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: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we examined whether antihypertensive treatment of young and adult hypertensive rats with the angiotensin-converting enzyme (ACE) inhibitor perindopril could restore the baroreflex vagal deficit and whether this was related to prevention of cardiac or vascular hypertrophy. Spontaneously hypertensive (SHR), stroke-prone spontaneously hypertensive (SHR-SP), and Wistar-Kyoto (WKY) rats were untreated or treated with perindopril (3 mg/kg/day) in the drinking water from 4-9 and from 14-20 weeks of age. Steady-state sigmoidal mean arterial pressure (MAP)-heart rate (HR) reflex curves were obtained in the conscious rats by the injection of pressor and depressor agents before and after atenolol (vagal component). Increased left ventricle to bodyweight ratio (LV/BW) indicated cardiac hypertrophy. After ganglion blockade, the minimum MAP produced by nitroprusside and the maximum produced by methoxamine were used as indications of vascular hypertrophy. Perindopril treatment reduced cardiac and vascular hypertrophy to different extents in SHR and SHR-SP. The 4-9 and 14-20 week treatments reduced MAP and both minimum and maximum blood pressure of the SHR to the levels of the untreated WKY. However, only in the older animals was LV/BW restored. In the SHR-SP, early treatment had a much greater effect on vascular hypertrophy than on LV/BW. The reverse occurred for the 14-20 week animals. In untreated hypertensive animals the baroreflex curves were shifted to the right with reduced vagal HR range. Perindopril treatment shifted the baroreflex curves back towards the WKY curves. Vagal HR range was strongly correlated with the LV/BW, whereas vagal HR range was less well related to the level of vascular hypertrophy or blood pressure. These results suggest that antihypertensive treatment can restore cardiac baroreflex function and that it is related to the reduction in cardiac hypertrophy. Although the mechanism of this relationship remains to be elucidated, these findings suggest that cardiac vagal afferents may be important.
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PMID:Importance of cardiac, but not vascular, hypertrophy in the cardiac baroreflex deficit in spontaneously hypertensive and stroke-prone rats. 153 47

1. Among patients with cerebrovascular disease, there is a direct and continuous association between blood pressure and the risk of stroke, but previous trials of blood pressure lowering in this patient group have been inconclusive. 2. PROGRESS (Perindopril Protection Against Recurrent Stroke Study) is a multicentre, randomized, placebo-controlled trial that aims to determine reliably the effect of angiotensin converting enzyme (ACE) inhibitor-based blood pressure lowering on stroke risk in patients with a history of cerebrovascular disease. If a 4 week run-in period on active perindopril is well tolerated, participants are randomized to either perindopril (4 mg) +/- indapamide (2.5 mg) or matching placebo(s). The primary study outcome is stroke and follow-up is for a minimum of 4 years. 3. For the pilot study nearly 5000 medical records were screened and 60 patients with recent cerebrovascular events were approached directly in hospital or at a clinic visit. Sixty-seven patients entered the run-in phase (52 from retrospective screening and 15 by prospective approach) and 60 patients proceeded to randomization. Treatment with perindopril was well tolerated; only three patients were withdrawn due to side effects and four were withdrawn for other reasons. The mean age of randomized patients was 68 years; 70% were male and 55% were 'non-hypertensive'. The mean entry blood pressure was 142/83 mmHg and following pre-randomization treatment this was reduced by 7/4 mmHg. 4. Most patients were identified by retrospective review of medical records, but this was less efficient than prospective methods. Blood pressure lowering was well tolerated by both hypertensive and non-hypertensive patients with cerebrovascular disease. The small numbers of patients and the non-randomized nature of the data reported limit the conclusions that can be drawn, but the results confirm the feasibility of the main study.
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PMID:Blood pressure lowering in patients with cerebrovascular disease: results of the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) pilot phase. 871 88

The efficacy of perindopril in congestive heart failure (CHF) class II-III (NYHA) was studied in a trial including 37 patients (35 males and 2 females) aged 39-71 years (mean age 57.9 +/- 1.4) with postinfarction cardiosclerosis. They had CHF class II-III and ejection fraction (EF) < 45%. Perindopril was given in a single daily dose 2-4 mg for 6 months. The treatment resulted in a significant lowering of CHF class (from 2.5 +/- 0.1 to 1.7 +/- 0.1 (p < 0.01). Exercise tolerance increased from 256.2 +/- 18.6 s to 349.8 +/- 27.0 s (p < 0.05). Pump and contractile functions of the myocardium improved: stroke volume increased by 12.7%, ejection fraction by 20.5%, total peripheral vascular resistance fell by 9.7%, circulating blood volume by 9.2%. Parameters of oxygen transport to tissues and tissue respiration also changed for the better. The authors state high efficacy of perindopril in CHF patients.
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PMID:[The angiotensin-converting enzyme inhibitor perindopril in the treatment of congestive heart failure]. 942 61

The aim of this study was to determine whether the prevention of stroke with perindopril treatment in stroke-prone spontaneously hypertensive rats (SHRSP) is associated with the preservation of the myogenic properties of the cerebral arteries. After weaning at 4 weeks of age, male SHRSP were fed a Japanese-style rat diet with high salt to induce stroke development. Treatment with perindopril was given by gavage every morning beginning at 6 weeks of age. There were three experimental groups: two groups treated with 4 mg.kg-1.day-1 perindopril for different durations (8 or 12 weeks) and one control group consisting of littermates given distilled water. All the control animals developed stroke and died within 14 weeks of age, and myogenic response of the middle cerebral arteries (MCA) to pressure increase was lost in these animals. In contrast, all the treated SHRSP survived during the treatment period, and myogenic response of the MCA was preserved. After withdrawal of the treatment, SHRSP treated for a longer period (12 weeks) also survived longer than those treated for a shorter period (8 weeks). The subsequent development of stroke and death following treatment withdrawal after 8 or 12 weeks of treatment was associated with the loss of pressure-dependent constriction in MCA. A longer treatment duration also increased the stiffness of the MCA, MCA from SHRSP after 12 weeks of treatment had smaller external and lumen diameters, and thicker walls than those from the 8-week treatment group. In a separate study, we found that treatment of SHRSP with 1 or 4 mg.kg-1.day-1 of perindopril for 24 weeks beginning at 6 weeks of age also protected them against death related to stroke, because these rats survived up to 43 weeks of age, when the experiment was terminated. We conclude that there is an association between the absence of myogenic response in cerebral arteries and stroke development in SHRSP. Perindopril treatment preserves the myogenic response of MCA in SHRSP and prevents the stroke development in these animals. A prolonged treatment could increase the survival of SHRSP through a remodelling of the MCA and increasing the stiffness of the cerebral arteries.
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PMID:Prevention of stroke and preservation of the functions of cerebral arteries by treatment with perindopril in stroke-prone spontaneously hypertensive rats. 956 46

BRAIN AND BLOOD PRESSURE IN EXPERIMENTAL ANIMALS: Our experiments in models of experimental hypertension in the rabbit in the early 1970s demonstrated that increased activity of bulbospinal pressor neurons containing noradrenaline or serotonin mediated the elevated arterial blood pressure. Other workers had demonstrated decreased activity of noradrenergic neurons in the medulla. Accordingly, I proposed the hypothesis that the hypertension in these models arose from 'disinhibition', due to unrestrained activity of descending pressor pathways, released from the inhibitory influences present in normal animals. Over the next 15-20 years, experiments from our group and from other laboratories demonstrated that there were two distinct bulbospinal pressor pathways descending from the rostral ventral medulla, one containing adrenaline, neuropeptide Y and glutamate, and the other containing serotonin, substance P and glutamate. It has also been established that the key depressor area is in the caudal ventrolateral medulla and that the main inhibitory input, restraining the activity of the bulbospinal pressor pathways, is a short gamma-aminobutyric acid (GABA) projection ascending from the caudal ventrolateral medulla to the rostral ventral medulla. More recent experiments in the spontaneously hypertensive rat (SHR) using the immediate-early gene c-fos as a marker of neuronal activity, have demonstrated that impaired activity of this short inhibitory GABA pathway in the SHR disinhibits the bulbospinal pressor pathway, thus contributing to the hypertension in this model. BLOOD PRESSURE AND STROKE IN HUMANS: The risks of primary stroke and of secondary or recurrent stroke are both directly related to the level of blood pressure and clinical trials have clearly demonstrated that lowering blood pressure markedly reduces the incidence of primary stroke. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was launched to test the hypothesis that lowering the blood pressure in subjects who have already had a stroke or a transient ischaemic attack will also reduce the risk of stroke. A major unresolved issue for practising clinicians is how to manage the raised blood pressure that is so common in the acute phase of stroke. Accordingly, the PROGRESS investigators are planning another major multinational trial to assess the benefits and risks of lowering blood pressure in the first 3 days after the onset of a stroke.
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PMID:Volhard Lecture. Brain, blood pressure and stroke. 988 69

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.
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PMID:Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats. 1072 May 93

High blood pressure is a known risk factor for multi-infarct dementia, a subtype of dementia caused by the occurrence of several strokes. However, this form of dementia is relatively uncommon and the influence of blood pressure on the risk of other subtypes of vascular dementia remains to be clarified. Furthermore, recent studies have suggested that vascular risk factors could also play a part in Alzheimer's disease. One of the aims of Perindopril Protection Against Recurrent Stroke Study (PROGRESS) is to test the hypothesis that blood pressure decreasing treatment based on perindopril would reduce the incidence of dementia among patients with cerebrovascular disease. The dementia procedures in PROGRESS involve a classical two-phase design, with an initial screening phase based mainly on the Mini-Mental State Examination - a simple, brief, and widely used screening test for dementia. The second phase involves a diagnostic assessment for dementia in individuals screened as positive according to the criteria of the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (4th ed.). In this project, two other domains of the relationship between vascular risk factors and cognition are being explored in relation to PROGRESS substudies. The apolipoprotein E polymorphism, a genetic risk factor for Alzheimer's disease, is being determined in each patient, as part of the genetic substudy. This will allow study of the relationship between this polymorphism and blood pressure, and of the effect of blood pressure decreasing treatment on the risk of dementia. The magnetic resistance imaging substudy will improve understanding of the relationship between blood pressure decreasing and the occurrence of cerebral white matter lesions, which are known to be related to cognitive decline and dementia.
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PMID:Blood pressure reduction and risk of dementia in patients with stroke: rationale of the dementia assessment in PROGRESS (Perindopril Protection Against Recurrent Stroke Study). PROGRESS Management Committee. 1093 86

Abundant evidence has accumulated showing that angiotensin converting enzyme (ACE) inhibitors reduce long-term cardiovascular morbidity and mortality rates in patients with heart failure and myocardial infarction. Fewer completed trials have assessed their potential benefits in this regard in hypertensive subjects, but evidence of benefit is beginning to accrue from studies examining patients with hypertension, particularly in the presence of diabetes and after infarction. Ongoing trials of blood pressure (BP) lowering using ACE inhibition fall into three main categories: 1) those comparing ACE inhibitors with older drugs such as diuretics and beta blockers; 2) those examining more aggressive versus less aggressive lowering of BP; and 3) those investigating BP lowering in patients at high risk for a cardiac event. Among those in the last group is the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), which examines the effects of perindopril-based ACE inhibitor therapy in both normotensive and hypertensive patients who have survived a stroke. This trial is particularly important because it serves as a model for studies of BP lowering across a wide range of BP and BP-related conditions.
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PMID:Ongoing trials of angiotensin-converting enzyme inhibition: what they can tell us. 1149 8

As the developing world becomes increasingly industrialized and urbanized, and its vast populations adopt more westernized diets and lifestyles, the burden of cardiovascular disease and disability is growing at an alarming rate. The results of prospective observational studies conducted in both western and eastern populations have established the strong association between the primary incidence of stroke and the level of blood pressure. Further, randomized clinical trials of antihypertensive therapy have demonstrated a reduction in primary stroke risk. Among persons with a history of cerebrovascular disease, data from the United Kingdom Transient Ischemic Attack Aspirin Trial (UKTIA) has demonstrated a similar relationship between blood pressure and secondary stroke risk. Trials of blood-pressure lowering in patients with a history of cerebrovascular disease also suggested a reduction in stroke risk. However, patients numbers in these trials were small, and the results were not conclusive. PROGRESS (Perindopril pROtection aGainst Recurrent Stroke Study) is a large, randomized, double-blind, controlled trial designed to provide a definitive answer to these questions. Its primary aim is to determine the effect of blood-pressure lowering on stroke incidence in patients with a history of a previous stroke or transient ischemic attack. A total of 6,105 patients were randomized to receive perindopril (plus indapamide) or placebo in seven regions of the world. The current mean follow-up period exceeds 30 months, and a total follow-up period of at least 4 years is planned. Secondary outcomes include the incidence of other major cardiovascular events, such as myocardial infarction, and of cognitive decline and dementia. Both the major event rate and the degree of adherence to randomized therapy exceed initial projections, which suggests that the study should have the power to achieve its main objectives by the planned completion date of 2001.
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PMID:Global impact of stroke. 1172 58

It is well established that blood pressure lowering is effective for the primary prevention of stroke and other cardiovascular disorders in subjects with blood pressures as low as 140/90 mmHg, and up to 80 years of age. Despite this knowledge, blood pressure levels are controlled in less than 25% of the hypertensive population worldwide. It has taken longer to prove that blood pressure lowering is equally effective for the prevention of recurrent stroke. The results of PROGRESS (Perindopril Protection Against Recurrent Stroke Study) have confirmed that a perindopril-based regimen in subjects with cerebrovascular disease substantially reduces the incidence of secondary stroke and primary myocardial infarction. It is daunting to recall that it has taken almost two decades for beta-blockers to be widely used for the secondary prevention of myocardial infarction, since widespread use of the PROGRESS regimen would prevent more than half a million strokes worldwide each year. The real challenge now is to implement novel and effective strategies for the control of blood pressure and other cardiovascular risk factors worldwide. Strategies should include lifestyle measures, such as stopping smoking, exercise and reducing overweight. There is a real need to identify hypertensive subjects and treat them with blood pressure lowering drugs for primary prevention. In subjects with established cardiovascular disease, consideration should be given to a range of proven interventions for secondary prevention, such as blood pressure lowering, irrespective of current blood pressure, anti-platelet drugs, statins for lowering cholesterol and glycaemic control in diabetics. Among new strategies to lower overall cardiovascular risk, consideration should be given to the development of single-pill combinations of drugs of known efficacy, including various combinations of ACE inhibitors, diuretics, beta-blockers, aspirin and statins, among others.
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PMID:Challenges for the prevention of primary and secondary stroke: the importance of lowering blood pressure and total cardiovascular risk. 1182 38


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