Effects of chronic AVP V2R blockade in congestive heart failure in sheep. Comparison with chronic ACE inhibition.
Explore the source record for details and available documents.
Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
L M Burrell
Publications and source records attributed to L M Burrell.
High-dose cyclophosphamide, etoposide and carboplatin with autologous bone marrow support for metastatic breast cancer: long-term results.
We report long-term results of high-dose cyclophosphamide, etoposide and carboplatin with ABMT in 20 patients with metastatic breast cancer. Median age of the group was 41 years, ECOG performance status = 0 in 18 patients and 1 in two patients. Twelve patients had received adjuvant chemotherapy. Predominant sites of metastases were lung (eight), chest wall (four), liver (four), bone (three) and lymph nodes (three). Response to pretransplant chemotherapy was complete (CR) in four patients, partial (PR) in 10 patients and stable (SD) in five patients. After high-dose chemotherapy eight patients were in CR, six PR, four SD and one progressive disease. Two patients died of regimen-related toxicities (candidal sepsis and alveolar hemorrhage). With a median follow-up period of 55 months (minimum 48 months), 12 patients have died of recurrent breast cancer, one died of toxicity of salvage chemotherapy, two are alive with disease, two are alive and free of progressive disease. One patient with relapsed disease was lost to follow-up. Median event-free survival is 6 months and median overall survival is 17 months. All three of the long-term disease-free survivors had predominantly nodal disease. Two of these three patients presented with metastatic disease and received high-dose chemotherapy with ABMT as part of initial therapy for breast cancer; two of three attained CR to standard-dose cytoreductive therapy; none received doxorubicin-containing adjuvant chemotherapy.
Adult↗
Vasopressin V1a and V2 receptor mRNA in deoxycorticosterone acetate-salt hypertension in the rat.
1. Vasopressin V1a and V2 receptors are differentially regulated in deoxycorticosterone acetate-salt hypertension. This paper investigated whether the changes were due to transcription changes in receptor mRNA assessed by in situ hybridization histochemistry (liver V1a receptor) and by reverse transcription-polymerase chain reaction (kidney V1a and V2 receptor). 2. Systolic blood pressure and plasma vasopressin levels were significantly elevated in deoxycorticosterone acetate-salt rats (n = 24) compared with water-control (n = 28) and salt-control rats (n = 28) (P < 0.001). Plasma sodium was elevated in deoxycorticosterone acetate-salt rats compared with both control groups (P < 0.01) and plasma osmolality was elevated in deoxycorticosterone acetate-salt rats compared with water-control rats (P < 0.05). 3. Binding kinetic studies demonstrated downregulation of liver V1a and kidney V2 receptors in deoxycorticosterone acetate-salt rats compared with water-control and salt-control rats (P < 0.05). This was not associated with any change in liver V1a receptor mRNA (P = 0.95), or in kidney V1a (P = 0.79) or V2 receptor mRNA (P = 0.96). 4. In deoxycorticosterone acetate-salt hypertension, downregulation of liver V1a and kidney V2 receptors occurs in the setting of stable vasopressin gene transcription. These results suggest that changes in receptor processing may be responsible for the differential regulation of vasopressin receptors that occurs in deoxycorticosterone acetate-salt hypertension.
Animals↗
New hormonal blockade strategies in cardiovascular disease.
The circulation is controlled by overlapping haemodynamic, structural and neurohumoral mechanisms. Many hormonal vasoactive substances, mostly derived from endothelial cells, are also growth regulators. Although neurohormonal systems are involved in normal physiological compensatory responses they often become maladaptive in conditions such as congestive heart failure. The success of blocking the renin angiotensin system by angiotensin converting enzyme (ACE) inhibitors has led to efforts to block other hormonal systems. Neutral endopeptidase (NEP), the major enzymatic pathway for degradation of natriuretic peptides, has a similar catalytic site to ACE. This has led to compounds that simultaneously inhibit both enzymes. Such dual ACE/NEP inhibitors show promise in experimental hypertension and heart failure. Similar dual NEP/ECE (endothelin converting enzyme) inhibitors are becoming available. The hormone vasopressin has dual actions on the vasculature and the kidney via specific membrane receptors. Specific orally active vasopressin receptor antagonists have been developed and their therapeutic potential in hypertension, heart failure and oedematous states are being explored.
Angiotensin-Converting Enzyme Inhibitors↗
Occupational upper extremity disorders in the federal workforce. Prevalence, health care expenditures, and patterns of work disability.
Upper extremity disorders (UEDs) account for a significant number of work-related illnesses in the US workforce. Little information exists on the distribution of UEDs, their associated health care and indemnity costs, or patterns of work disability. The study presented is an analysis of upper extremity claims within the federal workforce. In this study, the universe consisted of all claims accepted by the US Department of Labor, Office of Workers' Compensation Programs (OWCP), from October 1, 1993, through September 30, 1994. A total of 185,927 claims of notices of injury were processed during the study period, and of these, 8,147 or 4.4% had an UED diagnosis coded according to the International Classification of Diseases, Clinical Modification (ICD-9-CM). 5,844 claims involved a single UED diagnosis and were the only claims field by these employees between October 1, 1990, and September 30, 1994. These single claims with single diagnoses comprised the sample for further analysis. Mononeuritis and enthesopathies of the upper limb were the most common diagnoses, accounting for 43% and 31% of the claims, respectively. Women had a higher proportion of carpal tunnel syndrome, "unspecified" mononeuritis, and "unspecified" enthesopathies. The majority of claimants for both the mononeuritis- and enthesopathy-related diagnoses were between 31 and 50 years of age, received only health care benefits, and did not incur wage loss. Health care costs for mononeuritis and enthesopathy claims were $12,228,755 (M = $2,849). Carpal tunnel syndrome (CTS) and enthesopathy of the elbow were the most costly diagnoses, accounting for 57% and 16% of the total, respectively. Surgical services represented the highest expenditures in CTS claims. Physical therapy accounted for the majority of health care costs for enthesopathy cases. The mean number of workdays lost for CTS and enthesopathy claims were 84 and 79, and the average indemnity costs were $4,941 and $4,477, respectively. These findings indicate that while UEDs represent a relatively small percentage of all workers' compensation cases, the health care and indemnity costs are considerable. Also mean duration and pattern of work disability revealed that these disorders can result in chronic work disability similar to that observed in low back pain. The results highlight the need to determine whether interventions that account for the majority of costs significantly impact long-term outcomes. There is also a need to identify risk factors for prolonged disability in those who experience problems with delayed recovery.
Adolescent↗
Susceptibility to atrial fibrillation: a study in an ovine model of pacing-induced early heart failure.
INTRODUCTION: The development of susceptibility to atrial fibrillation (AF) is a common consequence of many forms of cardiovascular disease, especially heart failure. In this study we used a sheep model of pacing-induced stable early heart failure to describe, quantify, and relate the level of susceptibility to AF to changes in structural and electrophysiologic parameters. METHODS AND RESULTS: Epicardial electrodes were implanted on the atria and right ventricles of nine sheep. The AF threshold, atrial vulnerability period, atrial effective refractory period (ERP), and interatrial conduction time were examined during control and over a 6-week period of ventricular pacing at 190 beats/min. Left atrial (LA) area and left ventricular (LV) fractional shortening were monitored using echocardiography. There were significant increases in LA susceptibility to AF (P < 0.0003), LA area (P < 0.0002), and LA ERP400 (P < 0.0002). Rate of increase in LA area was related positively to AF susceptibility (P = 0.02) and inversely to LA ERP400 (P = 0.002). LV fractional shortening decreased to approximately 50% of control value (P < 0.00001). No changes were observed in right atrial electrophysiology. CONCLUSION: In this study, susceptibility (the ability of an extrastimulus to induce AF) was rigorously measured within a predetermined format. Significant relationships were found to exist between susceptibility, certain of the observed changes in atrial electrophysiology and structure.
Animals↗
Long-term effects of nonpeptide vasopressin V2 antagonist OPC-31260 in heart failure in the rat.
The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg . kg-1 . day-1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume (P < 0.01) and decreased urine osmolality (P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF (P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.
Animals↗
Effects of neutral endopeptidase inhibition in the rat remnant kidney model.
The orally active neutral metalloendopeptidase (NEP) inhibitor SCH34826 was given by oral gavage in a dose of 90 mg/kg twice daily for 3 days to rats with subtotal nephrectomy (n = 7) and effects were compared to a placebo group receiving phosphate buffer (n = 5). Inhibition of neutral endopeptidase in the remnant kidney was measured by in vitro autoradiography using the specific radioligand [125I]-SCH 47896. Treatment with the NEP inhibitor SCH34826 caused a 60% reduction in the neutral endopeptidase radioligand-binding site density in the kidneys of the SCH34826-treated animals compared to the placebo group (81.6+/-3.7 versus 214.5+/-4.2 dpm/mm2, p<0.01). This was associated with a marked increase in urinary atrial natriuretic peptide (ANP) from 3,930+/-295 to 9,094+/-1,089 pg/24 h in the SCH34826-treated group (p<0.01). Concomitantly there was a transient increase in natriuresis in the SCH34826-treated group [baseline 2.03+/-0.55 to 3.77+/-0.58 mmol/24 h on treatment day 1 (p = 0.02) and 2.58+/-0.19 mmol/24 h on treatment day 3 (p = 0.09)] which was not observed in the placebo group. Urinary protein excretion, glomerular filtration rate (determined by 99mTc-DTPA clearance), systemic blood pressure, plasma ANP concentration and urinary cyclic GMP excretion were not changed by SCH34826 treatment. These results suggest that oral administration of the NEP inhibitor SCH34826 inhibits renal neutral endopeptidase, increases urinary ANP and modulates natriuresis without alteration of systemic blood pressure, plasma ANP and renin level, glomerular filtration or protein excretion.
Analysis of Variance↗
Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus.
It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (P<0.001) or the NEP inhibitor (P<0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; P<0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (P<0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (P<0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatment of hypertension associated with diabetes mellitus and other forms of volume-dependent hypertension.
Analysis of Variance↗
Thirst in elderly subjects.
The hormonal changes associated with ageing, the occurrence of other medical condition and the use of medications increases the likelihood of conditions such as hyper- and hypo-natremia. Awareness of the homeostatic changes with age and the relations with disease and drugs will lead better management of fluid disorders in the elderly patient and hopefully a reduction in morbidity and mortality.
Aging↗
Angiotensin and bradykinin peptides in rats with myocardial infarction.
BACKGROUND: Angiotensin II (Ang II) stimulates cardiac hypertrophy and fibrosis, whereas bradykinin [BK-(1-9)] has cardioprotective actions and reduces infarct size following myocardial infarction. METHODS AND RESULTS: We investigated whether myocardial infarction and cardiac failure are associated with changes in circulating and tissue levels of angiotensin and bradykinin peptides. Myocardial infarction was produced in rats by coronary artery ligation and confirmed by electrocardiogram. Ang II, Ang I, BK-(1-9), and its metabolite BK-(1-7) were measured 1, 2, 3, 7, and 28 days after myocardial infarction. In comparison with sham operated rats, myocardial infarction reduced blood pressure and body weight, and produced cardiac hypertrophy and cardiac failure. Myocardial infarction increased plasma renin and ACE activity, reduced plasma angiotensinogen, and increased Ang II levels in plasma, aorta, kidney, and lung. Ang II levels in whole cardiac ventricles were similar in infarct and sham operated rats, but were positively correlated with heart weight/body weight ratio in infarct rats 3, 7, and 28 days after infarction. In a separate study of cardiac regions, Ang II levels were similar in infarct and sham operated rats, except at 7 days post surgery when right ventricular Ang II levels were higher in infarct rats. In infarct rats, Ang II levels were higher in the right ventricle and in the infarct than in the non-infarcted left ventricle at 7 days, but these differences were not apparent at 28 days after infarction. BK-(1-9) levels were increased in the heart and lung on days 2 and 3 post infarction, but not in the aorta or kidney. A decrease in BK-(1-7)/BK-(1-9) ratio suggested reduced metabolism of BK-(1-9) to BK-(1-7) in infarcted hearts. CONCLUSIONS: The transient activation of the circulating renin angiotensin system, and increased Ang II levels in the aorta, kidney, and lung may contribute to the systemic responses to myocardial infarction and cardiac failure. The correlations between cardiac Ang II levels and heart weight/body weight ratio noted for whole cardiac ventricles support a role for local Ang II levels in the process of myocardial remodeling post infarction. The increased cardiac BK-(1-9) levels in the acute phase of myocardial infarction were consistent with a role for this peptide in cardioprotection and limitation of infarct size.
Angiotensin II↗
Inhibition of neutral endopeptidase, the degradative enzyme for natriuretic peptides, in rat kidney after oral SCH 42495.
1. Inhibition of neutral endopeptidase (NEP), the degradative enzyme for atrial natriuretic peptide, was studied in vitro and in vivo using a previously characterized NEP inhibitor radioligand, 125I-labelled RB104. 2. SCH 42354, the active di-acid of the ethylester prodrug, SCH 42495, caused a concentration-dependent displacement of 125I-labelled RB104 from rat renal NEP. The concentration of SCH 42354 that displaced 50% of radioligand bound to the enzyme NEP (IC50) was 3.3 +/- 0.1 nmol/l (mean +/- SEM). Enalaprilat, an angiotensin converting enzyme inhibitor, did not displace 125I-labelled RB104 in concentrations up to 10 mumol/l. 3. In adult normotensive Sprague-Dawley rats, oral SCH 42495 (3-300 mg/kg) caused significant inhibition of renal NEP (P < 0.001). SCH 42495 had no effect on renal or plasma angiotensin converting enzyme activity, but high-dose SCH 42495 (300 mg/kg) caused a significant increase in plasma renin activity (P < 0.01). 4. In a time course study, oral SCH 42495 (30 mg/kg) caused rapid (within 30 min) and significant inhibition of renal NEP for up to 48 h (P < 0.001). No changes in plasma atrial natriuretic peptide or plasma angiotensin converting enzyme activity were seen. 5. These data provide evidence that short-term administration of the NEP inhibitor SCH 42495 results in inhibition of renal NEP and does not inhibit the circulating or the tissue renin-angiotensin system. The NEP inhibitor radioligand 125I-labelled RB104, is a useful tool to study tissue NEP inhibition after administration of NEP inhibitors.
Administration, Oral↗
Elevated vascular angiotensin converting enzyme mediates increased neointima formation after balloon injury in spontaneously hypertensive rats.
OBJECTIVE: To measure the effect of hypertension on neointima formation after balloon injury of rat aorta and its association with the local angiotensin converting enzyme (ACE) concentration. Balloon angioplasty of the thoracic aorta using a 2 French Fogarty catheter was performed in spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley (SD) rats. RESULTS: The injured aortic wall of SHR had already significantly higher ACE concentrations than did the uninjured aortic wall of normotensive SD rats (media: 729 +/- 37 dpm/mm2 in SHR versus 496 +/- 38 dpm/mm2 in SD rats, P < 0.01; intima: 83 +/- 5 dpm/mm2 versus 68 +/- 6 dpm/mm2 in SD rats, P < 0.01). Fourteen days after injury of the aorta the hypertensive rats had significantly higher neointima: media ratios than did the normotensive rats (0.83 +/- 0.09 versus 068 +/- 0.01, P < 0.01). This was associated with a significant increase in vascular media and neointima ACE concentrations in SHR (media 965 +/- 25 dpm/mm2, neointima 614 +/- 48 dpm/mm2) compared with those in normotensive SD rats after balloon angioplasty (media 669 +/- 23 dpm/mm2, neointima 287 +/- 33 dpm/mm2, P < 0.01). ACE inhibitor treatment with 10 mg/kg body weight lisinopril daily for 14 days by gavage reduced neointima proliferation in hypertensive and normotensive rats (neointima: media ratio: 0.35 +/- 0.02 for SHR, P < 0.01, versus untreated SHR with balloon injury; 0.28 +/- 0.01 for SD, P < 0.01, versus untreated SD rats with balloon injury). This was associated with significant vascular media ACE inhibition (SHR 149 +/- 9 dpm/mm2; SD rats 118 +/- 7 dpm/mm2; P < 0.01 versus untreated controls with balloon injury) and neointima ACE inhibition (SHR 73 +/- 4 dpm/mm2, SD rats 63 +/- 7 dpm/mm2, P < 0.01, versus untreated controls with balloon injury), but also lowered the blood pressure in SHR significantly (to 148 +/- 5 mmHg, P < 0.01, versus untreated SHR with balloon injury). When this drop in blood pressure was prevented by feeding the rats a high-salt diet (SHR with ACE inhibitor plus high salt-diet group blood pressure 193 +/- 3 mmHg, P = 0.57, versus untreated SHR) hypertension per se without the local ACE increase (ACE concentration in SHR with ACE inhibitor high-salt diet rats' media 167 +/- 10 dpm/mm2 and neointima 81 +/- 9 dpm/mm2) had only a mild effect on neointima formation after balloon angioplasty (neointima: media ratio 0.4 +/- 0.01 for SHR with ACE inhibitor plus high-salt diet versus 0.35 +/- 0.02 for SHR with ACE inhibitor plus normal-salt diet P < 0.05). Treatment with 10 mg/kg body weight angiotensin II subtype 1 receptor antagonist losartan potassium daily for 14 days by gavage was associated with a reduction in neointima formation similar to that observed with the ACE inhibitor both for SHR and for SD rats (neointima: media ratio 0.32 +/- 0.04 for SHR with losartan, 0.27 +/- 0.03 for SD rats with losartan; P < 0.01, versus untreated controls with balloon injury) suggesting that ACE inhibitor prevented neointima formation, at least in part by, reducing the local production of angiotensin II. CONCLUSION: Neointima formation after balloon angioplasty in SHR is increased compared with that in normotensive SD rats. This is due mainly to there being a higher degree of activation of the renin-angiotensin system in the aorta of the SHR before and after balloon injury compared with that in normotensive SD rats measured in terms of the increased vascular ACE concentrations. Blood pressure alone had only a moderate effect on neointima formation.
Angiotensin-Converting Enzyme Inhibitors↗
Modulation of genetic hypertension by short-term AVP V1A or V2 receptor antagonism in young SHR.
To characterize the role of arginine vasopressin (AVP) V(1A) or V2 receptors and the possible interaction with the renin-angiotensin system in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR), young male SHR were treated from 6 to 10 wk of age with AVP V(1A) receptor blockade, angiotensin-converting enzyme (ACE) inhibition, combination of V(1A) receptor blockade and ACE inhibition, V2 receptor blockade, and vehicle. Treatments were then withdrawn, and systolic blood pressure (SBP) was measured until 19 wk of age. At both 10 and 19 wk of age, SBP was significantly reduced with V(1A) receptor blockade, ACE inhibition, and combined treatment compared with vehicle treatment, although no treatment normalized SBP to levels of Donryu normotensive rats. Throughout the experimental period, no significant additive effects were observed with combined treatment. At 10 wk of age, plasma AVP concentration and 24-h urinary AVP excretion were increased with AVP V2 receptor blockade. At 19 wk of age, SBP was significantly higher in rats previously treated with V2 receptor blockade (233 +/- 3 mmHg) than with vehicle (221 +/- 2 mmHg) (P < 0.01). Left ventricular mass was significantly reduced in rats previously treated with ACE inhibition or combined treatment. These results suggest that AVP (via V(1A) receptors) and angiotensin II contribute to the pathogenesis of SHR hypertension, whereas the AVP V2 receptor may be involved in preventing the full expression of the hypertension, in male SHR.
Angiotensin-Converting Enzyme Inhibitors↗
Diffuse tumor microembolism: a rare cause of a high-probability perfusion scan.
Pulmonary tumor embolism is a rare but well-documented cause of respiratory failure in patients with cancer. This entity is probably clinically underrecognized and may represent an important cause of morbidity and mortality. A typical pattern of multiple peripheral subsegmental defects on perfusion lung scanning has been described. We present a case of a unilateral near absence of perfusion in a 53-year-old woman who on autopsy was found to have diffuse tumor microembolism. As new chemotherapeutic agents are developed for the treatment of malignancies, an early diagnosis may become more important. A high-probability perfusion scan should not dissuade the clinician from pursuing further evaluation. Cytologic findings of pulmonary venous blood may be diagnostic.
Breast Neoplasms↗
A risk-benefit assessment of losartan potassium in the treatment of hypertension.
Losartan potassium is the first of a new class of orally active antihypertensive drugs which antagonise the action of angiotensin (AT) II at the AT1 receptor subtype. Losartan potassium is converted by the liver to the active metabolite E-3174, which is a more potent antagonist at the AT1 receptor. E-3174 is responsible for most of the pharmacological effects of losartan potassium, and its long half-life contributes to the extended duration of action of the drug. Losartan potassium is effective as a once-daily antihypertensive agent. In mild to moderate hypertension, losartan potassium has similar efficacy to enalapril, atenolol and felodipine extended release. When losartan potassium is combined with hydrochlorothiazide there is a further reduction in blood pressure. Losartan potassium is well tolerated in mild, moderate and severe essential hypertension, with dizziness being reported as the only drug-related adverse effect. The overall rate of patient withdrawal from therapy due to adverse experiences with losartan potassium is lower (2.3%) than that of placebo (3.7%). First-dose hypotension is uncommon, perhaps due to the slower onset of action of the drug, and cough does not appear to be a significant problem. A number of areas concerning the safety and efficacy of losartan potassium remain to be clarified. In particular, long term tolerability studies are needed; cough only became apparent as an adverse effect of ACE inhibitors after 3 to 4 years of use. Postmarketing surveillance has shown that angioedema, a rare but life-threatening adverse effect of ACE inhibitors, also occurs with losartan potassium. Further data are needed on the use of losartan potassium in patients with renal impairment before accepting the recommendation that dosage adjustment is not necessary. The pharmacokinetics and pharmacodynamics of losartan potassium in patients with hepatic disease also require further investigation. Losartan potassium increases uric acid secretion and lowers plasma uric acid levels, which may be of benefit when losartan potassium is combined with a thiazide diuretic, but which may otherwise lead to uric acid stone formation and possibly to nephropathy. Simple control of blood pressure is no longer an adequate goal in the management of hypertension. Any new antihypertensive agent should also reduce cardiovascular events, prevent or cause regression of end-organ damage such as left ventricular hypertrophy, atherosclerosis and renal failure, and should not impair quality of life. Such data on losartan potassium are not currently available. Losartan potassium is likely to be used in patients who are intolerant of ACE inhibitors, but its future in the management of hypertension will depend on long term tolerability studies and data on its effects beyond simple blood pressure control.
Angiotensin Receptor Antagonists↗
Angiotensin II receptor antagonists. Potential in elderly patients with cardiovascular disease.
Raised blood pressure in the elderly is not a normal consequences of aging, but is a major risk factor for cardiovascular disease. Cardiac and cerebrovascular disease account for > 50% of deaths among people aged > 65 years. Because the percentage of elderly people in most populations is rising, blood pressure control in this group is becoming increasingly important. Several large intervention studies in the elderly have demonstrated that antihypertensive medication reduces cardiovascular morbidity and mortality. In addition, the absolute benefits of blood pressure reduction are higher in elderly compared with younger patients. ACE inhibitors are effective and well tolerated in the treatment of hypertension in the elderly. Their success led to interest in alternative ways of blocking the renin angiotensin system, and the subsequent development of angiotensin II (AII) receptor antagonists. Losartan was the first drug in this class to become commercially available. Since then, valsartan has been launched in some markets and others are likely to be launched in the near future. Losartan is effective in the treatment of essential hypertension and has a low incidence of adverse effects. First-dose hypotension is very uncommon and, at the present time, cough does not appear to be an adverse effect of these drugs, although long term tolerability studies are needed to confirm this. Angioedema, a rare but life-threatening adverse effect of ACE inhibitors, has also been associated with losartan. Current data suggest that All receptor antagonists are effective in elderly hypertensive patients, although further data are needed to confirm these findings. At present, All receptor antagonists are likely to be used in hypertensive patients who are intolerant of ACE inhibitors, although this may change with the availability of long term tolerability and clinical outcomes data.
Aged↗
Rationale and pharmacology of angiotensin II receptor antagonists: current status and future issues.
BACKGROUND: The renin-angiotensin system consists of a cascade of substrate-enzyme interactions that culminates with the production of angiotensin II, the active peptide responsible for all the known effects of the renin-angiotensin system. Blocking this enzymatic cascade has been the focus of considerable research to the extent that the renin-angiotensin system is implicated in the control of blood pressure, sodium and water homeostasis, and cardiovascular function and structure. ANGIOTENSIN CONVERTING ENZYME INHIBITORS: Angiotensin converting enzyme (ACE) inhibitors provide one way of blocking the renin-angiotensin system, and to this end the compounds have proved efficacious in the treatment of hypertension and cardiovascular disease. However, these compounds are limited in the extent to which they block the renin-angiotensin system, partly due to recently described alternate pathways for the genesis of angiotensin II and also because ACE is not a very specific enzyme and has multiple other potential substrates including bradykinin, tachykinins, neurotensin substance P, and others. ANGIOTENSIN II RECEPTORS: The development of angiotensin II receptor antagonists represents a new way to block the renin-angiotensin system at the receptor level. Irbesartan is a new angiotensin II receptor antagonist that provides specific and insurmountable antagonism of the AT1 receptor subtype, demonstrating a greater than 8500-fold specificity for the AT1 receptor, the subtype which mediates all the known actions of angiotensin, compared to the AT2 receptor. Comparative studies have demonstrated that irbesartan is 10 times more potent than losartan and slightly more potent than E3174, losartan's active metabolite. Preclinical pharmacological studies in a variety of animal models have demonstrated that irbesartan provides a dose-dependent, insurmountable blockade of angiotensin and reductions in blood pressure, urinary protein and glomerular sclerosis score.
Angiotensin Receptor Antagonists↗