Bernhard R. Winkelmann

Nitric-Oxide-Induced Reoxygenation Injury in the Cyanotic Immature Heart Is Prevented by Controlling Oxygen Content During Initial Reoxygenation

Reintroduction of high levels of molecular oxygen after a hypoxic period is followed by a burst of nitric oxide (NO), peroxynitrite, and oxygen free radicals (OFR), which are highly cytotoxic. This study indicates that hyperoxic reoxygenation of cyanotic immature hearts on cardiopulmonary bypass (CPB) induces a reoxygenation injury and that, by reducing NO and OFR production during institution of CPB with subsequent reoxygena tion under blood cardioplegic arrest, this oxygen-related damage can be avoided and biochemical and functional status improved. Of 25 immature piglets (3-5 kg, two to three weeks old), 6 underwent one hour of CPB including thirty minutes of aortic clamping with substrate-enriched modified blood cardioplegia (hypocalcemic, alkalotic, and hyperosmolar; warm induction-cold replen ishment-warm reperfusion) without preceding hypoxia (controls). Nineteen others were made hypoxic (arterial [PO2] 20-30 mmHg) for up to two hours by lowering the fraction of inspired oxygen (FIO2) on ventilator. These hypoxic piglets were then reoxygenated on CPB at different PO2 levels (hyperoxic, normoxic, or hypoxic) for five minutes, followed by the aforementioned blood cardioplegic (BCP) arrest regimen. Myocardial conjugated diene (CD) production as a marker of lipid peroxidation, and NO production, determined as its spontaneous oxidation products, nitrite (NO2 -) and nitrate (NO3 -), were assessed during blood cardioplegic induction, and antioxidant reserve capacity was determined by incubating myocardium in the oxidant t-butylhy droperoxide (t-BHP). Myocardial function was evaluated from end-systolic elastance (Ees, conductance catheter). Blood cardioplegic arrest caused no functional or biochem ical changes in normoxic control immature piglets. In contrast, brief reoxygenation at PO2 > 400 mmHg, followed by BCP-arrest (hyperoxic) resulted in marked CD production (42 ±4 vs 3 ±1 A233 nm/minute/100 g; P<0.05), and NO production (4500 ±500 vs 450 ±32 mmol/minute/100 g; P<0.05) during blood cardioplegic induction, reduced antiox idant reserve capacity (malondialdehyde [MDA] at 4.0 mM of t-BHP: 1342 ±59 vs 958 ± 50 nM/g protein; P<0.05), and caused profound myocardial dysfunction; Ees recovered only 21 ±2% (vs 104 ±7; P<0.05), despite the blood cardioplegic regimen shown to be cardioprotective in control normoxic piglets. Conversely, controlling initial PO2 to normoxic (100 mmHg) or hypoxic (20-30 mmHg) levels reduced lipid peroxida tion (CD production 16 ±2*, 2 ±1*† A233nm/minute/100 g) and NO production (1264 ±736*, 270 ± 182*† mmol/minute/100 g), restored antioxidant reserve capacity (MDA at 4.0mM of t-BHP: 940 ±95*, 982 ±88* nM/g protein), and allowed significant func tional recovery (58 ±11%* and 83 ±8%*†), in a PO2-dependent fashion. The authors conclude that reoxygenation of hypoxemic immature hearts by initiating hyperoxic CPB causes oxidant-related damage characterized by lipid peroxidation, enhanced NO production, and reduced antioxidants, leading to functional depression that nullifies the cardioprotective effects of blood cardioplegia. These detrimental effects can be reduced in a PO2-dependent fashion by controlling initial PO2 on CPB and subse quent reoxygenation during blood cardioplegic arrest. * = P<0.05 vs hyperoxic, † = P<0.05 vs normoxic (data are mean ± SE, ANOVA).

Ramipril in angina pectoris: short-term effects on glucose, insulin, C-peptide, adrenocorticotropic hormone, and cortisol levels

Abstract We studied the effects of the angiotensin-converting enzyme inhibitor ramipril on plasma levels of adrenocorticotropic hormone (ACTH), cortisol, glucose, insulin, and C-peptide in patients with coronary artery disease. Patients were randomly assigned to treatment with ramipril 5 mg once daily, ramipril 5 mg once daily in combination with 20 mg of the oral nitrate isosorbide dinitrate (ISDN), ISDN alone 20 mg twice daily, or placebo. After a 72-hour washout period from their previous vasoactive medication, 32 patients (1 woman, 31 men) aged 42 to 72 years (mean age, 63.3 years) received a single dose of the study medication. Plasma levels of ACTH, cortisol, glucose, insulin, and C-peptide were measured before drug administration and 1, 2, 3, 4, 5, 6, 8, and 24 hours after drug administration. After the initial 24-hour treatment period, a randomized, double-masked, placebo-controlled, four-way, crossover phase started in which each patient was treated with each study medication for 1 week. Individual treatment phases were separated by weekly washout periods, and plasma levels of insulin, C-peptide, and glucose were assessed in the morning at trough and 3 hours after intake of the study medication. The typical circadian variation was observed for cortisol, without any difference between the four treatment groups. On average, ACTH levels were significantly higher in the patients treated with ISDN alone. No significant effect on glucose, insulin, or C-peptide levels was observed among patients receiving the first dose of ramipril, ISDN, ramipril + ISDN, or placebo, nor between the crossover phases during continued treatment. We conclude that in patients with angina pectoris, a single dose of ramipril has no acute effects on insulin secretion and glucose utilization, nor does multiple dosing of ramipril affect glucose hemeostasis. Ramipril also did not affect circadian cortisol secretion. These findings also pertain to the combination of ramipril and ISDN. In contrast, after administration of a single dose of ISDN alone, a statistically significant increase in ACTH levels was observed. The increase in ACTH levels could be a marker for sympathetic nervous system activation resulting from counterregulation.

Neurohumoral effects of ramipril in angina pectoris: A double-blind, placebo-controlled trial against isosorbide dinitrate and the combination of ramipril plus isosorbide dinitrate

Abstract Elevated levels of neurohormones are directly correlated with cardiovascular risk. This double-blind, parallel-group study was designed to examine whether treatment with an angiotensin-converting enzyme (ACE) inhibitor, ramipril, could positively influence the plasma levels of neurohormones—plasma renin activity (PRA), aldosterone, atrial natriuretic peptide (ANP), and endothelin—and whether differences exist between treatments with ramipril, isosorbide dinitrate (ISDN) alone, ramipril + ISDN or placebo. Thirty-two patients (1 woman, 31 men) with congestive heart failure, aged 42 to 72 years (mean, 62.8 years), were enrolled in four parallel study groups. Test medications were administered as a single dose in a double-blind, parallel-group manner with a double-dummy technique as follows: ramipril (5 mg), ISDN (20 mg), the combination ramipril + ISDN, and placebo. PRA, aldosterone, ANP, and endothelin concentrations were estimated before and 1, 2, 3, 4, 6, 8, and 24 hours after drug administration. Plasma endothelin levels decreased significantly in the groups receiving ramipril treatment, whereas no change was seen after placebo or ISDN administration. No significant changes were seen for ANP, whereas PRA increased and aldosterone decreased in the groups receiving ramipril. A single dose of ramipril reduced plasma endothelin in patients with angina pectoris, whereas no significant changes were observed for ANP. The changes seen with PRA and aldosterone were as expected for ACE inhibitors.