Effects of l-NA and Sodium Nitroprusside on Ischemia/Reperfusion-Induced Leukocyte Adhesion and Macromolecular Leakage in Hamster Cheek Pouch Venules

doi:10.1006/mvre.2001.2324

Microvascular Research

Volume 62, Issue 2, September 2001, Pages 128-135

https://doi.org/10.1006/mvre.2001.2324 Get rights and content

Abstract

Our objective was to study how the topical application of a nitric oxide synthase inhibitor ( $l$ -NA, Nω-nitro- $l$ -arginine) and a nitric oxide donor, sodium nitroprusside (SNP), could modulate leukocyte adhesion (sticking) and microvascular permeability as altered by ischemia/reperfusion (I/R) and topically applied histamine after I/R. Golden hamsters were prepared for intravital microscopy. Ischemia was induced by an inflatable silicon rubber cuff mounted around the neck of the cheek pouch prepared for intravital microscopy. Saline, $l$ -NA, sodium nitroprusside, and histamine were applied in the superfusion solution. FITC–dextran was injected iv 30 min before initiation of ischemia as a marker of microvascular permeability. $l$ -NA 10⁻⁵ M inhibited both the increase in number of sticking leukocytes and the increase in vascular permeability after I/R compared with the untreated control group of hamsters. SNP neutralized this effect of $l$ -NA on leukocytes and vascular permeability and caused arteriolar dilation at the concentration used, 10⁻⁶ M. Both SNP and $l$ -NA + SNP enhanced the I/R-induced macromolecular leakage. The topical application of SNP and SNP + $l$ -NA did not modify the response to histamine after I/R compared with the untreated control group. In hamsters not subjected to I/R, histamine-induced macromolecular leakage was inhibited by $l$ -NA and $l$ -NA + SNP but was unchanged by SNP. It is concluded that inhibition of nitric oxide formation by $l$ -NA reduced both leukocyte adhesion in postcapillary venules and the increase in macromolecular leakage and that a NO donor such as SNP could enhance the macromolecular leakage response to I/R.

References (36)

BR. Duling
The preparation and use of the hamster cheek pouch for studies of the microcirculation
Microvasc. Res.
(1973)
M. Erlansson et al.
Modification of postischemic increase of microvascular permeability in the hamster by iloprost
Prostaglandins
(1991)
M. Erlansson et al.
Superoxide dismutase as an inhibitor of post-ischemic microvascular permeability increase in the hamster
Free Radical Biol. Med.
(1990)
M.B. Grisham et al.
Modulation of leukocyte–endothelial interactions by reactive metabolites of oxygen and nitrogen: Relevance to ischemic heart disease
Free Radical Biol Med.
(1998)
S.R. Hughes et al.
Evidence that endogenous nitric oxide modulates oedema formation induced by substance P
Eur. J. Pharmacol.
(1990)
A. Ialenti et al.
Modulation of acute inflammation by endogenous nitric oxide
Eur. J. Pharmacol.
(1992)
N.W. Kooy et al.
Agonist-induced peroxynitrite production from endothelial cells
Arch. Biochem. Biophys.
(1994)
S. Massberg et al.
The nature of ischemia/reperfusion injury
Transplant. Proc.
(1998)
W.G. Mayhan
Nitric oxide donor-induced increase in permeability of the blood–brain barrier
Brain Res.
(2000)
A.A. Noel et al.
Platelet-activating factor and nitric oxide mediate microvascular permeability in ischemia-reperfusion injury
Microvasc. Res.
(1996)

M.M. Ramirez et al.

Platelet activating factor modulates microvascular permeability through nitric oxide synthesis

Microvasc. Res.

(1995)

D.A. Wink et al.

Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide

Free Radical Biol. Med.

(1998)

E. Bouskela et al.

Leukocyte adhesion after oxidant challenge in the hamster cheek pouch microcirculation

J. Vasc. Res.

(1999)

M.J. Eppiheimer et al.

Ischemia/reperfusion-induced leukocyte–endothelial interactions in postcapillary venules

Shock

(1997)

M. Feletou et al.

Bradykinin and changes in microvascular permeability in the hamster cheek pouch: role of nitric oxide

Br. J. Pharmacol.

(1996)

D.N. Granger et al.

The microcirculation and inflammation: Modulation of leukocyte–endothelial cell adhesion

J. Leukocyte Biol.

(1994)

Y. Gurzoy-Ozdemir et al.

Role of endothelial nitric oxide generation and peroxynitrate formation in reperfusion injury after focal cerebral ischemia

Stroke

(2000)

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Rolling and sticking leukocytes were counted using DVD recordings. A leukocyte was considered as rolling when it was in contact with the venular wall and had lower velocity than circulating erythrocytes and as adherent when it was immobilized in one position for at least 30 s.20 At the end of each experiment, animals were euthanized, under anaesthesia, by an intravenous injection of potassium chloride (3M).
To assess protective effects of micronized purified flavonoid fraction (MPFF) on microcirculation in an original chronic model of hind limb venous hypertension with low blood flow in small animals.
Vein ligatures were performed on male hamsters, as follows: A-right femoral vein; A + B-right femoral vein and its right branch; A + C-right femoral vein and its left branch; A + B + C-right femoral and its right and left branches; D-external right iliac vein. In sham operated groups, similar vascular dissections were performed without ligatures. Superficial (epigastric) and central (jugular) venous pressure evaluations were made during a 10 week period. Hamsters subjected to A + B + C and D ligatures were selected for leukocyte rolling and sticking, functional capillary density (FCD), and venular and arteriolar diameter observations. D ligature was selected to evaluate pharmacological treatment efficacy. MPFF (100 mg/kg), concomitant active flavonoids of MPFF (diosmetin, hesperidin, linarin, and isorhoifolin) (10 mg/kg), diosmin (100 mg/kg) or drug vehicle were administered orally during 2 weeks before vein ligature and 6 weeks thereafter.
A, A + B and A + C models maintained venous return through collaterals. From the 2^nd to the 10^th weeks after vein ligatures, A + B + C and D models elicited a progressive increase of superficial venous pressure (3.83 ± 0.65 vs. 8.56 ± 0.72 mmHg, p < .001 and 4.13 ± 0.65 vs. 9.35 ± 0.65 mmHg, p < .001, respectively) with significant changes to the microcirculation. As D model significantly increased superficial venous pressure without affecting central venous pressure, it was used to evaluate the long-term effects of treatment. Compared with vehicle, MPFF, concomitant active flavonoids of MPFF, and diosmin, significantly decreased leukocyte-endothelium interaction and prevented FCD reduction. Only MPFF significantly prevented venular enlargement as observed in the vehicle treated group.
MPFF was more effective than diosmin in improving all microvascular variables. The superiority of MPFF over diosmin alone can be explained by the synergistic beneficial effects of the association between diosmin and active flavonoids of MPFF.
Microcirculatory effects of zinc on fructose-fed hamsters
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Citation Excerpt :
At least two reactive oxygen species are involved in the I/R induction of plasma leakage in the hamster cheek pouch: nitric oxide (NO) and superoxide (O2). As zinc is a cofactor for superoxide dismutase [25], in the present study, we analyzed the effect of dietary zinc on microvascular permeability. Cheek pouch preparation was chosen as the technique for microcirculatory assessment because it shows a stable blood flow and responsiveness to topic vasoactive drugs.
Fructose is a major dietary component directly related to vascular dysfunction and diseases such as obesity, diabetes, and hypertension. Zinc is considered a non-pharmacological alternative for treating diabetes due to its antioxidant and hyperglycemia-lowering effects in diabetic animals. Therefore, the aim of this study was to evaluate the effects of dietary zinc supplementation on the microcirculatory parameters of fructose-fed hamsters.
Male hamsters (Mesocricetus auratus) were fed drinking water substituted by 10% fructose solution for 60 days, whereas control animals were fed drinking water alone. Their microcirculatory function was evaluated using cheek pouch preparation, as well as their blood glucose and serum insulin levels. Their microcirculatory responses to acetylcholine (ACh, an endothelium-dependent vasodilator) and to sodium nitroprusside (SNP, an endothelium-independent vasodilator) as well as the increase in macromolecular permeability induced by 30 min of ischemia/reperfusion (I/R) were noted. Endothelium-dependent vasodilation was significantly increased in control animals with high zinc supplementation compared to the groups without zinc supplementation. Zinc was able to protect against plasma leakage induced by I/R in all control and fructose-fed groups, although the microvascular permeability was higher in animals fed drinking water substituted by 10% fructose solution compared to those fed filtered drinking water alone.
Our results indicate that dietary zinc supplementation can improve microvascular dysfunction by increasing endothelial-dependent dilatation and reducing the increase in macromolecular permeability induced by I/R in fructose-fed animals.
Effects of microbubbles and ultrasound on the microcirculation: Observation on the hamster cheek pouch
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Citation Excerpt :
Indeed, we found an increased number of adhered leukocytes compared with controls at time point 0 in the I/R, Hyp, and ES groups with and without microbubbles. Although one could expect that I/R causes a large increase on leukocyte adhesion compared with baseline, Simoes and co-workers,34 also using the hamster cheek pouch preparation, showed a decrease in the number of sticking leukocytes in postcapillary venules before and after 30 minutes of ischemia with N-nitro-L-arginine treatment. We observed that the number of sticking (adhered) leukocytes increased in the I/R, Hyp, and ES groups compared with the control group at time point 0 (Figure 3).
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Ultrasound, microbubbles, and their association were evaluated on the cheek pouch microcirculation in 96 male hamsters (n = 6 in each group): control; ischemia–reperfusion, 30 minutes total ischemia followed by reperfusion; hyperinsulinemia and hyperglycemia (substitution of the drinking water by 10% fructose solution for 3 months); and endotoxic shock (induced by Escherichia coli lipopolysaccharide). The heart rate, mean arterial pressure, number of rolling and adhered leukocytes, and arteriolar and venular diameters were analyzed.
Heart rate and mean arterial pressure were lower in the endotoxic shock group than in the control group. Ultrasound alone or associated with microbubbles decreased the number of rolling and adhered leukocytes in the ischemia–reperfusion and hyperinsulinemia and hyperglycemia groups and increased venular diameter in the ischemia–reperfusion group.
The use of ultrasound decreases inflammation. Although it has not been established that pseudo-anaphylaxis can be assessed by intravital microscopy, microbubble administration does not increase venular leukocyte adhesion.
Vascular dysfunction in ischemia-reperfusion injury
2005, Annals of Vascular Surgery
Microvascular dysfunction mediates many of the local and systemic consequences of ischemicreperfusion (I/R) injury, with a spectrum of changes specific to arterioles, capillaries, and venules. This review discusses the specific changes in the endothelium during I/R injury; describes the differential responses of the various levels of the vasculature including arterioles, capillaries, and venules; and explores mechanisms for remote organ injury. Vascular dysfunction is largely a consequence of changes in the endothelial cells themselves, affecting the integrity of barrier function, cytokine and adhesion molecule expression, and vascular tone. The bioavailability of nitric oxide, an important mediator of vasodilation, is profoundly decreased during the reperfusion period, resulting in impaired vasodilation of arterioles. Release of inflammatory mediators and increased expression of adhesion molecules initiate inflammatory and coagulation cascades that culminate in the occlusion of capillaries, known as the “noreflow” phenomenon. In postcapillary venules, the recruitpent and transmigration of leukocytes further compromise the integrity of the endothelial barrier and increase the oxidative burden, resulting in leakage and tissue edema. I/R injury can have significant and untoward consequenpes beyond the affected tissue, with such conditions as systemic inflammatory response syndrome. This review highlights recent progress in understanding of the varied phenomena of vascular dysfunction in I/R injury and some promising advances in the understanding and application of ischemic preconditioning and other potential therapies.
Inhibition of ischemia/reperfusion induced plasma leakage by α-tocopherol, trolox, and a shark cartilage preparation with anti-oxidant properties
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A shark-cartilage preparation (SCP) and α-tocopherol has been administered to hamsters which were kept on a normal laboratory animal diet and given orally SCP (1 or 10 mg/100g/day; Cartilade TM, Cartilage Technologies, Inc. St. Michael, Barbados, V.I.) or α-tocopherol (1mg/100g/day) for ten days. Control hamsters were kept on the same diet and received the same volumes of vehicles for α-tocopherol and SCP as treated hamsters. On the day of experiment hamsters were prepared for intravital microscopy of the hamster cheek pouch using FITC-dextran (fluorescein labeled dextran) as a marker of macromolecular leakage from postcapillary venules. The cheek pouch preparations were subjected to complete ischemia for 30 min followed by a reperfusion period of 60 min after which histamine was applied topically. Vascular permeability increase was quantified by counting sites with extravasation of fluorescent plasma (leaks) at postcapillary venules in the microcirculation. All hamsters responded to ischemia/reperfusion (I/R) and histamine application by reversible increases in macromolecular leakage. Treatment with SCP (1 or 10 mg/100g/day) caused significant (P< 0.05) 51% or 54% reductions in number of leaks following I/R. Oral treatment with α-tocopherol or topical treatment with the water soluble vitamin E analog Trolox inhibited macromolecular leakage significantly (P<0.05) to the same extent. Conclusion: Oral intake of a shark-cartilage preparation (SCP) and vitamin E may inhibit ischemia/reperfusion induced plasma leakage in the hamster.
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Regular ArticleEffects of l-NA and Sodium Nitroprusside on Ischemia/Reperfusion-Induced Leukocyte Adhesion and Macromolecular Leakage in Hamster Cheek Pouch Venules

Abstract

Microvasc. Res.

Prostaglandins

Free Radical Biol. Med.

Free Radical Biol Med.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Arch. Biochem. Biophys.

Transplant. Proc.

Brain Res.

Microvasc. Res.

Microvasc. Res.

Free Radical Biol. Med.

Leukocyte adhesion after oxidant challenge in the hamster cheek pouch microcirculation

J. Vasc. Res.

Ischemia/reperfusion-induced leukocyte–endothelial interactions in postcapillary venules

Shock

Bradykinin and changes in microvascular permeability in the hamster cheek pouch: role of nitric oxide

Br. J. Pharmacol.

The microcirculation and inflammation: Modulation of leukocyte–endothelial cell adhesion

J. Leukocyte Biol.

Role of endothelial nitric oxide generation and peroxynitrate formation in reperfusion injury after focal cerebral ischemia

Stroke

Regular Article
Effects of $l$ -NA and Sodium Nitroprusside on Ischemia/Reperfusion-Induced Leukocyte Adhesion and Macromolecular Leakage in Hamster Cheek Pouch Venules