Inhibition of Angiotensin Converting Enzyme Impairs Anti-staphylococcal Immune Function in a Preclinical Model of Implant Infection.

Background: Evidence suggests the renin-angiotensin system (RAS) plays key immunomodulatory roles. In particular, angiotensin-converting enzyme (ACE) has been shown to play a role in antimicrobial host defense. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) are some of the most commonly prescribed medications, especially in patients undergoing invasive surgery. Thus, the current study assessed the immunomodulatory effect of RAS-modulation in a preclinical model of implant infection. Methods:In vitro antimicrobial effects of ACEi and ARBs were first assessed. C57BL/6J mice subsequently received either an ACEi (lisinopril; 16 mg/kg/day), an ARB (losartan; 30 mg/kg/day), or no treatment. Conditioned mice blood was then utilized to quantify respiratory burst function as well as Staphylococcus aureus Xen36 burden ex vivo in each treatment group. S. aureus infectious burden for each treatment group was then assessed in vivo using a validated mouse model of implant infection. Real-time quantitation of infectious burden via bioluminescent imaging over the course of 28 days post-procedure was assessed. Host response via monocyte and neutrophil infiltration within paraspinal and spleen tissue was quantified by immunohistochemistry for F4/80 and myeloperoxidase, respectively. Results: Blood from mice treated with an ACEi demonstrated a decreased ability to eradicate bacteria when mixed with Xen36 as significantly higher levels of colony forming units (CFU) and biofilm formation was appreciated ex vivo (p < 0.05). Mice treated with an ACEi showed a higher infection burden in vivo at all times (p < 0.05) and significantly higher CFUs of bacteria on both implant and paraspinal tissue at the time of sacrifice (p < 0.05 for each comparison). There was also significantly decreased infiltration and respiratory burst function of immune effector cells in the ACEi group (p < 0.05). Conclusion: ACEi, but not ARB, treatment resulted in increased S. aureus burden and impaired immune response in a preclinical model of implant infection. These results suggest that perioperative ACEi use may represent a previously unappreciated risk factor for surgical site infection. Given the relative interchangeability of ACEi and ARB from a cardiovascular standpoint, this risk factor may be modifiable.

Garlic capsule and selenium-vitamins ACE combination therapy modulate key antioxidant proteins and cellular adenosine triphosphate in lisinopril-induced lung damage in rats.

BACKGROUND: Garlic capsule (GAR) and/or selenium- vitamin A, C, E (S-VACE) might be useful in the treatment of lung diseases. The present study evaluated the toxicity of lisinopril (LIS) in the lungs of male rats and the reversal effect of GAR and/or selenium-vitamins A, C, and E (S-VACE). METHODS: Group I served as the control, whereas animals in groups II, III, IV, and V received 28 mg of LIS/kg body weight by gavage. Group III was co-treated with GAR at a therapeutic dosage of 250 mg/kg body weight per day. Group IV was co-treated with S-VACE at dosage of 500 mg/kg body weight per day. Lastly, group V was co-treated with GAR and S-VACE at dosages of 250 and 500 mg/kg body weight per day, respectively. The experiment lasted for 8 days (sub-acute exposure). RESULTS: Administration of therapeutic dose of LIS to male rats depleted enzymatic antioxidants (superoxide dismutase and catalase) and cellular adenosine triphosphate content with concomitant increase in lipid peroxidation. Histopathology examination showed damage to the epithelial cells of the airways. These effects were prevented by both single and combination treatment of GAR and S-VACE in male rats with LIS-induced lung toxicity. CONCLUSIONS: We therefore concluded that the combination of GAR and S-VACE can be a novel therapy for the management of lung diseases in humans.

Renal toxicity of lisinopril and rosuvastatin, alone and in combination, in Wistar rats.

The aim of study was to evaluate the effect of commonly used lisinopril, rosuvastatin and their combined action on site-specific nephrotoxicity in rats using clusterin and microalbumin nephrotoxic biomarkers and other related parameters using oral gavage. Rosuvastatin at 2 different doses showed increase in urinary microalbumin levels whereas lisinopril and its combination with rosuvastatin at 2 different doses did not show urinary microalbumin excretion indicating beneficial effects of lisinopril in terms of reducing microalbumin. Urinary clusterin levels significantly increased in high-dose treated animals of lisinopril and rosuvastatin. The use of lisinopril plus rosuvastatin at low dose also led to worsened renal function by raising urinary clusterin levels (217 ± 4.6 ng/ml) when compared with the control (143 ± 3.3 ng/ml). Renal histopathology showed multifocal regeneration of tubules indicating proximal tubule damaged. These results indicate that lisinopril (50 mg/kg), rosuvastatin (100 mg/kg), lisinopril+rosuvastatin (20+40 mg/kg) and lisinopril+rosuvastatin (50+100 mg/kg) showed toxicity only on proximal tubules.

Effect of lisnopril, an angiotensin converting enzyme (ACE) inhibitor on spermatogenesis in rats.

The role of ACE inhibitors (Lisinopril) in reproductive function remains controversial. Some benefits seem to be derivable even in non-hypertensive males with low doses. This study was done using rat model to establish this fact. Male rats were divided into different groups to receive different doses of lisinopril. A control group received no drugs. The mean arterial pressure fell the most with 5 mg of lisinopril. The greatest increase in sperm count and motility was recorded for this same group. This response was dose dependent, falling as the drug dose fell. Lisinopril appeared to, in a dose dependent manner, improve sperm count and motility. In low doses, there is no significant change in arterial pressure. Infertile males with poor quality semen could benefit from a low dose of ACE inhibition. Where they are also hypertensive, ACE inhibition would be an appropriate first line treatment.

Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper.

Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PR-negative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu++, whereas H2O2 mimicked those effects. These data are consistent with the notion of a copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.

Left ventricular adaptation to chronic pressure overload induced by inhibition of nitric oxide synthase in rats.

Recent studies have indicated that chronic inhibition of nitric oxide synthase induces arterial hypertension without myocardial hypertrophy. We investigated the mechanisms of left ventricular (LV) adaptation to this condition. Also, we analyzed the effect of the angiotensin-converting enzyme inhibitor (ACEI), lisinopril, in this experimental model of ventricular pressure overload. Fifty-eight Wistar rats received eight weeks of treatment with either NW-nitro-L-arginine-methyl ester (L-NAME group, n = 19), lisinopril (LISINOPRIL group, n = 19) or the combination of both drugs (LNAMELIS group, n = 20). All results were compared to age and sex matched untreated rats (CONTROL group, n = 18). Tail-cuff blood pressure rose significantly in L-NAME treated rats (195 +/- 29 mm Hg) compared to the CONTROL (141 +/- 12 mm Hg), LISINOPRIL (97 +/- 13 mm Hg), and LNAMELIS (113 +/- 16 mm Hg) groups. There was no myocardial hypertrophy in the chronically hypertensive rats. The ventricular unstressed volume was significantly reduced in the L-NAME group (0.119 +/- 0.027 mL) compared to the CONTROL (0.158 +/- 0.026 mL) indicating a disproportional reduction in ventricular volume related to the myocardial mass. The chamber size modification resulted in a systolic stress which was comparable to the CONTROL even though the isovolumetric systolic pressure was higher. The systolic functional data indicated preserved myocardial contractility in L-NAME. LV compliance was increased in the LISINOPRIL group and myocardial passive stiffness was lower in all treated rats compared to CONTROL. We conclude that LV. adaptation to chronic pressure overload without hypertrophy involves changes in chamber geometry and myocardial diastolic mechanical properties. Also, ACEI fully prevents L-NAME induced hypertension, reduces myocyte cross-sectional area, and myocardial passive stiffness. The combination of L-NAME plus lisinopril decreases the load independent index of myocardial contractility.

Dual effects of lisinopril on puromycin aminonucleoside nephrosis in unilaterally nephrectomized rats.

The therapeutic effects of angiotensin converting enzyme inhibitor, lisinopril, on puromycin aminonucleoside (PAN)-induced nephrosis were investigated using unilaterally nephrectomized rats. Lisinopril showed potent dual effects on PAN nephrosis. Lisinopril treatment (50 mg/l in drinking water) from day 5 or day 9 reduced urinary protein excretion and suppressed the development of glomerular sclerosis at 8 weeks after PAN injection (150 mg/kg, i.p.), indicating a therapeutic effect on the nephrosis. Recovery of decreased anionic charge sites on the glomerular basement membrane was involved, at least in part, in the therapeutic action of lisinopril against proteinuria. On the other hand, oliguria and progressive azotemia derived from continuous deterioration of the renal function was induced if the treatment of lisinopril was started on the same day as PAN injection. The renal dysfunction induced by simultaneous administration of lisinopril with PAN could be abolished by combination dosing with sarcosine, an angiotensin II (AII)-receptor agonist. These results indicate that lisinopril treatment attenuates proteinuria by ameliorating the anionic charge barrier on the glomerular basement membrane and that it also protects against the development of chronic renal disease with segmental glomerular sclerosis, although AII depletion during the acute nephrotic stage exacerbates the renal damage in PAN nephrosis of unilaterally nephrectomized rats.

Toxicodynamic analysis of inflammatory reactions by an angiotensin converting enzyme inhibitor (lisinopril) in guinea-pig skin.

There have been reports of rash and angioedema in the treatment of hypertension with angiotensin converting enzyme (ACE) inhibitors. To evaluate the inflammatory reaction, we continuously infused lisinopril for three days into the peritoneal cavity of ovalbumin-sensitized guinea-pigs and tested intradermal inflammation with ovalbumin. Inflammatory responses were measured in two perpendicular directions serially, and the areas of rash were used as an index of inflammatory reaction induced by lisinopril. Inflammatory responses were dose-dependently enhanced by treatment with lisinopril. Plasma concentration of lisinopril required to produce 50% of the maximum potentiation of the inflammatory reaction in guinea-pig skin was 40 times plasma unbound concentration after the clinical treatment of lisinopril in patients.