Vascular effects of cyclosporin A and acute rejection in canine heart transplantation.

BACKGROUND: Alteration of coronary vascular regulation during acute rejection may induce graft dysfunction and promote the occurrence of coronary atherosclerosis in transplant recipients. We studied the effects of treated and untreated acute rejection on coronary vascular regulation. METHODS: Two groups of mongrel dogs (n = 7) underwent heterotopic heart transplantation (cervical position) and received either no treatment (group 1) or cyclosporin A (CyA), 10 mg.kg-1.day-1 (group 2). On day 7, recipient native and transplanted hearts were harvested and studied in organ chambers for coronary vascular reactivity. RESULTS: Transplanted hearts from group 1 displayed grade IV histologic rejection, whereas those from group 2 displayed grade IIIA to IV rejection. Intimal hyperplasia was found in the coronary arteries of both groups. Immunoperoxidase staining revealed the presence of factor VIII and of immunoglobulin M and G antibodies on the endothelium of both groups. Coronary relaxation to thrombin was impaired in transplanted hearts compared with native hearts (p < 0.05), and this was not influenced by CyA treatment. Conversely, endothelium-dependent relaxation to 5-hydroxytryptamine was enhanced in both CyA-treated (p < 0.01) and untreated groups (p < 0.05). A facilitating effect of CyA on 5-hydroxytryptamine also was seen in transplanted hearts in group 1 versus group 2 (p < 0.05), suggesting an intrinsic effect of CyA. Endothelium-independent relaxation to sodium nitroprusside and the contractile response to prostaglandin F2 alpha were not affected. CONCLUSIONS: In our model, acute rejection did not specifically impair cyclic guanosine monophosphate-mediated relaxation, but it did affect, in a receptor-specific manner, endothelium-dependent relaxation. Cyclosporin A appeared to enhance coronary endothelial sensitivity to 5-hydroxytryptamine.

Calcium-channel blockers preserve coronary endothelial reactivity after ischemia-reperfusion.

BACKGROUND: Calcium-channel blockers have been reported to improve myocardial recovery after ischemia-reperfusion, but their effects on coronary blood flow regulation remain to be defined. Experiments were designed to evaluate the effects of calcium antagonists on coronary artery vasoregulation exposed to ischemia-reperfusion. METHODS: Three groups of hearts (n = 6) were pretreated with a 10-minute infusion of either diltiazem, verapamil, or nifedipine at concentrations of 10(-9) mol/L to 10(-6) mol/L and exposed to 30 minutes of no-flow ischemia and 45 minutes of reperfusion. Another group (n = 6) received no pretreatment and was used as control. Endothelium-dependent and -independent relaxations were tested by assessing coronary flow increase to 5-hydroxytryptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L) infusion, respectively. Left ventricular pressure, its first derivative, and coronary basal flow were recorded before and after ischemia as well as during calcium antagonist infusion. RESULTS: Endothelium-dependent relaxation after ischemia was significantly improved with all three drugs in a dose-dependent fashion; nifedipine was found to be the more potent. Endothelium-independent relaxation was also significantly preserved with calcium antagonists regardless of the type, whereas left ventricular hemodynamics were not. During perfusion, nifedipine was found to have the most negative inotropic effect and to be the most potent vasodilator on the coronary circulation. Diltiazem was the less effective drug on both left ventricular hemodynamics and coronary circulation. CONCLUSIONS: This study indicates that preischemic infusion of calcium antagonists enhance endothelium-dependent and -independent coronary artery relaxation in the isolated rat heart model in a dose- and drug-dependent fashion. This can be achieved at low doses without affecting left ventricular hemodynamics and should contribute to preserve coronary artery autoregulation.

[Effects of chronic administration of captopril on vascular reactivity of the rat aorta]. / Effets de l'administration chronique du captopril sur la réactivité vasculaire de l'aorte du rat.

UNLABELLED: The vascular endothelial function is altered in certain vascular pathology such as arterial hypertension. However, the endothelial effect of the pharmacologic treatment of this pathology with angiotensin converting enzyme (ACE) inhibitor is poorly understood. To evaluate the effects of long-term treatment of captopril on the rat aortic vascular reactivity, 2 groups of spontaneously hypertensive rats (SHR) (n = 6) were studied for 12 weeks: the first group was treated with captopril (CAP) (2 g/l of water) while group 2 (OCAP) received no treatment. A third group without hypertension was considered as control group (CTL). At the end of the experiments, isolated aortic rings were studied in organ chambers for endothelial and smooth muscle vascular reactivity. The endothelial-dependent relaxations (EDR) to cumulative doses of acetylcholine, histamine or adenosine diphosphate were significantly decreased in the aortic segments of CTL compared to CAP (p < 0.05). Aortic segments from OCAP group demonstrated intermediate EDR responses between CAP and CTL groups. Smooth muscle relaxation to sodium nitroprusside was comparable among the 3 groups. Maximal smooth muscle contraction to progressive doses of norepinephrine was significantly higher in the CTL group compared to the hypertensive groups. CONCLUSION: Spontaneously hypertensive rats have an increased basal vascular tone. The increased EDR observed with hypertension partially compensates this hypercontractility. Chronic hypertension treatment with captopril partially normalizes EDR responses in the rat aorta suggesting the lost of the endothelial compensatory mechanism by ACE inhibitors.

[Cyclosporine A prevents ischemia-reperfusion induced myocardial dysfunction in the isolated heart of the rat]. / La cyclosporine A prévient la dysfonction myocardique induite par l'ischémie-reperfusion dans le coeur isolé de rat.

Cyclosporin A (CyA) has been shown to prevent mitochondrial injury following ischemia-reperfusion injury. Therefore, the present study was designed to investigate the effect of CyA on ischemia-reperfusion injury in the isolated rat heart preparation. Hearts from Sprague-Dawley rats were perfused in the Langerdorffmode at constant pressure (80 cm H2O) and paced (270 beats/min). After equilibration, hearts were treated with CyA (10(-5) mol/l) (n = 8) or its vehicle, cremophor (Cr) (n = 8) for 10 minutes before exposure to 30 minutes of global ischemia and 60 minutes of reperfusion. Hemodynamic variable vascular reactivity, and oxygen consumption (MVO2) were tested at baseline and at selected points during reperfusion Hemodynamic variables were significantly improved in the CyA group. The maximal mean percentage of preservation for left ventricular developed pressure (PDVG) was -14.9 +/- 10.7% and +31.5 +/- 23.6% respectively for Cr and CyA group (p<0.05) The maximal mean percentage of preservation for dp/dt was -11.7 +/- 11.4% and +28.3 +/- 29.9% respectively for Cr and CyA group (p < 0.05): the compliance, -dP/dt was also preserved, maximal mean preservation was -25.9 +/- 9.2% and +53.1 + 30.1% respectively in Cr and CyA group (p < 0.01). Oxygen debt was decreased at 30 minutes of reperfusion in the CyA-treated hearts: 0.06 x 10(-2) +/- 0.23 x 10(-2) cc/min/g compared to Cr-treated hearts: 0.61 x 10(-2) +/- 0.37 x 10(-2) cc/min/g (p = 0.05). The coronary endothelial dependent and independent responses were similarly decreased in both groups during reperfusion. Thus, in the isolated rat heart preparation, CyA preserves myocardial function (hemodynamic variables) and oxygen consumption without affecting the coronary vascular function during ischemia-reperfusion injury.

[Effect of cyclosporin A dosage on the vascular tone of the thoracic aorta of rats]. / Influence du dosage de la cyclosporine A sur la modulation du tonus vasculaire de l'aorte thoracique de rat.

Cyclosporine A (CyA) is known to affect the local release of endothelial-derived relaxing factor (EDRF). However, evidence that CyA could specifically alter endothelial signal transduction is not well understood. Experiments were designed to assess dose-dependent effect of CyA on vascular reactivity-specificity of the rat thoracic aorta. Three groups of rats (n = 10) were treated for 4 weeks with oral CyA 15 mg/kg/day (Gr 1), CyA 30 mg/kg/day (Gr 2), and olive oil (Gr 3), the CyA vehicle. At the end of the period, animals were euthanized and the thoracic aorta harvested for isometric assessment of endothelial and smooth muscle function in organ chambers. Maximal endothelial-dependent relaxation (Rmax) to acetylcholine dose-response was similarly affected in rats treated with CyA [Rmax (%): Gr 1: 33 +/- 8, Gr 2: 28 +/- 2, Gr 3:51 +/- 7, *p < 0.05]. At the opposite, response to adenosine diphosphate [Rmax (%): Gr 1: 11 +/- 2, Gr 2:24 +/- 3*, Gr 3:7 +/- 2, *p < 0.01] and histamine [dose-response CE50 (log M): Gr 1: +/- 12 +/- 0.05, Gr 2: +/- 5.45 +/- 0.05*, Gr 3: -4.85 +/- 0.08, *p < 0.05] were significantly enhanced in animals exposed to 30 mg/kg/day. Endothelium-independent relaxation to sodium nitroprusside (SNP) was comparable in all groups and dose-response to depolarizing (KCl) and non-depolarizing (norepinephrine) contractile agents were not affected either. These experiments suggest that CyA does not affect second messenger (cyclic-GMP) activation by an EDRF analogue (SNP) whereas signal transduction coupled to muscarinic, purinergic, and histaminergic receptors are either inhibited or enhanced by CyA in dose-dependent manner in the rat aortic model.

[Effect of vitamin E on the endothelial function of the regenerated aorta in rats following direct arterial injury]. / Influence de la vitamine E sur la fonction endothéliale de l'aorte de rat régénérée après traumatisme artériel direct.

Fibromuscular intimal injury is frequent after coronary or peripheral angioplasty. Peroxidation of circulating and membrane lipids have been implicated in intimal hyperplasia and endothelial dysfunction following direct arterial trauma. The aim of this study was to evaluate the effects of natural membrane antioxidant, vitamin E (VE), on the vascular reactivity of the regenerated endothelium. A first group of rats (n = 10) was pretreated with VE 100 IU/kg/day for a week before undergoing aortic (thoracic) endothelial denudation with a Fogarty catheter. Rats were then fed with the same VE supplemented diet for a 2-month period. A second group (n = 10), was similarly denudated and fed with soya oil (SO), VE vehicle, for the same period. A third group (n = 10) was denuded and used as control (CL). Endothelial-dependent and independent relaxations were assessed in organ chambers with acetylcholine (ACH), adenosine diphosphate (ADP), histamine (HIS), 5-hydroxytryptamine (5-HT) and sodium nitroprusside (SNP). Endothelial regeneration was evaluated with Evans blue staining. Vascular relaxation to SNP was not affected either by the regeneration process or the VE supplementation. However, endothelial-dependent relaxation to ACH and HIS were significantly impeded in the regenerated endothelium compared to control but was not influenced by the VE or the SO supplementation. Vascular contraction to 5-HT was significantly decreased in VE group compared to the other groups. Morphometric studies with Evans blue staining showed over 95% regeneration of the endothelial surface of the denuded aortas. Our results suggest that in spite of a complete anatomical regeneration, endothelial cells did not resume predenudation function. Endothelial-independent relaxation was preserved in all groups indicating that smooth muscle function was not altered by the regenerating process. The presence of dietary supplement of VE (up to 20 fold the daily requirement) did not prevent the endothelial dysfunction to ACH and HIS but attenuated the vaso-contraction to 5-HT and then could contribute to decreased vascular tone in endothelium-regenerated vessels.

[Effect of the ventricular preload on the basal and stimulated coronary circulation of the isolated rat heart]. / Influence de la précharge ventriculaire sur la circulation coronarienne basale et stimulée du coeur de rat isolé.

Langendorff perfused isolated rat heart is a common model for coronary blood flow study. Left ventricular preload can both increase coronary blood flow by direct inotropic effect or decrease it by rising transmural tension. Experiments were designed to determine optimal preload conditions for observation of basal (CBF) and 5-hydroxytryptamine (5-HT) stimulated coronary blood flow (SCBF) in the isolated rat heart model. Rat hearts (n = 6) were harvested and stabilized in the Langendorff apparatus and a left ventricular balloon was inserted and inflated at different volumes (0.05 to 0.4 ml) to stimulate preload. Left ventricular systolic (LVSP), diastolic (LVDP), myocardial oxygen consumption (MVO2) and extraction (MEO2) were also measured. Under basal conditions, optimal LVSP was obtained at 0.2 ml (111 +/- 15 mmHg). MVO2 was optimal at 0.2 ml of preload and decreased thereafter while MEO2 remained stable. Optimal CBF was reached at 0.2 ml of preload. Under 5-HT stimulation, CBF increased significantly (CBF: 8.2 +/- 0.6 ml/min vs SCBF: 16.4 +/- 1.0 ml/min, p < 0.01) while left ventricular hemodynamics did not differ from basal observations. At preload volume > 0.2 ml a significant drop in SCBF was observed (0 ml: 16.4 +/- 1 ml/min vs 0.4 ml: 11 +/- 1 ml/min, p < 0.01). MVO2 and MEO2 followed the same pattern observed under basal conditions. In basal and stimulated conditions, a hyperemic flow was also seen after deflation of the balloon with preload > = 0.2 ml in both CBF and SCBF suggesting myocardial oxygen debt. We conclude that in the Langendorff model preload affects coronary flow under both basal and 5-HT stimulation. A volume > 0.2 ml for rats of 350-400 g can impede CBF and generate myocardial oxygen debt as suggested by a decreased MVO2 and a post-deflation hyperemic flow. Left ventricular preload should be maintained under 0.2 ml for optimal coronary blood flow study in the Langendorff perfused rat heart model.

Clentiazem and diltiazem preserve endothelium-dependent relaxation following global rat heart ischemia.

OBJECTIVE: To evaluate the effects of the calcium channel blocker diltiazem and its chloride derivative clentiazem on coronary vasoregulation of isolated rat hearts exposed to ischemia-reperfusion. Diltiazem has been reported to prevent postreperfusion myocardial damage but its beneficial effects on coronary blood-flow regulation remain uncertain. METHODS: Two groups of hearts were pretreated with a 10 min infusion of either diltiazem (10(-9) to 10(-6) mol/L) or clentiazem (10(-9) to 10(-7) mol/L) (n = 6 for each concentration) and exposed to 30 mins of no-flow ischemia. Another group (n = 6) received no pretreatment and was used as control. Endothelium-dependent and -independent relaxation were tested by assessing coronary flow increase to 5-hydroxytriptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L) infusions, respectively, and were assessed before and after ischemia-reperfusion. Left ventricular pressure, dP/dt and coronary basal flow were also recorded. Postreperfusion results are expressed as a percentage of pre-ischemic value. Dunnet variance analysis was used to compare means of pretreated groups with the control group. RESULTS: Endothelium-dependent relaxation was significantly improved with both drugs. Optimal preservation was obtained with diltiazem 10(-6) mol/L (66 +/- 4%) and clentiazem 10(-7) mol/L (83 +/- 4%), whereas endothelial response was almost abolished in control hearts (6 +/- 11%, P < 0.01). Clentiazem was found to be more potent than diltiazem at low concentration (10(-9) mol/L, clentiazem 89 +/- 13% versus diltiazem 3 +/- 16%, P < 0.05). Optimal endothelium-independent relaxation preservation was achieved at 10(-8) mol/L in both groups (diltiazem 86 +/- 4%, clentiazem 82 +/- 8%, control 47 +/- 10%, P < 0.05). Left ventricular pressure and dP/dt were not affected by any pretreatment. However, postreperfusion coronary basal flow was significantly increased in control hearts. CONCLUSION: This study indicated that pre-ischemic infusion of diltiazem and clentiazem enhances endothelium-dependent and -independent coronary artery relaxation following reperfusion in the isolated rat heart model, without affective ventricular hemodynamics, and contributes to preservation of coronary artery autoregulation.

2,3-Butanedione monoxime preserves coronary artery endothelium-dependent relaxation during myocardial ischemia in the isolated rat heart.

OBJECTIVE: To evaluate the potential benefit of 2,3-butanedione monoxime (BDM) in preserving endothelium-dependent coronary artery relaxation during myocardial ischemia. MATERIALS AND METHODS: Langendorff-perfused rat heart model. Endothelium-dependent and independent relaxations were tested with infusion of 5-hydroxytryptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L), respectively. Four groups of hearts (n = 6) were used. Group 1 was perfused with BDM (25 mmol/L) without ischemia for 30 mins. Group 2 was perfused for 10 mins with BDM and exposed to 30 mins of no flow ischemia (37 degrees C). Group 3 was perfused with cold (4 degrees C) nonoxygenated BDM (30 mins) and group 4 (control) was exposed to 30 mins of no flow ischemia alone. Left ventricular pressure (LVP), left ventricular pressure first derivative (dP/dt) and coronary basal flow were evaluated before treatment and after 30 mins of reperfusion. RESULTS: BDM perfusion alone (group 1) did not affect coronary reactivity. Preservation of endothelium-dependent and -independent relaxation was significantly enhanced after ischemia in groups 2 and 3 (BDM-treated) compared with group 4 (control). No significant benefit was found regarding LVP and dP/dt in all groups. Postreperfusion coronary flow was decreased in all hearts except the controls (group 4), suggesting a residual BDM intrinsic effect on coronary flow. CONCLUSION: These experiments suggest that BDM can enhance preservation of coronary artery endothelium-dependent and -independent relaxation during myocardial ischemia in the isolated rat heart.

[Effects of cyclosporine A on the reactivity of the aorta with regenerated endothelium in rats]. / Les effets de la cyclosporine A sur la réactivité de l'aorte de rat avec endothélium régénéré.

Cyclosporine A (CyA) affects vascular reactivity but its effect on local vascular tone following endothelial regeneration is unknown. Experiments were designed to study the effects of CyA on endothelial and smooth muscle reactivity of endothelium-regenerated arteries. Three groups of rats (n = 8) were subjected to aortic mechanical denudation. Subsequently a first group was treated 8 weeks with CyA (20 mg/kg) and a second one with an equivalent volume of CyA vehicle: olive oil (OL). A last group was submitted to a standard diet and represented the control group (CTL). After 8 weeks, aortic rings were suspended in organ chambers for assessment of endothelial and smooth muscle function. Maximal endothelial dependent relaxation to acetylcholine (CyA: 52 +/- 3%, OL: 50 +/- 4%, CTL: 48 +/- 5%; p = NS), adenosine diphosphate (CyA: 30 +/- 7%, OL: 18 +/- 2%, CTL: 24 +/- 5%; p = NS) and histamine (CyA: 38 +/- 6%, OL: 43 +/- 4%, CTL: 47 +/- 5%; p = NS) were comparable among all groups. In aortic segments studies without endothelium, increased contraction to serotonine was significantly lessened in the OL group (CyA: 259 +/- 43%, OL: 153 +/- 11%, CTL: 243 +/- 24%; p < 0.05). Maximal tension to cumulative doses of norepinephrine was increased in rings without endothelium treated with CyA (CyA: 5.8 +/- 0.6 g, OL: 4.2 +/- 0.5 g, CTL: 4.0 +/- 0.2 g; p < 0.05). All these differences were abolished in rings studied with endothelium. Endothelial independent relaxation to sodium nitroprusside were similar among all groups. In conclusion, CyA does not specifically affect endothelium-dependent relaxation of the regenerated aortic endothelium. However, our model suggests that CyA increases vascular tone mediated by increased smooth muscle sensitivity to norepinephrine and serotonine but these effects are prevented by the regenerated endothelium. This experiment demonstrates the ability of the regenerated endothelium to prevent CyA-induced vascular toxicity.

[In vitro endothelial dysfunction after cold storage: comparison with various preservative solutions]. / La dysfonction endothéliale in vitro après entreposage froid: comparaison de différentes solutions de préservation.

Optimal solution for endothelial function preservation during cold storage for organ transplant has not yet been defined. To assess this issue, rat aortic rings (n = 28) were stored for 4 hours at 4 degrees C in different preservation solutions: Krebs Ringer (KR), normal saline (NS), rat blood (RB), and the University of Wisconsin solution (UW). Subsequently, rings were suspended in organ chambers for endothelial and smooth muscle assessment. Endothelial-dependent relaxation responses were tested by exposure to cumulative doses of acetylcholine (ACH), adenosine diphosphate (ADP), and histamine (HIS). Smooth muscle function was evaluated by exposure to norepinephrine (NE) and sodium nitroprusside (SNP). A fifth group not submitted to a storage period was used as control (CTL, n = 7). Results are expressed as maximal relaxation (%) from initial precontraction level. Compared to the CTL group, all storage groups showed a significant decrease in endothelial-dependent relaxations to ACH, ADP and HIS (p < 0.05). Among the stored groups, endothelial-dependent relaxation to ACH was significantly decreased in the NS group when compared to the UW group (p < 0.05). Endothelial-independent relaxation to SNP was comparable for all groups. However significant hypercontractility to NE was observed for all stored groups compared to the control group (p < 0.01). A significant decrease in ADP response was observed with NS and RB storage when compared to KR (p < 0.01). In conclusion, cold storage affects both endothelial and smooth muscle function by decreasing endothelial-dependent responses to ACH, ADP and HIS and increasing smooth muscle reactivity to NE. However, endothelial dysfunction was lessened with UW or KR storage compared to NS or RB.

[Effect of pentoxifylline on the vascular toxicity secondary to cyclosporine in rats]. / Influence de la pentoxifylline sur la toxicité vasculaire secondaire à la cyclosporine chez le rat.

Chronic administration of cyclosporine (CyA) has been shown to affect local vascular tone. Pentoxifylline (PTX), a xanthine-derived vasoactive agent, has been reported to prevent CyA toxicity but its effect on CyA-related increased vascular tone remains uncertain. In vitro experiments were designed to study the effects of PTX on endothelium-dependent and independent vasorelaxation of the rat thoracic aorta. Three groups of rats (n = 10) were respectively treated for 4 weeks with CyA (30 mg/kg/day), CyA and PTX (40 mg/kg/day), and CyA and PTX (80 mg/kg/day). At the end of the period, rings (4-5 mm) of aorta were harvested and suspended in organ chambers containing Krebs Ringer solution (37 degrees C, 95% O2, 5% CO2) for assessment of endothelial and smooth muscle reactivity. Endothelium-dependent relaxation to acetylcholine was significantly enhanced in animals treated with CyA and PTX (40 mg/kg/day) compared to those exposed to CyA alone (p < 0.05). Response to histamine and adenosine diphosphate was not affected. However, the use of PTX (80 mg/kg/day) significantly deteriorated the endothelial response to the same drugs (p < 0.05) suggesting a detrimental effect of PTX at this concentration. Endothelial-independent relaxation to sodium nitroprusside was comparable in all groups. The results suggest the clinical benefit reported with the use of PTX on patients chronically exposed to CyA may partly be due to an improvement of the vascular endothelial function. However, the toxicity encountered at high dose should cautioned its use in clinical setup.

[Effect of solutions of preservation on the vascular reactivity of human saphenous veins]. / Influence des solutions de préservation sur la réactivité vasculaire des veines saphènes humaines.

It is mandatory to preserve the vascular tone regulation of the saphenous vein in order to optimize its performance as a vascular conduit. To determine the optimal preservation solution, human saphenous vein segments (3-4 cm) were harvested, stored for 60 minutes in different preservation solutions and studied in organ chambers for endothelial and smooth muscle assessment. A 1st group (n = 10) was stored in the heparinized blood of the patient (SH), a 2nd group (n = 10) in physiologic saline solution (NaCl) and a 3rd group (n = 10) in Krebs Ringer (KR) solution. All solutions were maintained at room temperature (21 degrees C). Each preserved segment was paired to a control segment, harvested in the same patient, and studied before storage. Following 60 minutes of preservation decreased endothelial-dependent relaxation to acetylcholine and histamine was observed among the group stored in KR (p = 0.06 and p < 0.02 respectively) compared to the other groups. Endothelium-independent relaxation to sodium nitroprusside was not affected regardless of the solution used. However, veins stored in SH disclosed an increased contractility to norepinephrine (p < 0.04). When intergroup variability was considered (by variance analysis), no significant difference was seen between each group. This study suggests that KR and SH were not as efficient as NaCl in preserving saphenous endothelial function. Furthermore, storage in SH increased smooth muscle response to catecholamine. In this experimental setup, 0.9% NaCl solution is an acceptable preservation solution of the saphenous vein.

Effects of modified St Thomas' Hospital solution on coronary artery endothelium dependent relaxation in the isolated rat heart.

Addition of magnesium to a preservation solution such as St Thomas's Hospital solution has been shown to improve myocardial preservation. High concentration of magnesium can affect coronary artery endothelial-dependent relaxation. Isolated rat hearts were studied in the Langendorff apparatus to investigate whether magnesium-enriched hyperkalemic cardioplegic solution (HCS) could alter coronary endothelial function. Hearts in group 1 (n = 8) were perfused for 30 mins with a standard hyperkalemic cardioplegic solution (potassium chloride 24 mmol/L). Hearts in group 2 (n = 8) were perfused with modified St Thomas' Hospital solution (MST) containing 16 mmol/L of magnesium chloride and 24 mmol of potassium chloride. The endothelium dependent and endothelium independent relaxation of the coronary arteries were respectively assessed by infusing 5-hydroxytryptamine (5-HT) (1 x 10(-6) mol/L) and sodium nitroprusside (SNP) (1 x 10(-5) mol/L) before and after perfusion of cardioplegic solutions. Hearts in group 2 showed a reduction of the 5-HT-induced coronary flow increase following the MST exposure (before, 8.66 +/- 0.86 mL/min; after, 5.66 +/- 0.97 mL/min, P < 0.01) whereas hearts in group 1 were not significantly affected (before, 8.00 +/- 0.68 mL/min; after, 6.99 +/- 1.02 mL/min, not significant), suggesting endothelial dysfunction in the former. Coronary flow response to SNP was not affected in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic exposure to cyclosporine affects endothelial and smooth muscle reactivity in the rat aorta.

Chronic exposure to cyclosporine affects vascular reactivity. Experiments were designed to characterize the endothelium-dependent and endothelium-independent vascular reactivity of rats exposed to oral cyclosporin A (CyA). Two subsets of rats (n = 6) were treated with CyA (20 mg/kg/day) and olive oil (cyclosporine vehicle), respectively, for a period of 8 weeks. Aortic rings (4-5 mm) were suspended for isometric force measurement in organ chambers containing Krebs Ringer solution (37 degrees C, 95% O2, 5% CO2). The maximal endothelium-dependent relaxation to cumulative doses of acetylcholine was significantly decreased in the CyA-treated aortic rings compared to olive oil-treated ones (data expressed as percent of initial contraction; CyA, 50% +/- 3% versus olive oil, 37% +/- 7%; p < 0.05). However, endothelium-dependent relaxations to histamine and adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were not affected in both groups. An endothelium-dependent contraction to serotonin and aggregating platelets were observed in the CyA group, but not in the control group. The endothelium-independent contraction to norepinephrine was enhanced in the CyA group (CyA ED50, log -7.66 +/- 0.18 mol/L versus olive oil ED50, log -7.01 +/- 0.11 mol/L; p < 0.01). These experiments suggest that chronic exposure to cyclosporine A could contribute to augmenting vascular tone by (1) decreased release of endothelial relaxing factor mediated by muscarinic receptors, (2) increased production of endothelium-related constricting factor mediated by serotoninergic receptors, and (3) greater vascular smooth muscle sensitivity to circulating catecholamine.

Effects of University of Wisconsin solution on endothelium-dependent coronary artery relaxation in the rat.

University of Wisconsin (UW) solution has been reported to enhance myocardial preservation in heart transplantation. To evaluate the effects of UW solution on coronary artery endothelial function, we designed experiments to compare UW solution with a standard crystalloid hyperkalemic cardioplegic solution (CHCS). Isolated rat hearts were studied in a modified Langendorff apparatus for coronary endothelial function. Groups 1 and 2 were perfused with 4 degrees C CHCS (24 mmol/L of KCl) and UW solution, respectively, for 10 minutes at a pressure of 80 cm H2O, whereas group 3 underwent warm ischemia for 10 minutes. Groups 4 and 5 were perfused with and stored for 4 hours in cold (4 degrees C) CHCS and UW solution, respectively. Group 6 underwent 4 hours of topical cooling (4 degrees C) without any cardioplegic perfusion. All groups had 6 hearts each. Endothelium-dependent relaxation and endothelium-independent relaxation of the coronary arteries were tested by infusing 5-hydroxytryptamine (5HT) (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L), respectively, before and after perfusion with and storage in one of the two cardioplegic solutions. The coronary vasodilatation induced by 5HT and sodium nitroprusside was not altered in hearts perfused with (group 1) or perfused with and stored in CHCS (group 4). Coronary flow increase after 5HT infusion was significantly decreased in hearts perfused with (group 2) (before, 35% +/- 10%; after, 13% +/- 10%; p < 0.01) or perfused with and stored in UW solution (group 5) (before, 34% +/- 5%; after, -5% +/- 12%), indicating severe endothelial dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of different solutions of preservatives on the endothelial function of coronary arteries in rats]. / L'influence de différentes solutions de préservation sur la fonction endothéliale des artères coronaires du rat.

The effects of cold storage and type of preservation solution on coronary endothelial function are not well established. Experiments were designed to evaluate coronary endothelial-dependent relaxation after a 4-hour cold (4 degrees C) storage in different preservation solutions. Rat hearts, mounted in the Langendorff apparatus, were arrested with a 10-minute perfusion of 4 degrees C crystalloid hyperkaliemic cardioplegic solution (CHCS) (KCl 24 mEq/l) and stored for 4 hours in the following preservation solutions: CHCS (n = 6), Krebs-Ringer solution (KR) (n = 6), 0.9% NaCl (NS) (n = 6) and the University of Wisconsin solution (UW) (n = 6). A fifth group (n = 6) was perfused and stored in UW solution. Endothelium-dependent and independent coronary artery vasorelaxations were respectively tested by infusing 5-hydroxytryptamine (5-HT) (10(-6) mol/l) and sodium nitroprusside (SNP) (10(-5) mol/l) before and after the storage period. In hearts stored with CHCS or KR, coronary artery flow increase to 5-HT and SNP infusions were not significantly affected. However, in hearts preserved with NS or UW solutions, 5-HT coronary response was significantly decreased, indicating endothelial dysfunction. In addition to these findings, coronary flow increase to SNP infusion was decreased in the group perfused and stored with UW, suggesting smooth muscle dysfunction. These experiments suggest that 4-hour cold storage in NS or UW impairs endothelial-dependent coronary relaxation in the isolated rat heart model.