ABSTRACT
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.
Subject(s)
Angiotensin Receptor Antagonists , Isoenzymes/biosynthesis , Myocardial Infarction/metabolism , Myocardial Reperfusion Injury/metabolism , Protein Kinase C/biosynthesis , Receptors, Angiotensin/biosynthesis , Animals , Blood Pressure , Cardiotonic Agents/pharmacology , Cyclic GMP/metabolism , Dogs , Heart Rate , Isoenzymes/metabolism , Myocardial Infarction/drug therapy , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/pathology , Myocardium/enzymology , Protein Kinase C/metabolism , Protein Kinase C-epsilon , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Receptors, Angiotensin/metabolismABSTRACT
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.
Subject(s)
Adenocarcinoma/secondary , Cardiac Tamponade/diagnosis , Heart Neoplasms/secondary , Lung Neoplasms/pathology , Adenocarcinoma/complications , Adenocarcinoma/diagnosis , Cardiac Tamponade/etiology , Diagnosis, Differential , Echocardiography , Fatal Outcome , Female , Heart Neoplasms/complications , Heart Neoplasms/diagnosis , Humans , Lung Neoplasms/complications , Lung Neoplasms/diagnostic imaging , Middle Aged , Pericardial Effusion/diagnosis , Pericardial Effusion/etiology , Tomography, X-Ray ComputedABSTRACT
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.