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Volume 2, Number 2, June 2001PAPERNon-AT1-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil Previous studies have shown that angiotensin II (Ang II), by mediating rapid recruitment of collateral circulation, has a protective effect in the setting of acute ischaemia. In an experimental model of acute cerebral ischaemia in the gerbil, Fernandez et al. have reported that the mechanism of the protective effect of Ang II is blood pressure (BP)-independent,1 and that the AT1-receptor antagonist, losartan, but not the ACE inhibitor (ACE-I), enalapril, decreases mortality following unilateral carotid artery ligation.2 The aim of this study was to examine the reproducibility of the respective effects of losartan and enalapril, and to verify that these differential effects are drug class-related. Acute cerebral ischaemia was induced in anaesthetised gerbils by unilateral carotid ligation. The effect of pretreatment with two different ACE-I (enalapril and lisinopril), and two different AT1-receptor antagonists (losartan and candesartan), administered orally or intravenously, on mortality were compared. Kaplan-Meier survival curves at day three were analysed by a log-rank test. Pretreatment with both enalapril and lisinopril significantly decreased survival at day three compared with controls, while the AT1-receptor antagonists losartan and candesartan, despite similarly lowering BP, did not increase mortality. Coadministration of losartan and enalapril increased mortality to the same extent as enalapril alone. This study confirms that Ang II contributes to protective mechanisms against acute cerebral ischaemia through non AT1-receptor-mediated, BP-independent effects. JRAAS 2001;2:103-106. PAPEREffects of combination of low doses of angiotensin-converting enzyme inhibitor and diuretics on renal function in spontaneously hypertensive rats: comparison between acute and chronic treatment The goal of this study was to assess the effect of
acute or chronic treatment with S5590, a combination of the angiotensin-converting
enzyme inhibitor perindopril (0.76 mg/kg/day) and the diuretic indapamide
(0.24 mg/kg/day) on renal function in spontaneously hypertensive rats with moderate
renal injury. JRAAS 2001;2:107-111. PAPEREffects of losartan treatment on T-cell activities and plasma leptin concentrations in primary hypertension Recent evidence shows that leptin may contribute to elevated blood pressure (BP) and interact with the renin-angiotensin-aldosterone and cellular immune systems. Altered T-cell activities and changes in T-cell subset ratios have also been reported in hypertension. However, little is known about the effects of AT1-receptor antagonism on T-cell activities and plasma leptin concentrations in primary hypertension. We have, therefore, investigated the relationship between leptin and T-cell activities and the effect of an AT1-receptor antagonist, losartan, in primary hypertension. Twenty recently-diagnosed and untreated young adults (11 males and 9 females, age; 39.9±7.6 years, range 23–49 years, BMI; 27.6±3.7 kg/m2) and 20 normotensive healthy, age-, sex- and BMI-matched controls were studied. The [3H]-thymidine uptakes of cultured lymphocytes were determined, both spontaneously and after stimulation with phytohaemagglutinin. The tests were performed before and after three months of treatment with losartan. The results indicate that the blastogenic responses of T-cells to phytohaemagglutinin are significantly higher in the patient group compared with controls (p=0.02). After normalisation of BP, T-cell responses were significantly reduced and were lower than in the controls (p=0.01). Pretreatment plasma leptin levels were significantly higher in hypertensives than in controls (p=0.01). However, losartan treatment had no significant effect on leptin concentrations; moreover, no correlation between leptin levels and T-cell activity was found. Our data show that plasma leptin levels and T-cell activity are markedly enhanced in untreated essential hypertension and that the alteration of T-cell activity is not related to plasma leptin levels. Antihypertensive treatment with losartan decreases T-cell activities but does not influence plasma leptin levels. We conclude that leptin levels are not affected by AT1-receptor blockade and are not related to T-cell activity. JRAAS 2001;2:112-116. PAPERAngiotensin II-induced stimulation of collagen secretion and production in cardiac fibroblasts is mediated via angiotensin II subtype 1 receptors The possible contributions of the angiotensin receptor subtypes 1 (AT1) and 2 (AT2) to angiotensin II (Ang II)-induced changes in collagen secretion and production were studied using the specific angiotensin AT1- and AT2-receptor antagonists telmisartan and P-186, respectively. Cardiac fibroblasts (from normal male adult rats) from passage 2 were cultured to confluency and incubated in the presence of 10-10 to 10-6 M Ang II in serum-free Dulbecco's MEM medium for 24 hours. Collagen production and secretion were assayed by 3H-Proline incorporation; non-collagen production and secretion were also calculated. Ang II dose-dependently increased collagen secretion and production in rat adult cardiac fibroblasts in culture. Non-collagen secretion and production were also concentration-dependently increased by Ang II. Addition of 100 nmol/l Ang II increased (p<0.01) collagen secretion and production by 75±6 (SEM)% and 113±23%, respectively, and non-collagen secretion and production by 65±6% and 57±16%, respectively. Pretreatment of cardiac fibroblasts with telmisartan completely blocked the Ang II-induced increase in collagen secretion (p<0.001) and production (p<0.05) and in non-collagen secretion (p<0.01) and production (p<0.01). P-186 had no effect on the Ang II-induced increase in collagen secretion and production. Addition of telmisartan and P-186 did not affect collagen secretion and production in basal cardiac fibroblasts. Our data demonstrate that the effects of Ang II on collagen secretion and production in adult rat cardiac fibroblasts in culture are AT1-receptor mediated, since they were abolished by the specific AT1-receptor antagonist, telmisartan, but not by the specific AT2-receptor antagonist, P-186. JRAAS 2001;2:117-122. POPULAR The effects of telmisartan
and hydrochlorothiazide (HCTZ) alone and in combination on blood pressure (BP) and
renal excretory function were investigated in male spontaneously hypertensive rats
(SHR) after oral administration for five consecutive days. Four treatments were
studied: vehicle (0.5% Natrosol™), telmisartan 3 mg/kg, HCTZ 10 mg/kg,
and telmisartan 3 mg/kg+ HCTZ 10 mg/kg. The effects on BP and heart rate were studied
in 40 SHRs (10 animals per group) using an implanted telemetry device. Renal excretory
function was assessed in 76 SHRs (18 animals per group, of which nine were used
for urine sampling and nine for blood sampling). JRAAS 2001;2:123-128. POPULAR A previous study by our group
showed that 10 weeks of pretreatment with losartan reduced myocardial infarct size
and arrhythmias in a rat model of ischaemia-reperfusion. However, the effect
of a differing time course of pretreatment has not been investigated. 104 Sprague-Dawley
rats were randomised to four groups: a control, and three treatment groups in which
losartan (40 mg/kg/day) was administered in drinking water for one day, one week,
and four weeks respectively. After different durations of pretreatment, the rats
were subjected to 17 minutes of left coronary artery occlusion and 120 minutes
of reperfusion. Haemodynamic variables were not significantly different between
the four groups. Myocardial infarct size was unchanged after one day and one week
of pretreatment (52±7, 57±6% vs. control 55±3%), but was significantly
reduced by four weeks of pretreatment with losartan (38±6, p<0.05). Endothelial-dependent
vasorelaxation was significantly increased by four weeks of pretreatment (-81±4
vs. -62±7%, p<0.05). As an indicator of ischaemia, vascular endothelial
growth factor (VEGF) levels in ischaemic myocardium were decreased after one and
four weeks of pretreatment (0.75±0.05, 0.58±0.10 vs. 1.0, p<0.05, 0.01,
respectively). JRAAS 2001;2:129-133. PAPEREnhanced regional AT2-receptor and PKCε expression during cardioprotection induced by AT1-receptor blockade after reperfused myocardial infarction We assessed the effects of the angiotensin II (Ang II) type 1 receptor (AT1-receptor) blocker, candesartan, (CN, 1 mg/kg i.v. over 30 minutes pre-ischaemia) alone or after intracoronary administration of Ang II type 2 receptor (AT2-receptor) blocker (PD 123319), protein kinase C (PKC) inhibitor (chelerythrine), endothelial nitric oxide (NO) synthase inhibitor (NG-monomethyl-L-arginine or L-NMMA), and bradykinin (BK) -B2 receptor inhibitor (HOE140) on in vivo left ventricular (LV) function and remodelling (echocardiograms/ Doppler) and haemodynamics in 30 dogs with reperfused anterior infarction (90 minutes ischaemia, 120 minutes reperfusion), and ex vivo infarct size, AT1-receptor/AT2-receptor proteins and PKCε (immunoblots), and cyclic guanosine 3', 5' monophosphate (cGMP, immunoassay). Compared with controls, CN inhibited the Ang II pressor response, reduced LV preload, improved LV systolic and diastolic function, limited LV remodelling, decreased infarct size, and increased AT2-receptor and PKCε proteins in the infarct zone (IZ), and these responses were abrogated by PD 123319, chelerythrine, L-NMMA and HOE140. In addition, the increase in LV cGMP with CN was attenuated by PD 123319, L-NMMA and HOE140. The overall results suggest that AT2-receptor activation and signalling via BK, PKCε and cGMP contribute to cardioprotection associated with AT1-receptor blockade during ischaemia-reperfusion injury. JRAAS 2001;2:134-140. PAPERValsartan and candesartan can inhibit deteriorating effects of angiotensin II on coronary endothelial function - Article includes book review The angiotensin II (Ang II) AT1-receptor antagonists, valsartan
and candesartan, were compared with regard to their effect on Ang II-mediated changes
in parameters of coronary endothelial function. Ang II (10 μM) induced increased
concentrations of the vasoconstrictor endothelin, the procoagulatory substance
plasminogen-activator-inhibitor-1 (PAI-1) and the precursor of the matrix-metalloproteinase
1 (MMP-1) in endothelial cell cultures from human coronary arteries. These increases
were completely prevented by the addition of 10 μM valsartan or candesartan
and partially by the addition of lower concentrations of these drugs, i.e. 1 μM
and 0.1 μM. No significant difference between the effect of the two AT1-receptor
antagonists was observed. JRAAS 2001;2:141-143. POPULAR Since some drugs which block the renin-angiotensin system (RAS), such as angiotensin-converting
enzyme inhibitors (ACE-I) and spironolactone have been shown to improve symptoms, decrease
hospital admission rates and increase survival in patients with congestive heart failure, it has
been postulated that angiotensin II receptor blockers (ARBs) will also have a beneficial role in
heart failure management. JRAAS 2001;2:89-92. POPULAR Although meta-analyses of trials on the effect of salt reduction on blood pressure (BP) have
consistently shown a significant BP reduction in hypertensive patients, it has been suggested
that salt reduction has little or no such effect in normotensives. In contrast, a recent
meta-analysis by our group, which included studies of modest salt reduction over a prolonged
period, did show a significant decrease in BP, in both hypertensives and normotensives.
In addition, a prospective study of 1173 Finnish men and 1263 Finnish women, in whom 24-hour
urinary sodium excretion was measured at baseline, showed that lower salt intake was associated
with lower cardiovascular mortality, and that this effect was independent of other
cardiovascular risk factors. JRAAS 2001;2:93-95. POPULAR All components of the renin-angiotensin system have been found in the central nervous system. Both angiotensin receptor types, AT1 and AT2, and probably further receptor types are present in the brain and neuronal tissue. In the adult brain, the AT1-receptor dominates by far and mediates most of the known actions of angiotensin II (Ang II), such as the central regulation of blood pressure, body fluid and electrolyte homeostasis, sympathetic outflow and the release of hypothalamic and pituitary hormones. The AT2-receptor is highly expressed in the brain during foetal development and its expression can be altered in pathological situations. In general, the actions of Ang II mediated via AT2-receptors are directly opposed to those mediated via AT1-receptors. There is a large body of evidence that AT2-receptors contribute to the cellular processes which are initiated by tissue damage or injury. The AT2-receptor appears to act as a mediator of processes occurring during brain development, neuronal cell differentiation and regeneration, but has also been implicated in molecular events which lead to programmed cell death. This review provides an analysis of functions of Ang II in neuronal cells and the nervous system with the focus on the role of the AT2-receptor in neuronal tissue upon various physiological and pathophysiological situations. JRAAS 2001;2:96-102. |
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