SV) indexes (p less than 0.01). Only the hydralazine and isosorbide combination induced resting tachycardia. Balanced vasodilatation after selective alpha-adrenoceptor blockade (doxazosin) and angiotensin-converting enzyme (ACE) inhibition (enalaprilat) without increase in heart rate (HR) suggests that these therapies may have definite haemodynamic advantages over the hydralazine/ISDN combination.
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The rate of decrease in oxygen concentration was expressed as a percentage of baseline. Results of the highest dose of drug are shown. Decrease in MVO2 was greater in LVAD hearts (n = 8) compared with heart failure controls (n = 18) in response to the following drugs: bradykinin (-34+/-3% vs. -24+/-5%), enalaprilat (-37+/-5% vs. -23+/-5%) and amlodipine (-43+/-13% vs. -16+/-5%; p<0.05 from controls). The decrease in MVO2 in LVAD hearts was not significantly different from controls in response to diltiazem (-22+/-5% in both groups) and exogenous NO donor, nitroglycerin (-33+/-7% vs. -30+/-3%). N(w)-nitro-L-arginine methyl ester, inhibitor of NO synthase, attenuated the response to bradykinin, enalaprilat and amlodipine. Reductions in MVO2 in response to diltiazem and nitroglycerin were not altered by inhibiting NO.
The aim of the present study was to determine whether the new ACE inhibitor trandolapril was able to inhibit brain ACE activity in spontaneously hypertensive rats (SHRs). Therefore, we have measured ex vivo ACE activity in discrete brain areas of SHRs after a 2-week oral treatment with trandolapril (0.001, 0.01, 0.1 and 1 mg/kg/day). The effects of trandolapril were compared to those of enalapril (10 mg/kg/day), used as a reference compound. Enalapril induced a decrease in ACE activity in brain areas not protected by the blood brain barrier (subfornical organ and median eminence) and in cerebral cortex. Conversely, trandolapril at a dose of 0.01 mg/kg/day and above induced a dose-dependent inhibition of ACE activity in all brain areas assayed, including the supraoptic and paraventricular hypothalamic nuclei, septum, amygdala, hippocampus, cerebellar and cerebral cortex, nucleus of the tractus solitary and caudate nucleus. The inhibition was roughly similar in all brain areas studied. These data suggest that after chronic oral administration in SHRs, trandolapril or its metabolite, in contrast to enalapril or enalaprilat, was able to reach all brain areas of SHRs, including those protected by the blood brain barrier.
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urapidil reduces blood pressure without altering heart rate. The oral formulation is an effective choice in patients with hypertension and concomitant dyslipidaemia or type 2 diabetes mellitus, in whom the drug does not adversely affect and may improve lipid profiles and glucose metabolism. The intravenous formulation is effective in controlling various hypertensive crises and hypertension associated with pregnancy or surgery and is similar to or better than other first-line agents used in these conditions. Thus, urapidil may be a useful alternative to currently available antihypertensive agents.
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Three hundred twenty-seven men (mean age 63.3 +/- 10.9 years) with documented acute myocardial infarction were randomized to treatment with enalapril or placebo on a double-blind basis. Intravenous enalaprilat or placebo therapy was initiated within 24 h after the onset of symptoms. Oral therapy was continued at a target dose of 20 mg/day. Patients exercised maximally at 1 month and 6 months after infarction to symptom-limited end points on a cycle ergometer with a 20 W/min incremental protocol.
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Cocaine abuse can cause cardiovascular damage leading to hypertension, myocardial ischaemia and infarction. This might be partly due to the effects of cocaine on the microcirculation about which little is known, although its effects on the macrovessels are well documented. Accordingly, we used in vivo videomicroscopy to study the vasoconstrictive effect of cocaine on arterioles of different diameter. They were classified into three orders (A2, A3, A4) according to their position in the microvascular network and their diameter. Since calcium antagonists have been reported to exert a protective effect against the cardiovascular disorders induced by cocaine, we tested the hypothesis that this protective action occurs in the microcirculation. We found that intra-arterial administration of the calcium antagonist Nitrendipine greatly inhibited the vasoconstriction induced by cocaine in all three arteriole orders. The degree of inhibition ranged from 44 to 56%. Combined administration of benzodiazepine and an angiotensin converting enzyme inhibitor has also been reported to protect rats against cocaine-induced hypertension and to increase survival rates after a toxic dose of cocaine. Since the mechanisms of this protection are not yet clear, we also studied the effect of the angiotensin converting enzyme inhibitor Enalaprilat on cocaine-induced vasoconstriction. Intra-arterial administration of Enalaprilat inhibited this vasoconstriction slightly but significantly in arteriole orders 2 and 3 by 27 and 24% respectively, but not in order 4. We concluded that Nitrendipine is a powerful inhibitor of cocaine-induced vasoconstriction in the microcirculation. The small but significant inhibition found with Enalaprilat for the larger arterioles suggests that the local angiotensin II level may affect the response to cocaine. However, since the Enalaprilat-induced inhibition was very limited, we conclude that mechanisms other than those occurring in the peripheral microcirculation account for the protection afforded by Enalaprilat against the harmful effects of cocaine.