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17th May 2008 @ 2:18pm |
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Volume 1, Number 3, September 2000PAPERBlunted suppression of plasma renin activity in diabetes We have documented, contrary to expectation, that the renin-angiotensin-aldosterone system (RAAS) is stimulated normally by restriction of sodium intake in patients with Type 2 diabetes mellitus (DM) and hypertension. Conversely, plasma renin activity (PRA) is suppressed less than in normal subjects by a high-salt diet in these patients. Increasing plasma angiotensin II (Ang II) concentration through intravenous Ang II infusion also suppresses renin release, via the short feedback loop. In this study, we sought to ascertain whether the limited renin suppression in Type 2 diabetes mellitus via high-salt intake is a unique defect or part of a more generalised abnormality of PRA suppression. We studied 38 patients with Type 2 DM and hypertension, 158 hypertensive control patients, and 61 normotensive controls. All patients were studied while in metabolic balance on a 10 mEq sodium (Na) diet. The response to the Ang II infusion at 3 ng/kg/min for 45 minutes was measured. We found that PRA fell significantly in normal subjects, from 4.0±0.33 to 2.5±0.23 ng AngI/ml/hr (p=0.0056). In patients with essential hypertension, the Ang II infusion also led to a fall in PRA from 3.51±0.23 to 2.76±0.17 ng AngI/ml/hr (p=0.014). In patients with DM, despite a similar basal PRA (3.7±0.40 ng AngI/ml/hr), the infusion of Ang II did not influence PRA significantly (3.43±0.42 ng AngI/ml/hr; p>0.77), though these patients had the most robust mean arterial pressure response. Our data are in complete accord with the concept of high intrarenal Ang II in DM and suggest lower systemic Ang II despite comparable PRA. JRAAS 2000;1:252-256. PAPEREffects of losartan on haemodynamic parameters and angiotensin receptor mRNA levels in rat heart after myocardial infarction We investigated the haemodynamic parameters and the regulation of cardiac mRNA levels of the angiotensin receptor subtypes, AT1 and AT2, by the AT1-receptor antagonist losartan in rat heart during the acute phase of myocardial infarction. AT1- and AT2-receptor mRNA levels markedly increased at 30 minutes and peaked at 24 hours post myocardial infarction (12.6-fold increase for AT1- and 17.2-fold increase for AT2 compared with controls). Losartan significantly reduced mean blood pressure in sham-operated rats and decreased mean blood pressure and left ventricular end-diastolic pressure in myocardial infarction rats. However, the AT1- and AT2-receptor mRNA levels of losartan-treated rats showed a pattern similar to that of water-treated rats. The time-dependent increase of AT1- and AT2-receptor mRNA levels is associated with the early remodelling process of non-infarcted myocardium post MI and is independent of AT1-receptor blockade. JRAAS 2000;1:257-262. POPULAR In previous studies, we have shown that losartan possesses nitric oxide-dependent antithrombotic properties in various models of hypertension in rats. It was demonstrated that stimulation of AT2-receptors plays an important role in the pharmacological effects of AT1-receptor antagonists. Thus, in this study, we examine the participation of AT2-receptors in the antithrombotic action of losartan in renal hypertensive rats on venous thrombosis induced by a two-hour ligation of the vena cava. Losartan administration (30 mg/kg, p.o.) resulted in a marked decrease in thrombus weight (by 85%, p<0.001). PD123319, an AT2-receptor antagonist (10 mg/kg, i.v.), administered concomitantly with losartan, abolished its antithrombotic effect, whilst it had no influence on thrombus weight when given alone. A significant decrease in systolic blood pressure was observed in animals given losartan. PD123319 administration did not abolish this action of losartan and did not alter blood pressure when given alone. No changes in prothrombin time, activated partial thromboplastin time, or euglobulin clot lysis time were observed in animals administered losartan and/or PD123319. Similarly, primary haemostatics evaluated by bleeding time and platelet count did not change in any group of rats. In conclusion, we have shown that AT2-receptor stimulation is involved in the antithrombotic action of losartan in renal hypertensive rats. JRAAS 2000;1:263-267. PAPERThe antithrombotic effect of angiotensin-(1–7) closely resembles that of losartan Angiotensin-(1-7) [Ang-(1-7)]
is the bioactive peptide which may be responsible for some of the pharmacological
effects of losartan. Our previous study has demonstrated the antithrombotic action
of losartan in a model of experimental thrombosis. In the present study, we compared
the antithrombotic action of losartan and Ang-(1-7). JRAAS 2000;1:268-272. POPULAR Background: Insulin-like growth factor-1
(IGF-1), as well as
AT1-receptor
activation, plays a central role in growth processes of cardiac and vascular cells.
In order to assess relevant interactions of both systems, the effect of IGF-1 on
AT1-receptor expression was evaluated
in vascular smooth muscle cells. JRAAS 2000;1:273-277. PAPERLosartan reduces collagen content and intimal thickening of iliac arteries after balloon injury in rabbits Intimal thickening and formation of extracellular matrix are parts of the repair process after vascular injury. Similar processes occur after coronary angioplasty. Prior studies have shown that losartan inhibits intimal thickening in rat carotid arteries following balloon injury. However, the effects of losartan in reducing the collagen content of arteries after balloon injury have not been examined. The objectives of this study were to determine the change in collagen content after balloon injury and to analyse the mechanisms of reduction of collagen content and intimal thickening. Losartan (15 mg/kg/d) was administered orally from six days before to eight weeks after balloon injury in rabbits. Collagen content was measured histologically by the use of circularly polarised images of picrosirius red-stained sections. Collagen content in arterial intima was found to be significantly lower in the losartan-treated group (n=12) than in the control group (n=12) (21.6%±5.2% vs. 43.8%±7.6%, p<0.01). Losartan reduced the collagen content in arterial intima by 50.7% area fraction compared with that of control. The morphological observation showed that the intimal area and intimal-to-medial area ratio in the losartan-treated group were significantly less than in the control group (0.27±0.13mm2 vs. 0.52±0.29 mm2, 0.55±0.21 vs. 0.97±0.25, respectively, p<0.05). These data indicate that losartan reduces vascular collagen content and inhibits intimal thickening after balloon injury. The results also suggest that collagen accumulation in the intima may be an important factor in the development of the stenotic lesion and that the use of losartan may have therapeutic value to prevent stenosis after balloon injury. JRAAS 2000;1:278-282. POPULAR Many slow dissociating (insurmountable)
non-peptide angiotensin type 1 receptor (AT1)
antagonists contain, besides the acidic biphenyltetrazole substructure of losartan,
a second acidic group to stabilise antagonist-receptor complexes. To investigate
the involved basic amino-acids of the human AT1-receptor,
wild-type and mutant receptors were transiently transfected in CHO-K1 cells and
characterised by [3H]candesartan binding. Lys199 JRAAS 2000;1:283-288. PAPERThe effects of the addition of losartan on uric acid metabolism in patients receiving indapamide Objective: A number of adverse metabolic effects are associated
with indapamide administration, including an increase in serum uric acid levels.
It has been reported that losartan can significantly decrease serum uric acid
levels. However, there are no data on the effects
of combination therapy of losartan with indapamide on uric acid metabolism. JRAAS 2000;1:289-291. POPULAR Management of the symptoms of hypertension has been approached in many ways ranging from lifestyle changes to drug therapy. These strategies often reduce high blood pressure (BP) but they are not without significant drawbacks, including side effects and patient compliance problems. Most importantly, these approaches do not cure this complex disease. Rather, once symptoms are treated, the importance of hypertension as a major risk factor for other diseases such as stroke, ischaemic heart disease and progressive renal damage is masked. Efforts to minimise the effects of hypertension through improved therapy will continue until the cause of hypertension is determined and a cure is discovered. Pharmacological therapy is at a conceptual plateau, but the development of gene therapy provides researchers and clinicians with an opportunity to treat hypertension in a new and potentially better way. We have used anti-sense gene therapy targeting the renin-angiotensin-aldosterone system (RAAS) to not only control high BP, which accompanies hypertension, but also to attenuate other associated pathophysiological changes. JRAAS 2000;1:211-216. POPULAR Combining angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-I) is a new therapeutic approach to improving outcomes in hypertension, heart failure and renal disease. Evidence suggests that long-term ACE-inhibition results in incomplete renin-angiotensin-aldosterone system (RAAS) blockade, thus potentially reducing its full tissue protective effects. Recent studies have confirmed the importance of using ACE-I at doses higher than the recommended levels for blood pressure (BP) control in cardiovascular disease states where the RAAS is known to be chronically activated. Chronic RAAS activation results in progressive damage to target, end-organ function (e.g. vasculature, kidneys, heart), attributed to BP elevation and haemodynamic changes but also through its local, tissue-based effects (e.g. hypertrophy, fibrosis, remodelling). Combining two RAAS blockers that act at different sites of the renin-angiotensin cascade, rather than increasing the dose of either agent alone, should allow more effective tissue-based RAAS blockade, while sparing maximal doses of medications. A majority of the clinical studies, involving the addition of an ARB to ACE-I therapy, demonstrated additional but small reductions in BP when compared with high-dose monotherapy. The benefits of combining ACE-I and ARB therapies are to provide optimal tissue-RAAS blockade in order to maximally reduce target organ disease. The combined therapy of ARBs and ACE-I allows optimal blockade of the RAAS at relatively lower doses of both agents and is preferable to titrating to higher doses than the ACE-I to some undefined optimal level. JRAAS 2000;1:217-233. EDITORIAL REVIEWACE inhibitors and antihypertensive treatment in diabetes: focus on microalbuminuria and macrovascular disease Hypertension is a common complication of diabetes mellitus. The origins of increased blood pressure (BP) differ between the two types of diabetes. In Type 1 diabetes, the increase in BP is closely linked to the onset and progression of renal disease and is a major risk factor for overt nephropathy. In Type 2 diabetes, by contrast, because of the older age of the patient group, macrovascular and cardiac complications of hypertension are more prominent. In recent years, a number of clinical trials have been performed to investigate the effects of antihypertensive treatment on diabetic vascular and renal disease. JRAAS 2000;1:234-239. EDITORIAL REVIEWThe renin-angiotensin-aldosterone system and fibrinolysis Activation of the RAAS has
been linked with an increased risk of myocardial infarction and stroke,1,2,37,38
and recently these beneficial effects have, in part, been attributed to the effects
of the RAAS on the fibrinolytic system. Indeed, ACE seems to occupy a central position
in modulating the fibrinolytic balance, where an angiotensin II-mediated increase
of PAI-1 plays a major role. By contrast, the effect on bradykinin stimulated t-PA
release may be of lesser importance, although the data are conflicting. JRAAS 2000;1:240-244. EDITORIAL REVIEWEarly initiation of ACE inhibitor treatment after acute myocardial infarction - a missed therapeutic opportunity? There is a wealth of evidence supporting the use of ACE inhibitors in patients who have suffered a previous myocardial infarction and who have evidence of impaired left ventricular systolic dysfunction, in the presence or absence of clinically overt cardiac failure. The slowed progression of deteriorating cardiac performance and improved survival are closely associated with attenuation of cardiac remodelling, and this benefit is likely to continue with long-term treatment. Over recent years, substantial evidence has now accrued in favour of initiation of ACE inhibitor treatment within 24 hours to unselected myocardial infarction patients. A lower incidence of cardiac failure and improved survival are evident even within the first 24 hours, and the benefits of short-term early treatment persist for up to at least one year after myocardial infarction. Early treatment is associated with more frequent severe hypotension, necessitating careful patient selection and monitoring during treatment. Mechanisms underlying the benefits of very early treatment are probably related to attenuation of sympathetic nervous activity and/or anti-ischaemic effects, and there is no clear evidence advocating continued ACE inhibitor treatment beyond four to six weeks in patients with preserved left ventricular systolic function. Early initiation of ACE inhibitor treatment within 24 hours of myocardial infarction provides the opportunity to save lives, even in addition to other secondary prevention including aspirin, thrombolytic treatment and beta-blockade. Early initiation of ACE inhibitor treatment is an essential part of clinical care that should be delivered to all patients after myocardial infarction, to achieve maximal reduction of morbidity and mortality in this high-risk period. JRAAS 2000;1:245-251. |
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Gln
substitution decreased the affinity 45-fold for candesartan (95% insurmountable),
18-fold for EXP3174 (70% insurmountable), 10-fold for irbesartan (40% insurmountable)
and 5-fold for losartan (surmountable). His256