Effects Of AT1 Receptor Blockade Research Articles

Effects of angiotensin II type 1 receptor blockade in ApoE-deficient mice with post-ischemic heart failure.

We investigated in mice whether atherosclerosis exacerbates the development of post-ischemic heart failure and alters the beneficial effects of long-term angiotensin II type 1 receptor blockade in this model. ApoE-deficient (ApoE(-/-)) and C57BL/6J (C57) mice with myocardial infarction (coronary ligation) received vehicle (C57 and ApoE(-/-)) or irbesartan (Ir, 50mg/kg/d orally, C57-Ir and ApoE(-/-)-Ir). Ten months post myocardial infarction, survival rates were similar in C57 (58%) and ApoE(62%). Atherosclerosis induced no significant alteration in blood pressure, cardiac output (fluospheres), total peripheral resistance, or shortening fraction (echocardiography) but increased renal resistance (+50%, P<0.05). Chronic Ir treatment significantly improved survival to a similar extent in both C57-Ir (85%) and ApoE(-/-)-Ir (86%). It also decreased blood pressure to a similar extent in both strains (-16% and -18%, both P<0.05). In C57-Ir mice, Ir did not modify cardiac output or total peripheral resistance, but it decreased renal resistance (-28%, P<0.001) and left-ventricular weight (-28%, P<0.05). In ApoE(-/-)-Ir mice, Ir limited atherosclerotic lesions (-13%, P<0.05), increased cardiac output (+28%, P<0.05) and shortening fraction (+24%, P<0.05), and decreased total peripheral resistance (-33%, P<0.01), renal resistance (-61%, P<0.001), and left-ventricular weight (-27%, P<0.001). In conclusion, atherosclerosis does not worsen heart failure development in mice and, although the beneficial cardiovascular effects of AT1 receptor blockade are greater in ApoE(-/-) than in C57, reduction in mortality is similar in both strains.

Angiotensin AT1 receptor antagonist losartan and the defence reaction in the anaesthetised rat. Effect on the carotid chemoreflex.

Modulation at the level of the nucleus tractus solitarii (NTS) appears to be an effective way of controlling cardiovascular reflexes. Angiotensin II acting on angiotensin AT1 receptors at the central nervous system appears to have an important role in these modulatory processes. The hypothalamic defence area (HDA) is a potential source of descending fibres containing angiotensin II that innervate the NTS. We investigated the effect of AT1 receptor blockade in the NTS on the response to stimulation of HDA in anaesthetised rats treated with the neuromuscular blocking agent pancuronium bromide. The characteristic increase in heart rate, blood pressure and phrenic nerve activity evoked by electrical stimulation of HDA is decreased by the microinjection of the AT1 receptor antagonist losartan into the NTS and the cardiovascular response to carotid body chemical stimulation is also reduced. These results support the hypothesis that AT1 receptors in the NTS play a role in the modulation of cardiovascular reflexes, and modify the influence exerted on the processing of these reflexes by other areas of the central nervous system.

Long-term regulation of ENaC expression in kidney by angiotensin II.

We carried out semiquantitative immunoblotting of kidney to identify apical sodium transporter proteins whose abundances are regulated by angiotensin II. In NaCl-restricted rats (0.5 mEq Na/200 g BW/d), the type 1 angiotensin II receptor (AT1 receptor) antagonist, candesartan, (1 mg/kg of body weight per day SC for 2 days) markedly decreased the abundance of the alpha subunit of the epithelial sodium channel (ENaC). This subunit has been shown to be rate-limiting for assembly of mature ENaC complexes. In addition, systemic infusion of angiotensin II increased alphaENaC protein abundance in rat kidney cortex. The decrease in alphaENaC protein abundance in response to AT1 receptor blockade was associated with a fall in alphaENaC mRNA abundance (real-time RT-PCR), consistent with transcriptionally mediated regulation. The effect of AT1 receptor blockade on alphaENaC expression was not blocked by spironolactone, suggesting a direct role of the AT1 receptor in regulation of alphaENaC gene expression. Candesartan administration was also found to increase the abundances of the beta and gamma subunits. The increase in beta and gammaENaC protein abundance was not associated with a significant increase in the renal abundances of the corresponding mRNAs, suggesting a posttranscriptional mechanism. Immunocytochemistry confirmed the increase in beta and gammaENaC protein abundance and demonstrated candesartan-induced ENaC internalization in collecting duct cells. The results support the view that the angiotensin II receptor regulates ENaC abundance, consistent with a role for angiotensin II in regulation of collecting duct function.

Angiotensin II type 2 receptor blockade partially negates antihypertrophic effects of type 1 receptor blockade on pressure-overload rat cardiac hypertrophy.

We investigated the effects of angiotensin II type 2 (AT2) receptor blockade on the antihypertrophic effects of type 1 receptor (AT1) blockade in pressure-overload cardiac hypertrophy in adult rats. Cardiac hypertrophy was induced by banding the abdominal aorta above the renal arteries. The rats were treated with either an AT1 receptor antagonist TCV-116 (TCV, 10 mg/kg/day), an AT2 receptor antagonist PD123319 (PD, 20 mg/kg/day), or both for 4 weeks after the aortic banding. We measured systolic and diastolic blood pressure (BP), body weight (BW), left ventricular weight (LVW), and serum and cardiac angiotensin converting enzyme (ACE) activities. Aortic banding increased BP and LVW/BW, and TCV reversed both these increases. PD affected neither BP nor LVW/BW. TCV+PD reversed the increase in BP but not LVW/BW. Thus, PD was considered to counteract the antihypertrophic effect of TCV without affecting BP. All three treatments reduced cardiac ACE activity without affecting serum ACE activity. Our data demonstrated that AT2 receptor blockade negates the antihypertrophic effects of AT1 receptor blockade in an adult rat model of pressure-overload cardiac hypertrophy. AT2 receptors may mediate the signaling pathways involved in growth inhibition, which could counteract mediation of the cellular growth signaling pathways by AT1 receptors.

Role of augmented expression of intermediate-conductance Ca2+-activated K+ channels in postischaemic heart.

1. The rat intermediate conductance calcium-activated potassium channel (ImK) was cloned from a cDNA library of vascular smooth muscle cells (VSM) in rat pulmonary artery. The ImK distributes in a variety of tissue, including VSM, endothelial cells, leucocytes and fibroblasts. The ImK has a tyrosine phosphorylation consensus site in the proximal portion of the C-terminus and motifs exist for the DNA-binding protein AP-1 in the promoter, suggesting this channel is upregulated and active in cell cycle functions. The aim of the present study was to examine the role of ImK in postischaemic cardiovascular remodelling in relation to the angiotensin AT1 receptor-mediated AP-1 signalling pathway. 2. Rats underwent left coronary artery ligation for periods between 1 day and 3 weeks. The temporal profile of expression of ImK mRNA was analysed by RNase protection assay. To test the effect of AT1 receptor blockade, candesartan (3 mg/kg per day) was administered via an osmotic mini-pump implanted in the intraperitoneal space 3 days prior to coronary occlusion. 3. ImK expression in postischaemic hearts showed a significant increase with two distinct peaks; the first peak at day 3 (2.7-fold compared with control levels; P < 0.001) and the second after 2 weeks (1.5-fold; P < 0.01). Reperfusion following 30 min of ischaemia markedly accelerated and augmented the first peak at days 1-3 (4.8-fold), but completely abolished the second peak after 1-2 weeks (0.8-fold). In situ hybridization of ImK mRNA and immunostaining of ImK protein with specific antibody revealed that this was not only the result of the increase in ImK expression in vascular cells, but also related to infiltration of mononuclear leucocytes and fibroblasts into the ischaemic region. Candesartan inhibited cardiac hypertrophy and perivascular fibrosis of coronary arterioles in the non-ischaemic region. Candesartan also abrogated both peaks in ImK expression. 4. These findings indicate that both the inflammatory reaction and the postischaemic cardiovascular remodelling promote increased expression of ImK in postischaemic hearts via the AT1 receptor-mediated AP-1 signalling pathway.

Blood pressure-independent effect of angiotensin AT1 receptor blockade on renal endothelin-1 production in hypertensive uremic rats.

We recently reported that treatment of uremic rats with reduced renal mass with the angiotensin II (Ang II) subtype 1 receptor (AT1) antagonist losartan reduces endothelin-1 (ET-1) levels in blood vessels and in glomeruli. Although this suggests an important role for Ang II in the modulation of ET-1 production, the concomitant decrease in blood pressure may also be involved. The present study was designed to investigate whether the modulation of ET-1 production in uremic rats is related to tissue-specific effects of AT1 receptor blockade or to the antihypertensive effect of losartan. One week after renal mass reduction, uremic rats were treated with the conventional triple therapy (TRx) [reserpine (5 mg/l), hydralazine (80 mg/l) and hydrochlorothiazide (25 mg/l)] or losartan (20 mg/kg per day) for 6 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma and urine, as well as in vascular and renal tissues were measured by a specific radioimmunoassay after sample extraction and purification. Before treatment, systolic blood pressure was significantly higher in uremic animals compared to sham-operated controls (165+/-4 versus 123+/-2 mmHg, respectively; P < 0.01). Treatment with the TRx or with losartan normalized systolic blood pressure in uremic rats, whereas it was further increased in untreated uremic animals. At week 6, serum creatinine, proteinuria and urinary ET-1 and transforming growth factor-beta1 (TGF-beta1) excretion, as well as vascular and glomerular ET-1 content were increased in uremic rats compared to the controls (P < 0.01). Treatment of uremic rats with the TRx or with losartan reduced ET-1 content in the thoracic aorta and the mesenteric arterial bed (P < 0.01). However, losartan, but not the TRx, significantly attenuated the rise of serum creatinine, proteinuria and urinary ET-1 and TGF-beta1 excretion, as well as ET-1 content in glomeruli of uremic rats. Compared with the controls, renal preproET-1 mRNA expression was also significantly higher in uremic rats. Treatment of uremic rats with losartan prevented renal preproET-1 mRNA overexpression, indicating that changes in glomerular ET-1 content and urinary ET-1 excretion were related to modulation of renal ET-1 production. These findings indicate that the effect of losartan on ET-1 production in peripheral blood vessels may be mediated, in part, by the reduction of blood pressure. In contrast, the reduction of renal ET-1 production is mediated by tissue-specific effects of AT1 receptor blockade, and may contribute to the renal protective effects of losartan.

Glucocorticoid modulation of cardiovascular and autonomic function in preterm lambs: role of ANG II.

The mechanisms by which antenatal glucocorticoids facilitate postnatal circulatory function in preterm infants are uncertain but may be related to augmented angiotensinergic functions. To test the hypothesis that the effects of glucocorticoids on postnatal cardiovascular and sympathetic activity are mediated via the renin-angiotensin system, we studied the effects of AT(1) receptor blockade on postnatal changes in heart rate (HR), mean arterial blood pressure (MABP), renal sympathetic nerve activity (RSNA), and baroreflex control of HR in prematurely delivered lambs. After maternal administration of betamethasone (12 mg im 48 and 24 h before delivery), chronically instrumented preterm lambs (118- to 123-day gestation, term 145 days) were studied before and after delivery by cesarean section; fetuses received either the AT(1) receptor antagonist losartan (10 mg iv, n = 6) or saline (n = 6) 1 h before delivery. A third group of animals (n = 6) received losartan without prior exposure to betamethasone. Compared with fetal values, betamethasone-treated animals demonstrated significant increases (P < 0.05) in MABP (47 +/- 2 to 58 +/- 2 mmHg) and RSNA (181 +/- 80% of fetal value) 1 h after delivery. Betamethasone + losartan-treated lambs also displayed increases in MABP (48 +/- 1 to 55 +/- 3 mmHg) and RSNA (198 +/- 96% of fetal value) 60 min after birth, similar to betamethasone alone lambs. Losartan alone treated animals had no postnatal increase in either MABP or RSNA, responses similar to those seen in nontreated sheep delivered at the same gestational age. The sensitivity of baroreflex-mediated changes in HR in response to increases in MABP was less in both groups of betamethasone-treated animals; no effect was seen with losartan. These results suggest the postnatal increases in MABP and RSNA seen with antenatal glucocorticoid treatment are not mediated by stimulation of peripherally accessible AT(1) receptors. We speculate that augmented cardiovascular function in glucocorticoid-treated premature lambs is dependent, in part, on a generalized sympathoexcitatory response and that this effect of glucocorticoids is mediated by central mechanisms.

Prevention of atherosclerosis by specific AT1-receptor blockade with candesartan cilexetil.

Several studies indicate that blockade of the renin-angiotensin-aldosterone system (RAAS) can prevent atherosclerosis and vascular events, but the precise mechanisms involved are still unclear. In this study, we investigated the effect of the AT 1-receptor blocker, candesartan, in the prevention of atherosclerosis in Watanabe heritable hyperlipidaemic (WHHL) rabbits and also the effect of AT1-receptor blockade in the uptake of oxidised LDL by macrophage cell cultures. In the first set of experiments, 12 WHHL rabbits were randomly assigned to three groups: placebo, atenolol 5 mg/kg daily or candesartan 2 mg/kg daily for six months. Compared with controls and atenolol-treated rabbits, candesartan treatment resulted in a significant 50-60% reduction of atherosclerotic plaque formation and a 66% reduction in cholesterol accumulation in the thoracic aorta. Studies in macrophage cultures indicated that candesartan prevented uptake of oxidised LDL-(oxLDL)-cholesterol by cultured macrophages. Candesartan inhibited the uptake of oxLDL in a dose-dependent manner, reaching a maximum inhibition of 70% at concentrations of 5.6 µg/ml. Further studies in other animal models and well-designed trials in humans are warranted to further explore the role of AT1-receptor blockade in the prevention of atherosclerosis.

Effects of losartan on the collagen degradative enzymes in hypertrophic and congestive types of cardiomyopathic hamsters.

The present study was undertaken to determine the effects of AT1 receptor blockade which occurred in response to losartan, on the extracellular matrix (ECM) degradation process in the Bio 14.6 (n = 12) and Bio 53.58 (n = 12) strains which are referred as models of hypertrophic and dilated cardiomyopathy, respectively. The administration of losartan (30 mg/kg/day) in hamsters from 10-20 weeks of age reduced the accumulation of the left ventricular collagen matrix in both of the Bio 14.6 and the Bio 53.58 strains. According to the RT-PCR, the levels of mRNA for matrix metalloproteinase (MMP) and the tissue inhibitor of MMP (TIMP) were examined. MMP-1, -2, -3, and -9 were more enhanced in both myopathic strains than in the control F1beta, strains. With losartan, the levels of MMP-1, -2, -9, TIMP-1 and -2 decreased in the both strains but those for MMP-3 did not in Bio 14.6 strains. TIMP-3 and -4 mRNA levels did not change in any of the experimental hamsters, whether treated or untreated with losartan. The Western blots also showed similar observations in the both strains as seen in mRNA expressions although MMP-2 in the Bio 53.58 strains did not differ between treated and untreated with losartan. Although losartan has an inhibitory effect on collagen accumulation in the development of cardiomyopathy, MMPs (-1, -2, -9) and TIMPs (-1, -2) seem to be susceptible to responding to losartan in Bio cardiomyopathic hamsters.

Renin Angiotensin System Antagonists and Anesthesia

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

Attenuation of myocardial stunning by the AT1 receptor antagonist candesartan.

The effect of AT1 receptor blockade on myocardial stunning is still somewhat ambiguous. In some prior studies, coronary occlusion was of too long duration such that the effects of infarction and stunning on the recovery of contractile function could not be distinguished. In others, blood pressure was decreased such that the improved wall excursion could be the consequence of reduced afterload and/or of attenuated stunning. The present study, therefore, investigated the effect of the AT1 receptor antagonist candesartan in a pure model of myocardial stunning with controlled systemic hemodynamics. Fourteen anesthetized open-chest dogs were subjected to 15 minutes occlusion of the left circumflex coronary artery (LCx) and 4 hours subsequent reperfusion. Systemic hemodynamics (micromanometer), regional myocardial blood flow (colored microspheres), and posterior wall thickening (PWT, sonomicrometry) were measured, and data were compared between 7 placebo controls (group 1) and 7 dogs receiving 1 mg/kg candesartan i.v. before LCx occlusion (group 2). Left ventricular peak pressure was kept constant by an intra-aortic balloon, and heart rate did not change throughout the protocol. Regional myocardial blood flow was not different between the groups under control conditions, increased in response to candesartan in group 2 (posterior subendocardial blood flow from 0.99 +/- 0.18 to 1.57 +/- 0.45; p < 0.05 vs. control conditions), but was not different during myocardial ischemia and at 4 hours of reperfusion between the groups. Under control conditions and during myocardial ischemia, PWT was also not different between the groups. At 4 hours of reperfusion, PWT was still depressed in group 1 (-1.5 +/- 3.4% vs. 17.7 +/- 5.6% during control conditions, p < 0.05), whereas PWT had recovered in group 2 (11.4 +/- 3.7% at 4 hours reperfusion vs. 18.3 +/- 2.7 during control conditions, NS, p < 0.05 vs. group 1). In conclusion, pretreatment with the AT1 receptor antagonist candesartan improved the functional recovery of reperfused myocardium. This attenuation of myocardial stunning was not based on more favorable systemic hemodynamics or regional myocardial blood flow.

Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs.

We studied the effect of the angiotensin II type 1 (AT1)-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemia in pigs. The effects of AT1-receptor blockade on infarct size in different species remain controversial and its potential cardioprotective mechanisms are still unclear. In pigs, infarct development closely resembles that observed in humans. A total of 62 enflurane-anesthetized pigs underwent a protocol of 90-min low-flow ischemia and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood flow (microspheres) and infarct size (TTC [triphenyl tetrazolium chloride]-staining) were determined. Left ventricular peak pressure decreased with candesartan (1 mg/kg i.v.) from 97+/-2 standard error of the mean (SEM) to 86+/-5 mm Hg and was then readjusted by aortic banding. In placebo pigs (n=9), infarct size was 21.8+/-4.8% of the area at risk. Candesartan (n=7) reduced infarct size to 9.7+/-2.5% (p < 0.05). Pretreatment with the AT2-receptor antagonist PD123319 (3 microg/kg/min intracoronarily [i.c.]; n=8), the bradykinin B2-receptor antagonist HOE140 (0.01 microg/kg/min i.c.; n=8) or the cyclooxygenase inhibitor indomethacin (10 mg/kg i.v.; n= 8) per se did not affect infarct size but did abolish the reduction of infarct size achieved by candesartan (PD123319 + candesartan (n=7): 23.2+/-4.7%; HOE140 + candesartan (n=7): 18.2+/-4.0%; indomethacin + candesartan (n=8): 21.1+/-5.2%). Hemodynamics, regional myocardial blood flow during ischemia and the area at risk were comparable among all groups of pigs. Reduction of infarct size by the AT1-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT2) activation, bradykinin and prostaglandins.

Effects of acute AT1 receptor blockade by candesartan on arterial pressure and renal function in rats.

Experiments were performed on normal anesthetized rats to determine the effects of candesartan, a novel AT1 receptor antagonist, on the arterial pressure and renal hemodynamic responses to bolus doses of angiotensin II (ANG II) and on renal hemodynamics and sodium excretion. Control arterial pressure responses to bolus ANG II doses of 10, 50, 100 and 1,000 ng were 26 +/- 6, 54 +/- 7, 57 +/- 7, and 79 +/- 7 mmHg; the decreases in cortical renal blood flow (CRBF), measured with laser-Doppler flowmetry, were 47 +/- 9, 64 +/- 8, 71 +/- 6, and 82 +/- 6%. The vasoconstrictor responses to ANG II up to 1,000 ng were completely blocked by candesartan doses of 1 and 0.1 mg/kg, whereas treatment with 0.01 mg/kg candesartan attenuated the arterial pressure and CRBF responses. The higher doses of candesartan (1 and 0.1 mg/kg) elicited rapid decreases in arterial pressure, leading to associated decreases in sodium excretion. Renal blood flow (RBF), glomerular filtration rate (GFR), and urine flow also decreased following treatment with candesartan at 1 mg/kg. In contrast, when candesartan was given at 0.01 mg/kg, which did not decrease arterial pressure significantly, there were significant increases in GFR (16 +/- 4), RBF (9 +/- 2), urine flow (11 +/- 2), sodium excretion (35 +/- 7), and fractional sodium excretion (39 +/- 8%). The inability to overcome blockade, even with very high ANG II doses, indicates that candesartan is a potent noncompetitive blocker of ANG II pressor and renal vasoconstrictor effects. The lower candesartan dose that did not cause significant hypotension elicited substantial increases in RBF, GFR, and sodium excretion, revealing the direct renal vasodilator and natriuretic effects of AT1 receptor blockade.

Area postrema lesion attenuates the long-term hypotensive effects of losartan in salt-replete rats.

We reported that the AT1 receptor antagonist losartan decreases arterial pressure in sodium-replete rats and that this response is attenuated in area postrema-lesioned (APx) rats (J. P. Collister, B. J. Hornfeldt, and J. W. Osborn. Hypertension 27: 598-606, 1996). In that study, food intake for the 3-wk period after sham lesion was restricted to that observed in APx rats. Food-restricted sham rats had lower arterial pressures and attenuated responses to losartan compared with control rats fed ad libitum. The present study examined whether these differences persisted months, rather than weeks after APx or sham lesions. Losartan was administered for 10 days to APx and two groups of sham rats 3 mo after APx or sham surgery. The first sham group was food restricted (SFR) for 3 wk after surgery, whereas the second sham group was allowed ad libitum (SAL) access to food. By day 8 of losartan administration, both sham groups demonstrated a marked hypotension (SFR: -38 +/- 4; SAL: -33 +/- 4 mmHg). This response was attenuated (P < 0.05) on the same day in APx rats (-17 +/- 3 mmHg). This trend continued throughout days 9 and 10. Because both sham groups responded similarly to losartan (yet significantly different from APx rats), these results demonstrate that transient decreases in food intake do not affect the response to losartan if rats are allowed an adequate recovery period. We conclude that the area postrema mediates part of the long-term hypotensive effects of AT1 receptor blockade in the conscious rat.

Effects of AT1 Receptor Blockade on Blood Pressure and the Renin-Angiotensin System in Spontaneously Hypertensive Rats of the Stroke Prone Strain

The aim of the study was to assess the effects of chronic angiotensin I receptor blockade on blood pressure, the renin-angiotensin system in plasma and kidney and the extent of renal damage in spontaneously hypertensive rats of the stroke prone strain (SHRsp). Four months old male SHRsp rats were orally treated with a high (10 mg/kg b.w. per day) or a low dose (1 mg/kg b.w. per day) of the AT1 receptor antagonist Telmisartan and compared to Losartan- (20 mg/kg b.w. per day), Captopril-treated (50 mgkg b.w. per day) or untreated control groups for 38 days. Despite a similar extent of blood pressure reduction in all groups (except low dose Telmisartan), high dose Telmisartan but not Losartan or Captopril significantly reduced left ventricular weight by 24% compared to controls (p<0.05). Renal damage as assessed by urinary albumin or glomerulosclerosis index was significantly reduced in all treatment groups (p<0.02). Plasma renin concentration was significantly elevated (p<0.02) and plasma angiotensinogen significantly lowered (p<0.05) in all pharmacologically treated group compared to controls. In the kidney, renin-mRNA as well as AT1 receptor gene expression were elevated in all treatment groups, but no significant changes were found for renal angiotensinogen-mRNA. Chronic oral treatment of genetically hypertensive rats by the AT1 receptor antagonist Telmisartan reveals a blood pressure lowering and reno-protective effect of this drug comparable to other AT1 receptor antagonists or converting enzyme inhibitors, and demonstrates a marked reduction of cardiac hypertrophy by Telmisartan in this model

Effect of AT1 receptor blockade on cardiac collagen remodeling after myocardial infarction.

Previous work has shown that cardiac fibrosis occurs after myocardial infarction (MI) in non-infarcted ventricular tissue and that this event is associated with abnormal cardiac function. Our aim was to investigate the effect of AT1 receptor blockade on cardiac collagen remodeling in post-MI rat heart remote from the infarct site by addressing collagen mRNA abundance, posttranslational hydroxylation of collagen monomers, and mature collagen deposition. Prolyl 4-hydroxylase (PH) mediates hydroxylation of procollagen alpha-chains in the endoplasmic reticulum of cardiac fibroblasts and thus regulates the downstream formation and secretion of helical procollagen molecules. The effects of losartan (15 mg/kg/day) on collagen deposition and mRNA abundance were monitored in viable left and right ventricles in sham-operated (control) and experimental groups in the presence or absence of losartan. Immunoreactive PH concentration in viable tissues as well as cardiac function in control and experimental groups was determined by ELISA. Immunohistochemical staining and 4-hydroxyproline assays confirmed that losartan treatment attenuates fibrosis in experimental hearts. Northern analysis revealed that losartan treatment of 1, 2, or 4 week experimental groups had no effect on collagen mRNA abundance compared to untreated post-MI rats. On the other hand, immunoreactive PH concentration was significantly decreased in the post-MI group treated with losartan. Determination of cardiac mass and cardiac function revealed that losartan treatment was associated with attenuated cardiac hypertrophy and improved left ventricular (LV) function in experimental animals. AT1 blockade is associated with a significant decrease in cardiac fibrosis in treated post-MI rats, and this trend is positively correlated to a significant decrease in immunoreactive PH compared to untreated experimental animals. The expression of cardiac PH may be regulated by angiotensin via AT1 receptor activation, and the suppression of PH with losartan treatment may be an important mechanism for modulation of collagen deposition in the post-MI rat heart.

Cardiac collagen remodeling in the cardiomyopathic Syrian hamster and the effect of losartan.

Although increased deposition of collagen proteins has been described in cardiomyopathy, little is known of the temporal relationship between events in collagen gene transcription and the occurrence of cardiac fibrosis, the removal of collagen by matrix metalloproteinases (MMPs), or of the regulation of these events by angiotensin AT1 receptors in this disease. We sought to study steady-state collagen mRNA abundance and the deposition of specific collagen subtypes in right and left ventricular muscle of Syrian cardiomyopathic (CMP) hamsters at different stages of cardiomyopathy. Using zymography, we also investigated the gelatinolytic activities of different MMPs to gain some information about collagen removal in experimental hearts. Finally, we investigated the effect of AT1 receptor blockade (losartan) on collagen remodeling. We observed that the mRNA levels of types I and III collagens were significantly increased in all four experimental groups (35, 65, 120, and 200 day) in left ventricular tissue when compared to control (F1-beta strain) values. The mRNA levels of these collagen species in experimental right ventricular tissue samples were only elevated significantly in the 35 and 200 day experimental groups when compared to controls. Fibrillar collagen deposition was elevated in left and right ventricular CMP samples after a lag period from the occurrence of corresponding increases in mRNA abundance. Although 2-week losartan treatment of 65, 120 and 200 day experimental groups had no significant effect on left ventricular fibrillar collagen concentration or collagen mRNA abundance when compared to vehicle-infused CMP hamsters, AT1 receptor blockade was associated with complete regression of cardiac hypertrophy. Both MMP-1 (54 kDa band) and MMP-2 (58 and 62 kDa bands) activities were increased in left ventricular CMP tissues at 65, 120 and 200 days when compared to F1-beta controls. Losartan treatment was associated with significant attenuation of MMP activities in cardiomyopathic samples at 65 and 120 days. Thus, elevation of mRNA abundance of fibrillar collagen genes occurs at very early stages in this model of cardiomyopathy, and corresponding collagen proteins were subsequently deposited in the cardiac interstitium at later stages. As collagen concentration was significantly increased in later stages of cardiomyopathy studied herein (120 and 200 day groups), our data support the hypothesis that collagen synthesis exceeds the capacity of collagen removal during the progression of cardiomyopathy. Nevertheless, cardiac collagen remodeling may be facilitated by elevated MMP activity in cardiomyopathic stages in this experimental model, and we suggested that attenuation of MMP activity in the presence of losartan may be a cardioprotective mechanism of this agent.

Additive effects of AT1 receptor blockade with valsartan and ace inhibition in patients with heart failure

Additive effects of AT1 receptor blockade with valsartan and ace inhibition in patients with heart failure

Effect of AT1 Receptor Blockade on Expression of Genes for Type-1 Angiotensin II(AT1) Receptor Subtypes in Spontaneously Hypertensive Rats.

Effect of AT1 Receptor Blockade on Expression of Genes for Type-1 Angiotensin II(AT1) Receptor Subtypes in Spontaneously Hypertensive Rats.