ramipril and Ischemia

Ramipril attenuates renal Fibroblast growth factor-23 (FGF-23) expression, ameliorates proteinuria and normalizes serum phosphate in the diabetic Zucker rat with progressive renal disease suggesting that the renoprotective effect by this drug may be in part due to a FGF-23-lowering effect of angiotensin-converting enzyme (ACE) inhibition.. In this nonrandomized study, we tested whether ACE-inhibition reduces circulating FGF-23 in type-2 diabetics with stage-1 chronic kidney disease (CKD) and proteinuria. Intact FGF-23, the eGFR, proteinuria and the endothelium-dependent flow-mediated (FMD) response to ischemia and other parameters were measured at baseline and after 12-weeks of treatment with ramipril (n = 68) or amlodipine (n = 32).. Blood Pressure (BP) fell to a similar extent (p < 0.001) in the two groups. However, 24 h proteinuria and the FMD improved more (both p < 0.01) in ramipril-treated patients than in amlodipine-treated patients. Changes in proteinuria (r = 0.47) and in FMD (r = -0.49) by ramipril were closely associated (p < 0.001) with simultaneous changes in FGF-23 and this link was confirmed in multiple regression analyses. In these analyses, the relationship between FMD and proteinuria changes attained statistical significance (p < 0.01) only in a model excluding FGF-23 suggesting that endothelial dysfunction and FGF-23 share a common pathway conducive to renal damage.. Findings in this study contribute to generate the hypothesis that FGF-23 may be implicated in proteinuria and in endothelial dysfunction in diabetic nephropathy (clinicaltrials.gov (NCT01738945)).

Topics: Adult; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelium, Vascular; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Follow-Up Studies; Humans; Ischemia; Kidney Failure, Chronic; Male; Middle Aged; Phosphates; Proteinuria; Ramipril; Regression Analysis; Retrospective Studies

In a placebo-controlled, double-blinded, randomized study we evaluated the effect of ramipril prior to thrombolysis on the course of PAI-1 plasma levels and on the frequency of postinfarct ischemic events in patients with acute myocardial infarction. Fifty-one out of 99 patients received 2.5 mg ramipril orally prior to thrombolysis and 12 h later. The blood samples for determination of PAI-1 plasma levels were collected on admission and 2, 4, 8, 12 and 24 h after thrombolysis. Postinfarct ischemic events were registered until coronary angiography was performed and defined as recurrent chest pain and/or evidence of ischemic signs on the ECG (ST-depression or ST-segment elevation of 1 mm in one or more inferior or anterior leads). Coronary angiography was performed within 7 days after the onset of myocardial infarction. Patients were classified into two groups: those without reperfusion of the infarct-related artery (TIMI grade 0 or 1) and those with reperfusion of the infarct-related artery (TIMI grade 2.3). On admission, PAI-1 plasma levels were similar in both groups (ramipril: 47.1 [4.8] ng/ml; placebo: 49.1 [4.8] ng/ml). The PAI-1AUC was 77.2 [6.7] ng/ml/h in the ramipril group and 95.4 [6.2] ng/ml/h in the placebo group (p = 0.013). Significant differences between groups were observed at 4, 8 and 12 h after thrombolysis (4 h: 85.5 (11.3) vs. 116 (12.3) ng/ml, p < 0.01; 8 h: 79.1 (11.2) vs. 100.9 (9.3) ng/ml, p < 0.01; 12 hrs: 71.3 (9.5) vs. 87.4 (7.7) ng/ml, p < 0.05). The relative frequency of postinfarct ischemic events was significantly lower in the ramipril group (2.5% versus 7.1%, p = 0.001). Additionally, we observed a significant higher rate of TIMI grade 2 and 3 of the infarct-related artery in patients receiving oral ramipril compared to the placebo group (73% versus 54%; p = 0.035). Our study demonstrates a favorable effect of ramipril on the fibrinolytic system after thrombolysis associated with a lower rate of postinfarct ischemic events within the first days after myocardial infarction. Therefore, the application of ramipril prior to thrombolysis appears to be a reasonable concomitant treatment which may reduce early infarct-related complications.

Topics: Adult; Aged; Cause of Death; Double-Blind Method; Drug Therapy, Combination; Emergency Medical Services; Female; Hemodynamics; Humans; Hypotension; Ischemia; Middle Aged; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Ramipril; Thrombolytic Therapy

Bradykinin is both a potent vasodilatator and a central inflammatory mediator. Similar to findings in myocardial reperfusion injury, bradykinin might mediate the protective effects of angiotensin-converting enzyme (ACE) inhibition after liver ischemia via increased bradykinin-2-receptor (B-2) stimulation. On the other hand, B-2-inhibition has been shown to reduce liver reperfusion injury. This study was designed to investigate the role of Bradykinin in hepatic reperfusion injury.. Twenty eight rats were allocated randomly to Sham procedure (Sham), 30-min normothermic ischemia (ischemia), ischemia with Ramiprilat (ACE-I), or ischemia with Ramiprilat and B-2-inhibitor HOE 140 (ACE-I+B-2-I). Liver microcirculation and leukocyte adherence were investigated using intravital microscopy 30 min after reperfusion (n = 7 per group). In addition, serum activities of AST and ALT were measured for 7 days (n = 28).. Ischemia was associated with a loss of perfused sinusoids, sinusoidal vasoconstriction, and a reduction in microvascular blood flow. Permanent leukocyte adherence increased both in sinusoids and in postsinusoidal venoles. ACE-I restored sinusoidal perfusion, normalized vasoregulation, maintained sinusoidal blood flow, and inhibited leukocyte adhesion. ACE-I+B-2-I abolished the protective effects linked to ACE-I. Ischemia-induced liver cell injury after 5 h of reperfusion was ameliorated by ACE-I. In the ACE-I+B-2-I group, reduction in liver cell injury was reversed.. After hepatic ischemia, ACE-I reduced reperfusion injury in a B-2-dependent manner. These results suggest a pivotal role for bradykinin in the treatment of reperfusion injury by Ramiprilat, mediating sinusoidal dilation and blunting hepatic inflammation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Flow Velocity; Bradykinin; Bradykinin B2 Receptor Antagonists; Cell Adhesion; Endothelial Cells; Female; Ischemia; Leukocytes; Liver; Microcirculation; Ramipril; Rats; Rats, Wistar; Receptor, Bradykinin B2; Reperfusion Injury; Vasoconstriction

1. The concept that angiotensin II exerts pro-angiogenic activity is not universally accepted. We evaluated whether inhibition of the renin-angiotensin system (RAS) would influence reparative angiogenesis in a murine model of limb ischaemia. 2. Perfusion recovery following surgical removal of the left femoral artery was analysed by laser Doppler flowmetry in mice given the ACE inhibitor ramipril (1 mg kg(-1) per day), the AT(1) antagonist losartan (15 mg kg(-1) per day), or vehicle. Muscular capillarity was examined at necroscopy. Ramipril-induced effects were also studied under combined blockade of kinin B(1) and B(2) receptors. Furthermore, the effects of ischaemia on AT(1) gene expression and ACE activity were determined. 3. In untreated mice, muscular AT(1a) gene expression was transiently decreased early after induction of limb ischaemia, whereas AT(1b) mRNA was up-regulated. ACE activity was reduced in ischaemic muscles at 1 and 3 days. Gene expression of AT(1) isoforms as well as ACE activity returned to basal values by day 14. Spontaneous neovascularization allowed for complete perfusion recovery of the ischaemic limb after 21 days. 4. Reparative angiogenesis was negatively influenced by either ramipril (P<0.02) or losartan (P<0.01), leading to delayed and impaired post-ischaemic recovery (50 - 70% less compared with controls). Ramipril-induced effects remained unaltered under kinin receptor blockade. 5. The present study indicates that (a) expression of angiotensin II AT(1) receptors and ACE activity are modulated by ischaemia, (b) ACE-inhibition or AT(1) antagonism impairs reparative angiogenesis, and (c) intact AT(1) receptor signalling is essential for post-ischaemic recovery. These results provide new insights into the role of the RAS in vascular biology and suggest cautionary use of ACE inhibitors and AT(1) antagonists in patients at risk for developing peripheral ischaemia.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Extremities; Femoral Artery; Gene Expression; Ischemia; Losartan; Male; Mice; Neovascularization, Physiologic; Peptidyl-Dipeptidase A; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Angiotensin; Receptors, Bradykinin; Renin-Angiotensin System; RNA, Messenger; Signal Transduction

Angiotensin converting enzyme (ACE) inhibition exerts positive effects on the microvasculature of normotensive animals, although this concept is not universally accepted. Recently, ACE inhibitors have been suggested to be useful for rescue in peripheral ischemia.. We investigated whether chronic treatment with the ACE inhibitor ramipril may have a positive impact on the defective healing response to ischemia that is typical of spontaneously hypertensive rats (SHR). Unilateral limb ischemia was induced in 20-week-old SHR by surgically removing the left femoral artery. Rats were allowed to regain consciousness and then were randomly allocated to treatment with ramipril (1 mg/kg body weight in drinking water) or vehicle for 28 days.. The SHR failed to develop reparative angiogenesis in response to ischemia, thus having inadequate perfusion recovery. Ramipril reduced both tail-cuff systolic blood pressure (180 +/- 7 v 207 +/- 2 mm Hg in the vehicle group at 28 days, P < .05) and intra-arterial mean blood pressure (115 +/- 6 v 135 +/- 5 mm Hg in the vehicle group, P < .05). These effects were associated with increased responsiveness to endothelium-dependent vasodilatation by acetylcholine. Treatment with ramipril did not influence muscular capillary and arteriole density but accelerated the rate of perfusion recovery, leading to complete healing within 28 days after surgery.. These results indicate that ACE inhibition by ramipril may be useful for the treatment of peripheral vascular complications in hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Hemodynamics; Hindlimb; Hypertension; Ischemia; Male; Microcirculation; Ramipril; Rats; Rats, Inbred SHR

We investigated the influence of myocardial collagen volume fraction (CVF, %) and hydroxyproline concentration (microg/mg) on rat papillary muscle function. Collagen excess was obtained in 10 rats with unilateral renal ischemia for 5 wk followed by 3-wk treatment with ramipril (20 mg. kg(-1). day(-1)) (RHTR rats; CVF = 3.83 +/- 0. 80, hydroxyproline = 3.79 +/- 0.50). Collagen degradation was induced by double infusion of oxidized glutathione (GSSG rats; CVF = 2.45 +/- 0.52, hydroxyproline = 2.85 +/- 0.18). Nine untreated rats were used as controls (CFV = 3.04 +/- 0.58, hydroxyproline = 3.21 +/- 0.30). Active stiffness (AS; g. cm(-2). %L(max)(-1)) and myocyte cross-sectional area (MA; micrometer(2)) were increased in the GSSG rats compared with controls [AS 5.86 vs. 3.96 (P < 0.05); MA 363 +/- 59 vs. 305 +/- 28 (P < 0.05)]. In GSSG and RHTR groups the passive tension-length curves were shifted downwards, indicating decreased passive stiffness, and upwards, indicating increased passive stiffness, respectively. Decreased collagen content induced by GSSG is related to myocyte hypertrophy, decreased passive stiffness, and increased AS, and increased collagen concentration causes myocardial diastolic dysfunction with no effect on systolic function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Elasticity; Glutathione Disulfide; Hydroxyproline; Hypertension, Renovascular; In Vitro Techniques; Ischemia; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Ramipril; Rats; Rats, Wistar; Reference Values