Effect of chronic AT(1) receptor antagonism on postischemic functional recovery and AT(1)/AT(2) receptor proteins in isolated working rat hearts.

To determine whether chronic angiotensin II (Ang II) type I receptor (AT(1)R) antagonism improves recovery of left ventricular (LV) function after ischemia-reperfusion (IR) and increases AT(1)R and Ang II type 2 receptor (AT(2)R) protein expression in isolated working rat hearts, rats were randomized to pretreatment with either losartan (30 mg/kg/day) or UP269-6 (3 mg/kg/day), or no drug (control), for 1 week or 3 weeks before IR (50 min perfusion, 25 min ischemia, 40 min reperfusion). In vitro LV work and power and ex vivo AT(1)R and AT(2)R proteins (immunoblots) were measured. Compared to baseline perfusion, LV work and power showed variable recovery in control, losartan, and UP269-6 groups. Compared to control, losartan preserved recovery of LV work and power while UP269-6 showed less recovery after IR at both 1 week and 3 weeks. Both antagonists increased AT(2)R but not AT(1)R protein. The duration of pretreatment did not affect the expression of AT(1)R or AT(2)R proteins. The results indicate that chronic AT(1)R blockade over 1 or 3 weeks increases AT(2)R (not AT(1)R) protein expression and may preserve but not improve postischemic functional recovery compared to controls in isolated working rat hearts.

Angiotensin II reduces infarct size and has no effect on post-ischaemic contractile dysfunction in isolated rat hearts.

1. In order to test the hypothesis that angiotensin II exacerbates myocardial ischaemia-reperfusion (IR) injury, we examined the effects of graded angiotension II concentrations of angiotensin II on IR injury in both working and non-working (Langendorff) isolated rat hearts. 2. Non-working hearts were subjected to 30 min aerobic perfusion (baseline) then 25 min of global, no-flow ischaemia followed by 30 min of reperfusion either in the absence (control, n=7) or presence of 1 (n=6) or 10 nM (n=5) angiotensin II). Recoveries of LV developed pressure and coronary flow after 30 min reperfusion in control hearts (58+/-9 and 40+/-8% of baseline levels, respectively) were no different from hearts treated with 1 or 10 nM angiotensin II. Infarct size (determined at the end of reperfusion by triphenyltetrazolium chloride staining) was reduced by angiotensin II in a concentration-dependent manner (from a control value of 27+/-3 to 18+/-4% and 9+/-3% of the LV, respectively). 3. Working hearts were subjected to 50 min pre-ischaemic (pre-I) aerobic perfusion then 30 min of global, no-flow ischaemia followed by 30 min of reperfusion either in the absence (control, n=14) or presence of 1 (n=8), 10 (n=7) or 100 nM (n=7) angiotensin II). In controls, post-ischaemic (post-I) left ventricular (LV) work and efficiency of oxygen consumption were depressed (43+/-9 and 42+/-10% of pre-I levels, respectively). The presence of angiotensin II throughout IR had no effect on LV work compared with control. 4. Thus, angiotensin II reduces infarct size in a concentration-dependent manner but has no effect on contractile stunning associated with IR in isolated rat hearts.

Postischemic apoptosis and functional recovery after angiotensin II type 1 receptor blockade in isolated working rat hearts.

OBJECTIVE: To determine whether chronic angiotensin (AngII) type I receptor (AT1R) blockade inhibits cardiomyocyte (CM) apoptosis and attenuates left ventricular (LV) dysfunction after ischemia-reperfusion (IR) in the isolated working rat heart. METHODS: Postischemic recovery of LV developed pressure, the apoptotic index (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labeling or TUNEL assay), and changes in expression of apoptotic markers Bcl-2, Bax, p53 and caspase-3 (Western immunoblots) were measured after IR (50 min aerobic perfusion; 25 min global ischemia; 40 min reperfusion) in working rat hearts that were randomized to five groups of six each along 1 week or 3 week pretreatment arms: sham (no drug, no perfusion); no drug, aerobic perfusion; and oral AT1R blockers losartan (30 mg/kg per day) or UP269-6 (3 mg/kg per day), or no drug before IR. RESULTS: Compared to the no drug group after IR, losartan (not UP269-6) preserved functional recovery in 1 and 3 week groups. However, both losartan and UP269-6 reduced the apoptotic index and normalized the increase in Bax, decrease in Bcl-2 and increase in p53 and caspase-3 after IR. A bell-shaped relation between apoptosis and functional recovery after IR was flattened by AT1R blockade. CONCLUSION: The results indicate that IR is associated with LV dysfunction and CM apoptosis involving activation of p53, caspase-3, and increased Bax/Bcl-2 ratio in the working rat heart. Importantly, chronic AT1R blockade inhibited the apoptosis and changes in expression of the markers without improving functional recovery, implying that decrease in apoptosis does not necessarily translate into decreased LV dysfunction.

Enhanced regional AT(2)-receptor and PKC(epsilon) expression during cardioprotection induced by AT(1)-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 (N(G)-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 PKC(epsilon) (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 PKC(epsilon) 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, PKC(epsilon) and cGMP contribute to cardioprotection associated with AT1-receptor blockade during ischaemia-reperfusion injury.

Differential morphometric and ultrastructural remodelling in the left atrium and left ventricle in rapid ventricular pacing-induced heart failure.

BACKGROUND: Heart failure induced by rapid ventricular pacing (RVP) is associated with left atrial (LA) but not left ventricular (LV) hypertrophy. OBJECTIVE: To determine whether differences in wall tension correlate with the differential ultrastructural remodelling in the LA and LV chambers, changes in ultrastructure, systolic function and wall tension (an index of wall stress) were compared in dogs after RVP (n=7) and with no RVP (n=9). RESULTS: Compared with dogs with no RVP (controls), dogs with RVP had increased collagen volume fraction (5.3% versus 8.3%), myocyte cross-sectional area (245 versus 366 microm(2)) and hydroxyproline (222 versus 323 microg/mg protein) in the LA (all P<0.05), but not in the LV. The increase in systolic wall tension produced by RVP was greater in the LA (five versus 43 units, P<0.0004) than in the LV (227 versus 290 units, P<0.01) chambers and correlated closely with the collagen volume fraction (r=0.87), which in turn correlated with myocyte cross-sectional area (r=0.98). In the left atrium, wall tension correlated with wall stress (r=0.99). CONCLUSIONS: The results suggest that differential wall tension may provide the stimulus for differential ultrastructural remodelling (with more hypertrophy and collagen) between LA and LV chambers in RVP-induced cardiomyopathy.

Enhanced expression of angiotensin II type 2 receptor, inositol 1,4, 5-trisphosphate receptor, and protein kinase cepsilon during cardioprotection induced by angiotensin II type 2 receptor blockade.

We hypothesized that the cardioprotective effect of angiotensin II type 2 receptor (AT(2)R) blockade with PD 123,319 (PD) on the recovery of left ventricular (LV) mechanical function after ischemia/reperfusion (IR) in the isolated working rat heart is associated with the enhanced expression of AT(2)R protein and mRNA as well as an increase in inositol 1,4,5-trisphosphate type 2 receptor (IP(3)R) and protein kinase Cepsilon (PKCepsilon) proteins. We assessed AT(2)R, angiotensin II type 1 receptor (AT(1)R), IP(3)R, and PKCepsilon protein expression (Western blots) and AT(2)R mRNA levels (Northern blots) in myocardium from isolated working rat hearts that were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes). Groups of adult rat hearts (n=6) were exposed to no IR, no IR+PD (0.3 micromol/L), IR, and IR+PD. Compared with no IR and no IR+PD, IR decreased (P<0.05) functional recovery and AT(2)R mRNA and protein, as well as AT(1)R mRNA (not protein) and IP(3)R and PKCepsilon proteins. Compared with IR, PD+IR improved LV functional recovery (P<0.05) and markedly increased AT(2)R mRNA and protein (P<0.001). However, PD did not change AT(1)R mRNA or protein. More importantly, PD+IR markedly increased IP(3)R and PKCepsilon proteins. The downregulation of AT(2)R mRNA and protein with IR and their upregulation with PD indicate that the effects of PD are AT(2)R specific. The overall results suggest that the cardioprotective effect of acute PD treatment on LV functional recovery after IR in the isolated working rat heart is specifically due to AT(2)R blockade and is associated with enhanced downstream IP(3)R and PKCepsilon signaling.

Influence of beta-adrenoceptor tone on the cardioprotective efficacy of adenosine A(1) receptor activation in isolated working rat hearts.

This study investigated the role of beta-adrenoceptors in the cardioprotective and metabolic actions of adenosine A(1) receptor stimulation. Isolated paced (300 beats min(-1)) working rat hearts were perfused with Krebs-Henseleit solution containing 1.2 mM palmitate. Left ventricular minute work (LV work), O(2) consumption and rates of glycolysis and glucose oxidation were measured during reperfusion (30 min) following global ischaemia (30 min) as well as during aerobic conditions. Relative to untreated hearts, N(6)-cyclohexyladenosine (CHA, 0.5 microM) improved post-ischaemic LV work (158%) and reduced glycolysis and proton production (53 and 42%, respectively). CHA+propranolol (1 microM) had similar beneficial effects, while propranolol alone did not affect post-ischaemic LV work or glucose metabolism. Isoprenaline (10 nM) impaired post-ischaemic function and after 25 min ischaemia recovery was comparable with 30 min ischaemia in untreated hearts (41 and 53%, respectively). Relative to isoprenaline alone, CHA+isoprenaline improved recovery of LV work (181%) and reduced glycolysis and proton production (64 and 60%, respectively). In aerobic hearts, CHA, propranolol or CHA+propranolol had no effect on LV work or glucose oxidation. Glycolysis was inhibited by CHA, propranolol and CHA+propranolol (50, 53 and 52%, respectively). Isoprenaline-induced increases in heart rate, glycolysis and proton production were attenuated by CHA (85, 57 and 53%, respectively). The cardioprotective efficacy of CHA was unaffected by antagonism or activation of beta-adrenoceptors. Thus, the mechanism of protection by adenosine A(1) receptor activation does not involve functional antagonism of beta-adrenoceptors.

Cardiac tamponade as the first clinical manifestation of metastatic adenocarcinoma of the lung.

A 62-year-old woman presented in the emergency department with new onset of dyspnea and clinical signs of cardiac tamponade. She had a history of cigarette smoking and a family history of adenocarcinoma, pancreatic and breast carcinoma. An emergency two-dimensional echocardiogram confirmed the diagnosis of cardiac tamponade. Therapeutic pericardiocentesis resulted in prompt relief. Cytology confirmed malignant glandular cells, consistent with a metastatic adenocarcinoma. Computerized chest tomography confirmed pulmonary involvement.

Opposite effects of amlodipine and enalapril on infarct collagen and remodelling during healing after reperfused myocardial infarction.

OBJECTIVES: To compare the effects of the calcium channel blocker amlodipine versus the angiotensin-converting enzyme inhibitor enalapril with or without reperfusion on infarct collagen and remodelling during healing after anterior myocardial infarction (MI). ANIMALS AND METHODS: In vivo left ventricular (LV) remodelling and function (by quantitative echocardiography) and hemodynamics were measured over six weeks in dogs that were randomized 24 h after reperfusion (2 h after anterior MI) or no reperfusion to oral amlodipine (5 mg bid, n=6), enalapril (5 mg bid, n=6), placebo (bid, n=6) or sham surgery (n=6) for six weeks. Ex vivo infarct size, infarct collagen (hydroxyproline), collagen volume fraction and LV topography were measured at six weeks. RESULTS: Compared with placebo controls without reperfusion over six weeks in vivo, enalapril or amlodipine with or without reperfusion produced LV unloading and preserved volumes, shape and function, but enalapril limited LV hypertrophy more than amlodipine. However, compared with no reperfusion, amlodipine preserved infarct wall thickness and shape while enalapril decreased infarct wall thickness and increased the shape index. Ex vivo at six weeks, scar size as a percentage of risk was similar in the MI groups. Importantly, enalapril decreased infarct collagen already lowered by reperfusion, while amlodipine preserved infarct collagen after reperfusion and increased collagen volume fraction in spared myocardium. CONCLUSIONS: Preservation of infarct collagen limits infarct remodelling during healing after reperfused MI and preserves LV shape. Amlodipine and enalapril exert opposite effects on infarct collagen and remodelling after reperfused MI.

Characterization of cardioprotection mediated by AT2 receptor antagonism after ischemia-reperfusion in isolated working rat hearts.

BACKGROUND: Whether cardioprotection induced by the angiotensin II (AngII) type 2 receptor (AT(2)R) antagonist PD123,319 (PD) after ischemia-reperfusion (IR) is influenced by the concentration of PD, presence of AngII, timing of exposure, or inhibition of proton production from glucose metabolism is not known. METHODS AND RESULTS: We examined these factors in isolated working rat hearts subjected to IR injury, no treatment (control), or treatment with N(6)-cyclohexyl adenosine (CHA, 0.5 micromol/L), an adenosine A(1) receptor agonist that induces cardioprotection by decreasing protons ("positive" control). Compared with control, 1 micromol/L PD present throughout IR improved recovery of left ventricular work (73 +/- 5 vs. 40 +/- 8%) to the level with CHA (82 +/- 5%), but 0.1 micromol/L PD did not (58 +/- 6 vs. 40 +/- 8%). AngII (1 nmol/L) did not effect postischemic recovery associated with 1 micromol/L PD (73 +/- 7%) but improved that associated with 0.1 micromol/L PD (86 +/- 3%). PD (1 micromol/L), present solely during reperfusion, enhanced postischemic left ventricular recovery to 72 +/- 5%. Also, PD (1 micromol/L) did not affect glycolytic rates or proton production in nonischemic or IR hearts. CONCLUSION: PD-induced cardioprotection is 1) PD concentration-dependent, 2) AngII-sensitive, 3) mediated during reperfusion, and 4) independent of proton production, suggesting that reduction in IR injury and indirect AT(1)R stimulation might be involved.

Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-epsilon in acutely reperfused myocardial infarction in the dog. Effect of UP269-6 and losartan on AT1 and AT2-receptor expression and IP3 receptor and PKCepsilon proteins.

To determine whether cardioprotection after chronic angiotensin II (Ang II) type 1 (AT(1)) receptor blockade involves Ang II type 2 (AT(2)) receptor expression and protein kinase C-epsilon (PKC(epsilon)) activation, we measured in vivo haemodynamics and left ventricular (LV) remodelling and dysfunction (echocardiogram/ Doppler) and ex vivo AT(1)/AT(2)-receptor expression, IP(3)R (1, 4, 5-inositol trisphosphate type 2 receptor) and PKC(epsilon) proteins in dogs with acutely reperfused (90 minutes ischaemia, 90 minutes reperfusion) myocardial infarction (MI) following seven days of AT(1)-receptor blockade with oral losartan or UP269-6. The animals were randomised to sham; sham + losartan or UP269-6; MI alone; MI + losartan; MI + UP269-6. More marked AT(1)-receptor blockade with UP269-6 (greater inhibition of Ang II pressor responses) was associated with a smaller increase in preload, less systolic and diastolic dysfunction, less infarct expansion, and smaller LV diastolic and systolic volumes. However, both AT(1)-receptor antagonists decreased infarct size. Importantly, MI decreased AT(1)-receptor and AT(2)-receptor expression while MI after AT(1)-receptor antagonism increased AT(1)-receptor (mRNA, not protein) and AT(2)-receptor (mRNA and protein) expression as well as IP(3)R and PKC(epsilon) proteins and cyclic guanosine 3', 5' monophosphate (cGMP). These results suggest that cardioprotection induced by chronic AT(1)-receptor antagonism involves enhanced AT(2)-receptor expression and possibly downstream signalling through IP(3)R, PKC(epsilon) and cGMP.

Efficacy of pretreatment with the angiotensin II type 1 receptor blocker UP269-6 and losartan in the dog: effect on hemodynamics and ischemia-reperfusion.

BACKGROUND: Whether pretreatment with the novel oral angiotensin II (AngII) type 1 receptor (AT(1)R) antagonist UP269-6 (UP) can produce more effective AT(1)R blockade than losartan (LN) for cardioprotection during ischemia-reperfusion (IR) in the dog has not been determined. METHODS AND MATERIALS: We compared the effect of UP (n = 5) and LN (n = 5) on serial in vivo hemodynamics, AngII pressor responses, and left ventricular (LV) volumes and function (echocardiograms) during escalation to optimal oral dosage over 7 days (day 0 to day 6), and acute IR (15 minutes ischemia, 30 minutes reperfusion) and ex vivo AT(1)R protein (Western immunoblots) with additional sham (n = 5) and IR (n = 5) controls on day 6. Compared with LN, UP produced greater vasodepression and decrease in diastolic volume during dose escalation and greater inhibition of the AngII pressor response over the range of escalating concentrations (0.05, 0.10, 0.25, and 0.50 microg/kg) on day 6. Acute IR after UP pretreatment resulted in less increase in LV filling pressure and LV diastolic and systolic volumes and greater ejection fraction, although UP and LN had similar effects on AT(1)R protein. CONCLUSION: Pretreatment with UP269-6 over 7 days produces more effective pharmacological AT(1)R blockade and cardioprotection after acute IR than LN in the dog.

Cardioprotection induced by AT1R blockade after reperfused myocardial infarction: association with regional increase in AT2R, IP3R and PKCepsilon proteins and cGMP.

BACKGROUND: We hypothesized that the cardioprotective effect of angiotensin II (AngII) type 1 receptor (AT(1)R) blockade during in vivo ischemia-reperfusion (IR) might be associated with an increase in AngII type 2 receptor (AT(2)R) protein, as well as 1,4,5-inositol trisphosphate type 2 receptor (IP(3)R) and protein kinase C(epsilon) (PKC(epsilon)) proteins and cyclic guanosine 3',5' monophosphate (cGMP). METHODS AND RESULTS: We studied the effects of the AT(1)R blocker, candesartan, on in vivo left ventricular (LV) systolic and diastolic function and remodeling (echocardiogram/Doppler) and hemodynamics during canine reperfused anterior infarction (90-minute ischemia, 120-minute reperfusion), and ex vivo infarct size and AT(1)R/AT(2)R, IP(3)R, and PKC(epsilon) proteins (immunoblots), and cGMP (enzyme immunoassay). Compared with controls, candesartan (1 mg/kg intravenously over 30-minute preischemia) inhibited the AngII pressor response, decreased preload and afterload, improved LV systolic and diastolic function, limited LV remodeling, decreased infarct size (55% vs 27% risk; P <.000003), markedly increased AT(2)R, IP(3)R, and PKC(epsilon) proteins in the infarct zone, but not the AT(1)R protein, and increased infarct more than noninfarct cGMP. CONCLUSIONS: The overall results suggest that cardioprotective effects of AT(1)R blockade on acute IR injury might involve AT(2)R activation and downstream signaling via IP(3)R, PKC(epsilon), and cGMP.

Electrophysiologic properties and ventricular fibrillation in normal and myopathic hearts.

This study tests the hypothesis that moderate myocardial dysfunction is associated with altered myocardial anisotropic properties and structurally altered ventricular fibrillation (VF). Mongrel dogs were randomized to either a control group or a group that was rapidly paced at 250 beats/min until the left ventricular ejection fraction was < or = 40%. Changes in anisotropic properties and the electrical characteristics of VF associated with the development of moderate myocardial dysfunction were assessed by microminiature epicardial mapping studies. In vivo conduction, refractory periods, and repolarization times were prolonged in both longitudinal and transverse directions in myopathic animals versus controls. VF was different in myopathic versus control animals. There were significantly more conducted deflections during VF in normal hearts compared with myopathic hearts. Propagated deflection-to-deflection intervals during VF were significantly longer in myopathic hearts compared with controls (125.5 +/- 49.06 versus 103.4 +/- 32.9 ms, p = 0.009). There were no abnormalities in cell size, cell shape, or the number of intercellular gap junctions and there was no detectable change in the expression of the gap junction proteins Cx43 and Cx45. Moderate myocardial dysfunction is associated with significant electrophysiological abnormalities in the absence of changes in myocardial cell morphology or intercellular connections, suggesting a functional abnormality in cell-to-cell communication.

Inhibition of apoptosis after ischemia-reperfusion in rat myocardium by cycloheximide.

Macromolecular synthesis inhibitors protect cells from apoptosis in many systems. To determine whether the protein synthesis inhibitor cycloheximide (CHX) might inhibit apoptosis and protect the myocardium during ischemia-reperfusion, we subjected isovolumic isolated perfused rat hearts to 25 min of normothermic global ischemia followed by reperfusion. We monitored coronary flow, end-diastolic pressure and rate-pressure product (RPP) throughout and assessed apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL). Regardless of the treatment regimen (only before ischemia; only during reperfusion; or both before ischemia and during reperfusion), CHX significantly improved functional recovery during reperfusion. These effects were most pronounced when CHX was present during reperfusion. When hearts were treated with CHX only during reperfusion the recovery of sinus rhythm was more frequent in the CHX-treated hearts than control hearts (80% v 53%) and earlier for CHX-treated than control hearts: 6.4 +/- 2 v 19.4 +/- 4.7 min of reperfusion. The maximal RPP recoveries for the CHX-treated hearts were 45 +/- 4.0% (P=0.005) of pre-ischemic values, compared to 26 +/- 3% for controls. In control hearts reperfused for 2 h, TUNEL identified 49.5 +/- 10 intact nuclei and 7.5 +/- 2 fragmented nuclei per 1000 nuclei counted. A significantly lower incidence of labeled nuclei with or without fragmentation was observed in CHX treated hearts: 7.6 +/- 3.4 (P=0.009) intact labeled nuclei and 1.8 +/- 0.7/10(3)fragmented labeled nuclei. Our results suggest that CHX-induced inhibition of apoptosis in reperfused myocardium is cardioprotective and promotes functional recovery in vitro.

Limitation of left ventricular hypertrophy and dysfunction by ACE inhibition after anterior Q-wave myocardial infarction.

To determine whether limitation of left ventricular (LV) hypertrophy with angiotensin-converting enzyme inhibition after myocardial infarction (MI) is associated with improved systolic and diastolic function, quantitative two-dimensional echocardiograms and Doppler of 40 patients, who were randomized on day 3 after a first Q-wave anterior MI to receive therapy with captopril (12.5 mg t.i.d.) or placebo for 6 weeks, were analyzed for LV volumes (Simpson's rule) and mass (3D reconstruction), remodeling parameters and peak early (E) and late (A) transmitral flow velocities and deceleration times (DT) at 3 days, 6 weeks, 6 months and 1 year. Compared to placebo over 1 year, captopril limited (p < 0.001) the increase in diastolic volume and mass, increased LV ejection fraction and diastolic E/A ratio, and decreased DT, the frequency of E and A reversal, infarct expansion and aneurysm frequency but volume/ mass ratio was unchanged. Captopril over the first 6 weeks after a first Q-wave anterior MI limited LV remodeling and hypertrophy and improved both systolic and diastolic function up to 1 year.

Intrinsic ANG II type 1 receptor stimulation contributes to recovery of postischemic mechanical function.

To determine whether intrinsic angiotensin II (ANG II) type 1 receptor (AT1-R) stimulation modulates recovery of postischemic mechanical function, we studied the effects of selective AT1-R blockade with losartan on proton production from glucose metabolism and recovery of function in isolated working rat hearts perfused with Krebs-Henseleit buffer containing palmitate, glucose, and insulin. Aerobic perfusion (50 min) was followed by global, no-flow ischemia (30 min) and reperfusion (30 min) in the presence (n = 10) or absence (n = 14) of losartan (1 mumol/l) or the cardioprotective adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA, 0.5 mumol/l, n = 11). During reperfusion in untreated hearts (controls), left ventricular (LV) minute work partially recovered to 38% of aerobic baseline, whereas proton production increased to 155%. Compared with controls, CHA improved recovery of LV work to 79% and reduced proton production to 44%. Losartan depressed recovery of LV work to 0% without altering proton production. However, exogenous ANG II (1-100 nmol/l) in combination with losartan restored recovery of LV work during reperfusion in a concentration-dependent manner, suggesting that postischemic recovery of function depends on intrinsic AT1-R stimulation.

Effect of the novel angiotensin II type 1 receptor antagonist L-158,809 on acute infarct expansion and acute anterior myocardial infarction in the dog.

OBJECTIVES: To assess the effect of the angiotensin II type 1 receptor (AT1-R) antagonist L-158,809 on acute infarct expansion and left ventricular (LV) function during acute anterior myocardial infarction. METHODS: Dogs were randomized to receive intravenous L-158,809 (0.1 mg/kg bolus and 0.6 microgram/kg/min infusion) or vehicle beginning 1 h after permanent left anterior descending coronary artery ligation and continued for 48 h. In vivo LV remodelling and function (quantitative echocardiography) and hemodynamics over 48 h, and postmortem remodelling after 48 h were measured. RESULTS: L-158,809 produced 90% to 100% inhibition of the angiotensin II pressor response during the infusions. With respect to percentage changes over the 48 h in vivo, compared with vehicle controls, L-158,809 decreased mean arterial pressure (-20 +/- 4 versus -9 +/- 2%, P = 0.03) and left atrial pressure (-38 +/- 5 versus 25 +/- 6%, P < 0.0001) but did not change heart rate. These unloading effects were associated with a smaller percentage increase in infarct expansion index (-5 +/- 7% versus 27 +/- 2%, P = 0.001) and LV diastolic volume (11 +/- 11% versus 52 +/- 6%, P = 0.008), less shape deformation, fewer apical aneurysms (0 versus 100%, P = 0.0003), better global ejection fraction (49 +/- 2% versus 39 +/- 2%, P = 0.005), less ST segment elevation and fewer Q waves. Also compared with vehicle controls, with L-158,809 postmortem infarct size (19.8 +/- 2.4% versus 50.4 +/- 4.7% of risk region, P = 0.0002) and expansion index (2.06 +/- 0.09 versus 2.76 +/- 0.18, P = 0.006) were less and thinning ratio greater (0.92 +/- 0.02 versus 0.60 +/- 0.05, P = 0.0001). CONCLUSIONS: The novel AT1-R antagonist L-158,809 produces significant AT1-R blockade, reduces LV loading, and effectively limits acute infarct expansion and early LV remodelling during canine myocardial infarction.