Biomedical subjects

Marcel Lebel

Publications and source records attributed to Marcel Lebel.

16 recordsLinked to original sources

PubMed2006

Atherosclerotic renovascular disease.

Atherosclerotic renovascular disease is a combination of renal artery stenosis and renal ischemia. Blood pressure does not rise until the stenosis is 60% or greater. Disease of both large and small blood vessels is often accompanied by the loss of glomerular filtration rate. Activation of the renin-angiotensin-aldosterone system leads to vasoconstriction and salt retention. Risk factors for atherosclerotic renovascular disease include long-standing hypertension, diabetes, smoking and dyslipidemia. The prevalence of the condition in patients with hypertension resistant to two medications is 20%. As yet, there is no single ideal screening test or evidence-based recommended screening algorithm. Magnetic resonance angiography and computed tomography angiography are noninvasive and have high sensitivity and specificity, but also have high costs associated with them. The captopril renal scan has low sensitivity and specificity in people with renal disease (the population most likely to require the test). Doppler ultrasonography has high sensitivity and specificity in experienced hands, and the renal resistance index, which can easily be added to this test, can identify those with microvascular disease who may not benefit from revascularization. The best determinant of patient outcome is not the degree of renal artery stenosis but the degree of renal parenchymal disease. To date, renal revascularization has not been associated with improved renal survival compared with medical treatment alone. Today, the approach to atherosclerotic renovascular disease is determined by the patient's blood pressure and renal function; possibly, in the future, it will be determined by the result of the renal resistance index as part of a screening algorithm. If the blood pressure is uncontrollable or the renal function is deteriorating, the patient should be considered for renal revascularization initially, with a percutaneous endovascular stent. The management of hypertension involves the use of combinations of antihypertensive agents at doses sufficient to control blood pressure. Medical management also includes aggressive lipid-lowering therapy.

Atherosclerosis↗

PubMed2006

Antihypertensive and renal protective effects of renin-angiotensin system blockade in uremic rats treated with erythropoietin.

BACKGROUND: Correcting anemia with recombinant human erythropoietin (rhEPO) in chronic renal failure has been associated with an increased blood pressure (BP), which may accelerate the decline in renal function. This has been attributed, in part, to the activation of the renin-angiotensin system. The present study was designed to investigate the protective effect of the angiotensin II-receptor blocker losartan compared with the angiotensin-converting enzyme inhibitor captopril and conventional triple therapy (TRx) in uremic rats receiving rhEPO therapy. METHODS: Renal failure was induced by renal mass ablation followed by a 3-week stabilization period. Uremic rats were then divided into five groups with similar systolic BP: vehicle; rhEPO (100 U/kg, subcutaneously, three times per week); rhEPO + losartan (20 mg/kg/d); rhEPO + captopril (20 mg/kg/d); and rhEPO + TRx (reserpine 5 mg/L, hydralazine 80 mg/L, hydrochlorothiazide 20 mg/L). Systolic BP as well as blood and renal parameters were assessed before and after a 3-week treatment period. Renal histology was evaluated at the end of the study. RESULTS: The uremic rats developed hypertension, anemia, proteinuria, and increased urinary endothelin-1 (ET-1) excretion. The rhEPO corrected the anemia but aggravated the hypertension (P < .01), glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Treatment with losartan, captopril, and the TRx prevented the rhEPO-induced increased in systolic BP. The TRx was less effective in preventing histologic injuries despite similar systolic BP reduction. CONCLUSIONS: Blockade of the renin-angiotensin system is highly effective in preventing both hypertension and renal histologic damage in rhEPO-treated uremic rats and this benefit seems to extend beyond the antihypertensive effect.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

Estimation of heparin leak into the systemic circulation after central venous catheter heparin lock.

BACKGROUND: Although most catheter problems in haemodialysis are related to infection or clotting, bleeding associated with the heparin lock is of clinical importance especially during peri-operative conditions. The objective of this in vitro study is to estimate the volume of heparin that may leak into the circulation immediately after performing a catheter lock. METHODS: Different volumes (ml) of a dextrose solution were used to perform a catheter lock on haemodialysis catheters. The tip of the catheter was placed in a test tube containing water for a pre-specified period. The final concentrations of dextrose in the test tube were used to determine the volume of solution that leaked from the catheter. RESULTS: When the total lumen volume was filled, the catheter leak was estimated to be 0.59+/-0.03 and 0.71+/-0.04 ml after 15 and 25 s, respectively. There was a continuous leak of 1.23+/-0.41, 2.20+/-0.34 and 3.38+/-0.23 ml at 5, 15 and 30 min, respectively, after performing a catheter lock on a catheter with a total lumen volume of 4.5 ml. The catheter leak was significantly reduced when only 3.7 ml of solution was used to fill the total lumen volume of 4.5 ml. CONCLUSION: The present study demonstrates a significant early and late leakage from the catheter that occurs after performing a catheter lock. When applied to heparin, the volume of the unwanted catheter leak may result in adverse clinical events, especially following haemodialysis sessions and during peri-operative periods. However, these results are hypothesis-generating, and clinical studies are necessary to evaluate the efficacy of underfilling.

Catheters, Indwelling↗

PubMed2005

Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats.

OBJECTIVE: We investigate the role of transforming growth factor-beta (TGF-beta) in hypertension and renal failure progression in uremic rats, and whether it modulates the endothelin (ET) system. DESIGN: Following renal mass reduction, uremic rats (Nx) received the pan-specific TGF-beta neutralizing antibody 1D11 (0.5 mg/kg, three times/week), the isotype control antibody 13C4 or the AT1 antagonist losartan (10 mg/kg per day) for 6 weeks. RESULTS: Before treatment, the blood pressure was higher in Nx rats and increased further over time in Nx+13C4 rats. At the end of the study, Nx+13C4 rats exhibited increased serum creatinine, proteinuria and renal expression and excretion of TGF-beta1 and ET-1. ET-1 concentrations were greater in vascular and renal tissues, whereas the ETB receptor expression was reduced. Renal injuries were comprised of blood vessel hypertrophy, glomerular sclerosis, tubular atrophy and interstitial fibrosis, which was associated with increased alpha-smooth muscle actin expression. Treatment of uremic rats with the 1D11 antibody attenuated the increase in blood pressure and the decline in renal function. Losartan normalized the blood pressure and significantly attenuated the increase in serum creatinine and proteinuria. However, both treatments prevented renal TGF-beta1 and ET-1 overexpression, and prevented all renal histological injuries. The 1D11 antibody only improved ETB receptor expression. CONCLUSIONS: Neutralization of TGF-beta attenuates hypertension and renal failure progression in uremic animals, in part, by preventing renal injury processes. These effects may be related to the modulation of the ET system, preventing renal ET-1 overproduction and the reduction of ETB receptor expression. Our data also suggest that TGF-beta1 is involved, at least in part, in the pathological effects related to angiotensin II in chronic renal failure.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats.

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.

6-Ketoprostaglandin F1 alpha↗

PubMed2005

The 2005 Canadian Hypertension Education Program recommendations for the management of hypertension: part 1- blood pressure measurement, diagnosis and assessment of risk.

OBJECTIVE: To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with high blood pressure (BP). OPTIONS AND OUTCOMES: For persons in whom a high BP value is recorded, the assignment of a diagnosis of hypertension is dependent on the appropriate measurement of BP, the level of the BP elevation and the duration of follow-up. In addition, the presence of cardiovascular risk factors and target organ damage should be assessed to determine the urgency, intensity and type of treatment. For persons diagnosed as having hypertension, estimating overall risk of adverse cardiovascular outcomes requires an assessment of other vascular risk factors and hypertensive target organ damage. EVIDENCE: MEDLINE searches were conducted from November 2003 to October 2004 to update the 2004 recommendations. Reference lists were scanned, experts were polled, and the personal files of the authors and subgroup members were used to identify other studies. Identified articles were reviewed and appraised using prespecified levels of evidence by content and methodological experts. As per previous years, only studies that had been published in the peer-reviewed literature were included; evidence from abstracts, conference presentations and unpublished personal communications was not included. RECOMMENDATIONS: This document contains recommendations for BP measurement, diagnosis of hypertension and assessment of cardiovascular risk for adults with high BP. These include the accurate measurement of BP, criteria for diagnosis of hypertension, and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory BP monitoring, and the role of echocardiography for those with hypertension. Key features of the 2005 recommendations include an expedited diagnostic algorithm for hypertension and an endorsement of the use of home/self and ambulatory BP assessment as validated techniques in establishing the diagnosis of hypertension. VALIDATION: All recommendations were graded according to the strength of the evidence and voted on by the 43 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported in the present paper received at least 95% consensus. These guidelines will continue to be updated annually.

Blood Pressure Monitoring, Ambulatory↗

PubMed2005

The 2005 Canadian Hypertension Education Program recommendations for the management of hypertension: part II - therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. While changes in cardiovascular morbidity and mortality were the primary outcomes of interest, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity/mortality data in this field, and for certain comorbid conditions, other relevant outcomes, such as development of proteinuria or worsening of kidney function, were considered. EVIDENCE: MEDLINE searches were conducted from November 2003 to October 2004 to update the 2004 recommendations. Reference lists were scanned, experts were contacted, and the personal files of the subgroup members and authors were used to identify additional published studies. All relevant articles were reviewed and appraised independently, using prespecified levels of evidence, by content and methodology experts. As per previous years, only studies that had been published in the peer-reviewed literature were included; evidence from abstracts, conference presentations and unpublished personal communications was not included. RECOMMENDATIONS: Lifestyle modifications to prevent and/or treat hypertension include the following: perform 30 min to 60 min of aerobic exercise on four to seven days of the week; maintain a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a reduced fat, low cholesterol diet with an adequate intake of potassium, magnesium and calcium; restrict salt intake; and consider stress management (in selected individuals). Treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and any comorbid conditions. Blood pressure should be lowered to 140/90 mmHg or less in all patients, and to 130/80 mmHg or less in those with diabetes mellitus or chronic kidney disease. Most adults with hypertension require more than one agent to achieve target blood pressures. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers and angiotensin receptor antagonists. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine calcium channel blockers and angiotensin receptor antagonists. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or thiazides in patients with diabetes mellitus without albuminuria) are appropriate first-line therapies; and in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended. All hypertensive patients should have their fasting lipids screened, and those with dyslipidemia should be treated using the thresholds, targets and agents recommended by the Canadian Hypertension Education Program Working Group on the management of dyslipidemia and the prevention of cardiovascular disease. Selected patients with hypertension, but without dyslipidemia, should also receive statin therapy and/or acetylsalicylic acid therapy. VALIDATION: All recommendations were graded according to the strength of the evidence and voted on by the 43 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Antihypertensive Agents↗

PubMed2004

Endothelin-1 levels and cardiovascular risk factors in renal transplant patients.

OBJECTIVE: Circulating endothelin-1 (ET-1) levels have been reported to be associated with vascular complications and endothelial dysfunction in nontransplanted patients. The aim of this study was to investigate the relationship between ET-1 levels and major cardiovascular (CV) risk factors in renal transplant (RTX) patients with stable graft function. METHODS: ET-1 levels were determined in 156 RTX patients and the relationship between circulating ET-1 levels and CV risk factors including age, gender, kidney function, blood lipids, diabetes, and hypertension was studied. RESULTS: Circulating ET-1 levels were found to be positively correlated with creatinine (r = 0.25, p < 0.01) and systolic blood pressure (r = 0.20, p < 0.05) and inversely correlated with high-density lipoprotein cholesterol (HDL-C) levels (r = -0.27, p < 0.01). Patients with high and intermediate total cholesterol/HDL-C ratios (TC/HDL-C) had significantly higher ET-1 levels when compared to patients with low ratios (7.02 +/- 3.74, 6.79 +/- 2.67, and 5.37 +/- 3.04 pg/ml, respectively, p < 0.002). Only creatinine, HDL-C, and age >40 years were shown to be independent correlates for ET-1 levels according to multivariate analyses. Interestingly, ET-1 levels were significantly higher (+26%, p < 0.03) in RTX patients with documented CV disease, as compared to those without, when matched for age, gender, and presence of diabetes. CONCLUSIONS: Increased circulating ET-1 levels are associated with low HDL-C and documented CV disease in RTX. This is likely a reflection of vascular endothelial damage and dysfunction and therefore may represent an increased risk for atherosclerosis.

Adult↗

PubMed2004

Thromboxane blockade reduces blood pressure and progression of renal failure independent of endothelin-1 in uremic rats.

This study was designed to investigate the role of eicosanoids, thromboxane A2 (TXA2) and prostacyclin (PGI2) as well as their relationship with endothelin-1 (ET-1) in the pathogenesis of renal parenchymal hypertension. Uremic rats were prepared by renal mass ablation and compared with sham-operated controls. The stable metabolites of TXA2 (TXB2) and PGI2 (6-keto-PGF1alpha) and immunoreactive ET-1 concentrations were measured by specific RIAs in biological fluids and in vascular and renal tissues. To investigate the functional role of TXA2 in the progression of hypertension and renal failure, a group of uremic rats were treated with ridogrel (25 mg/kg/day), a TXA2 synthase inhibitor and receptor antagonist. Renal preproET-1 expression was assessed by Northern blot analysis. Systolic blood pressure (SBP), serum creatinine and proteinuria were found to be higher in uremic rats as compared to sham-operated controls (P < 0.01). TXB2 and ET-1 concentrations were increased in blood vessels, the renal cortex and in urine (P < 0.05). 6-keto-PGF1alpha concentrations were also increased in blood vessels and the renal cortex but decreased in urine (P < 0.05). Ridogrel significantly lowered SBP and proteinuria (P < 0.05) and blunted the increase of serum creatinine. Treatment with ridogrel resulted in a marked fall in vascular, renal and urine TXA2 concentrations, while ET-1 and 6-keto-PGF1alpha concentrations remained unchanged. The preproET-1 expression was higher in uremic rats than in the controls and was unaffected by ridogrel. These results suggest that TXA2 is involved in the pathogenesis of hypertension and renal failure progression in rats with subtotal 5/6 nephrectomy and that this effect is independent of the ET-1 system.

Animals↗

PubMed2004

The 2004 Canadian Hypertension Education Program recommendations for the management of hypertension: Part I--Blood pressure measurement, diagnosis and assessment of risk.

OBJECTIVE: To provide updated, evidence-based recommendations for the assessment of the diagnosis, cardiovascular risk and identifiable causes for adults with high blood pressure. OPTIONS: For persons in whom a high blood pressure value is recorded, the assignment of a diagnosis of hypertension is dependent on the appropriate measurement of blood pressure, the level of the blood pressure elevation and the duration of follow-up. In addition, the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases should be assessed to determine the urgency, intensity and type of treatment. For persons diagnosed as having hypertension, defining overall risk of adverse cardiovascular outcomes requires an assessment of concomitant vascular risk factors, including laboratory testing, a search for target organ damage and an assessment for modifiable causes of hypertension. Home and ambulatory blood pressure assessment and echocardiography are options for selected patients. OUTCOMES: The identification of persons at increased risk of adverse cardiovascular outcomes; the quantification of overall cardiovascular risk; and the identification of persons with potentially modifiable causes of hypertension. EVIDENCE: Medline searches were conducted from November 2001, one year before the period of the last revision of the Canadian recommendations for the management of hypertension, to October 2003. Reference lists were scanned, experts were polled, and the personal files of subgroup members and authors were used to identify other studies. Identified articles were reviewed and appraised using prespecified levels of evidence by content experts and methodological experts. VALUES: A high value was placed on the identification of persons at increased risk of cardiovascular morbidity and mortality, and persons with identifiable and potentially modifiable causes of hypertension. BENEFITS, HARMS AND COSTS: The identification of persons at higher risk of cardiovascular disease will permit counselling for lifestyle maneuvers and introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. The identification of specific causes of hypertension may permit the use of cause-specific interventions. For certain subgroups of patients and specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and/or mortality. RECOMMENDATIONS: The document contains recommendations for blood pressure measurement, diagnosis of hypertension and assessment of cardiovascular risk for adults with high blood pressure. These include the accurate measurement of blood pressure, criteria for diagnosis of hypertension, and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory blood pressure monitoring, and the role of echocardiography for those with hypertension. VALIDATION: All recommendations were graded according to strength of evidence and voted on by the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. Only the recommendations that achieved high levels of consensus are reported. These guidelines will be updated annually.

Adult↗

PubMed2004

The 2004 Canadian recommendations for the management of hypertension: Part II--Therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the management of hypertension in adults. OPTIONS AND OUTCOMES: For patients who require pharmacological therapy for hypertension, a number of antihypertensive agents may be used. Randomized trials evaluating first-line therapy with diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), alpha-blockers, centrally acting agents or angiotensin receptor antagonists were reviewed. Also, randomized trials evaluating other agents, such as statins or acetylsalicylic acid, in patients with hypertension were reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. In addition, other relevant outcomes such as development of end-stage renal disease or changes in blood pressure were examined where appropriate. EVIDENCE: MEDLINE searches were conducted from November 2001 to October 2003 to update the 2001 Recommendations for the management of hypertension. Reference lists were scanned, experts were contacted, and the personal files of the subgroup members and authors were used to identify additional published studies. All relevant articles were reviewed and appraised independently, using prespecified levels of evidence by content and methodology experts. RECOMMENDATIONS: This document contains detailed recommendations and supporting evidence on treatment thresholds, target blood pressures and choice of agents for hypertensive patients with or without comorbidities. Lifestyle modifications are a key component of any antiatherosclerotic management strategy and detailed recommendations are contained in a separate document. Key recommendations for pharmacotherapy include the following: treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and comorbidities, with particular attention to systolic blood pressure; blood pressure should be lowered to 140/90 mmHg or less in all patients, and 130/80 mmHg or less in those with diabetes mellitus or renal disease (125/75 mmHg or less in those with nondiabetic renal disease and more than 1 g of proteinuria per day); most adults with hypertension require more than one agent to achieve target blood pressures; for adults without compelling indications for other agents, initial therapy should include thiazide diuretics; other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), ACE inhibitors (in non-Blacks), long-acting dihydropyridine CCBs or angiotensin receptor antagonists; other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine CCBs or angiotensin receptor antagonists; certain comorbidities provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or thiazides in patients with diabetes mellitus without albuminuria) are appropriate first-line therapies; and in patients with mild to moderate nondiabetic renal disease, ACE inhibitors are recommended; all hypertensive patients should have their fasting lipids screened and those with dyslipidemia should be treated using the thresholds, targets and agents as per the Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease; and selected patients with hypertension should also receive statin and/or acetylsalicylic acid therapy. VALIDATION: All recommendations were graded according to the strength of the evidence and voted on by the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. Individuals with irreconcilable competing interests (declared by all members, compiled and circulated before the meeting) relative to any specific recommendation were excluded from voting on that recommendation. Only recommendations achieving at least 70% consensus are reported here. These guidelines will continue to be updated annually.

Adult↗

PubMed2003

Relationship between eicosanoids and endothelin-1 in the pathogenesis of erythropoietin-induced hypertension in uremic rats.

Recent studies suggest a possible link between recombinant human erythropoietin (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids. The current study was designed to evaluate the role of eicosanoids such as thromboxane (TX) A and prostacyclin (PGI ) and of endothelin-1 (ET-1) and the relationship between these vasoactive substances in rhEPO-induced hypertension in uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 6-week stabilization period. In protocol A, rats were divided into four groups: vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ET receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks. At the end of the study, immunoreactive eicosanoid metabolites (TXB and 6-keto-PGF, stable metabolites of TXA and PGI ), and ET-1 were measured in either the thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia but aggravated the hypertension. Both drugs were effective in preventing the progression of hypertension in rhEPO-treated rats although ABT-627 was more potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB in blood vessels and ABT-627 decreased tissue levels of both vasopressors. The concentration of 6-keto-PGF was not significantly changed. Ridogrel significantly decreased tissue TXB concentrations but had no effect on ET-1 levels. These results suggest that endothelium-derived vasoconstrictor autacoids (TXA and ET-1) are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats. TXA probably serves as a mediator of the vascular effect of ET-1.

Animals↗

PubMed2003

Endothelin-1 in chronic renal failure and hypertension.

Investigation into the role of endothelin-1 (ET-1) in renal function has revealed two major direct actions leading to the control of extracellular volume and blood pressure. These are the regulation of renal hemodynamics and glomerular filtration rate and the modulation of sodium and water excretion. In the rat remnant kidney model of chronic renal failure, ET-1 production is increased in blood vessels and renal tissues. These changes are related to an increase in preproET-1 expression and correlate with the rise in blood pressure, the development of cardiovascular hypertrophy, and the degree of renal insufficiency and injury. Selective ETA receptor blockade prevents the progression of hypertension and the vascular and renal damage, supporting a role for ET-1 in chronic renal failure progression. The increase in ET-1 production can be associated with other local mediators, including angiotensin II, transforming growth factor-beta1 and nitric oxide, the local production of which is also altered in chronic renal failure. In human patients with essential hypertension, atherosclerosis, and nephrosclerosis, plasma ET-1 levels are increased compared with patients with uncomplicated essential hypertension. Similarly, plasma ET-1 concentrations are markedly increased in patients with end-stage renal disease undergoing dialysis, and this correlates with blood pressure, suggesting that ET-1 may contribute to hypertension in these patients. The treatment of anemia in patients with renal failure with human recombinant erythropoietin increases blood pressure by accentuating the underlying endothelial dysfunction and the elevated vascular ET-1 production. Overall, these results support a role for ET-1 in hypertension and the end-organ damage associated with chronic renal failure. ETA receptor blockade may then represent a potential target for the management of hypertension and cardiovascular and renal protection.

Animals↗

PubMed2002

Functional tests for primary aldosteronism: value of captopril suppression.

With the introduction of more simple screening tests such as the aldosterone/renin ratio, the detection rate of primary aldosteronism has increased considerably. Until now, no reference values have been available for reporting the aldosterone/renin ratio using plasma aldosterone values expressed in SI units (pmol/L) and plasma active renin (ng/L) measured by immunoradiometric assay. We studied 153 subjects who had either normal blood pressure, essential hypertension, or primary aldosteronism. Essential hypertensive patients usually have aldosterone/renin (pmol/L/ng/L) ratios below 100, whereas ratios for patients with primary aldosteronism are above 140. Results that fall between 100 and 140 suggest a need for repeat testing. Patients with elevated aldosterone/renin ratios require confirmatory testing to demonstrate nonsuppressive autonomous aldosterone production. To this end, salt loading is widely used, but this approach may be contraindicated in patients with severe hypertension. The captopril suppression test appears as effective as salt loading in confirming a diagnosis of primary aldosteronism. In addition, the captopril test is safe, well tolerated, and cost-effective.

Aldosterone↗

PubMed2002

The 2001 Canadian recommendations for the management of hypertension: Part one--Assessment for diagnosis, cardiovascular risk, causes and lifestyle modification.

OBJECTIVE: To provide updated, evidence-based recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. OPTIONS: For persons in whom a high blood pressure value is recorded, hypertension is diagnosed based on the appropriate measurement of blood pressure, the level of the blood pressure elevation and the duration of follow-up. In addition, the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases must be assessed to determine the urgency, intensity and type of treatment. For persons receiving a diagnosis of hypertension, defining the overall risk of adverse cardiovascular outcomes requires an assessment of concomitant vascular risk factors, including laboratory testing, a search for target organ damage and an assessment for modifiable causes of hypertension. Home and ambulatory blood pressure assessment and echocardiography are options for selected patients. OUTCOMES: The outcomes were: the identification of persons at increased risk of adverse cardiovascular outcomes; the quantification of overall cardiovascular risk; and the identification of persons with potentially modifiable causes of hypertension. EVIDENCE: Medline searches were conducted from one year before the period of the last revision of the Canadian recommendations for the management of hypertension (May 1999 to May 2001). Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other studies. Identified articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. In addition to an update of the previous year's review, new sections on assessing overall cardiovascular risk and endocrine causes are provided. VALUES: A high value was placed on the identification of persons at increased risk of cardiovascular morbidity and mortality, and of persons with identifiable causes of hypertension. BENEFITS, HARMS AND COSTS: The identification of persons at higher risk of cardiovascular disease will permit counseling for lifestyle manoeuvres and introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. The identification of specific causes of hypertension may permit the use of cause-specific interventions. In certain subgroups of patients, and for specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity or mortality. RECOMMENDATIONS: The present document contains recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. These include the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory blood pressure monitoring, the role of echocardiography and lifestyle modifications. VALIDATION: All recommendations were graded according to the strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Only those recommendations achieving high levels of consensus are reported. These guidelines will be updated annually. ENDORSEMENT: These guidelines are endorsed by the Canadian Hypertension Society, The Canadian Coalition for High Blood Pressure Prevention and Control, The College of Family Physicians of Canada, The Heart and Stroke Foundation of Canada, The Adult Disease Division and Bureau of Cardio-Respiratory Diseases and Diabetes at the Centre for Chronic Disease Prevention and Control, Health Canada.

Antihypertensive Agents↗

PubMed2002

The 2001 Canadian recommendations for the management of hypertension: Part two--Therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the therapy of hypertension in adults. OPTIONS: For patients with hypertension, a number of antihypertensive agents may control blood pressure. Randomized trials evaluating first-line therapy with thiazides, beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, alpha-blockers, centrally acting agents or angiotensin II receptor antagonists were reviewed. OUTCOMES: The health outcomes that were considered were changes in blood pressure, cardiovascular morbidity, and cardiovascular and/or all-cause mortality rates. Economic outcomes were not considered due to insufficient evidence. EVIDENCE: MEDLINE was searched for the period March 1999 to October 2001 to identify studies not included in the 2000 revision of the Canadian Recommendations for the Management of Hypertension. Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other published studies. All relevant articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and mortality. BENEFITS, HARMS AND COSTS: Various antihypertensive agents reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific classes of drugs, blood-pressure lowering has been associated with reduced cardiovascular morbidity and/or mortality. RECOMMENDATIONS: The present document contains detailed recommendations pertaining to treatment thresholds, target blood pressures, and choice of agents in various settings in patients with hypertension. The main changes from the 2000 Recommendations are the addition of a section on the treatment of hypertension in patients with diabetes mellitus, the amalgamation of the previous sections on treatment of hypertension in the young and old into one section, increased emphasis on the role of combination therapies over repeated trials of single agents and expansion of the section on the treatment of hypertension after stroke. Implicit in the recommendations for therapy is the principle that treatment for an individual patient should take into consideration global cardiovascular risk, the presence and/or absence of target organ damage, and comorbidities. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Individuals with potential conflicts of interest relative to any specific recommendation were excluded from voting on that recommendation. Only those recommendations achieving high levels of consensus are reported here. These guidelines will continue to be updated annually.

Antihypertensive Agents↗