Ann Thorac Surg 1997;63:1050-1056
© 1997 The Society of Thoracic Surgeons
Original Article: Cardiovascular
Calcium-Channel Blockers Preserve Coronary Endothelial Reactivity After Ischemia-Reperfusion
Francois Dagenais, MD,
Raymond Cartier, MD,
Charleen Hollmann, RN,
Josie Buluran, BS
Department of Cardiovascular Surgery, Montreal Heart Institute, Montreal, Quebec, Canada
Accepted for publication October 30, 1996.
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Abstract
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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.
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Introduction
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Until the late 1960s, the endothelium was considered an inert nonthrombogenic cellular barrier. After the discovery of prostacyclin in 1977 [1] and the nonprostanoid compound termed endothelium-derived relaxing factor (EDRF) by Furchgott and Zawadzki [2] in 1980, the endothelial physiology has developed in one of the most exciting and attracting field in cardiovascular research. The EDRF, of which the free radical nitric oxide is the main representative, induces relaxation of the underlying smooth muscle and is recognized as a potent inhibitor of platelet aggregation and adhesion [3]. Decrease in EDRF release may promote local vasoconstriction and platelet aggregation. Recently, endothelial dysfunction has been implicated in the pathogenesis of diseases such as atherosclerosis [4], hypertension [5], diabetes [6], coronary and cerebral vasospasm [7], and ischemia-reperfusion [8]. Ischemia-reperfusion affects endothelium-dependent relaxations mediated by EDRF in a time-dependent fashion [9]. The mechanism underlying this dysfunction is in part attributed to the generation of free radicals during reperfusion [10, 11]. Experimentally, cardioplegic arrest and heart storage during cardiac transplantation are known to induce coronary endothelial dysfunction [12]. Ultimately, such a deleterious effect on the endothelium may produce coronary vasospasm and decrease myocardial performance in the perioperative period. Drug therapy to reduce or prevent endothelial injury during ischemia-reperfusion could maintain coronary vasoregulation and possibly preserve global heart function. Although calcium-channel blockers were initially designed as antianginal agents, they were found to help preserve the ischemic myocardium in experimental as well as clinical settings [13–15]. The mechanism underlying this beneficial effect remains unclear but appears to relate to negative inotropic and chronotropic properties of calcium antagonists [16], improvement of collateral blood flow [17], or prevention of severe ventricular arrhythmias during reperfusion [18]. Preservation of the endothelial function after ischemia could contribute to maintain myocardial integrity. Beneficial effects of calcium antagonists on the endothelium have been suggested in different studies, but the effects of calcium-channel blockers on the coronary endothelial function after ischemia-reperfusion are not clear.
The main objective of this study is to evaluate the effects of pretreatment with calcium-channel blockers on coronary endothelial function after ischemia-reperfusion injury. Nifedipine, verapamil, and diltiazem were selected, as these compounds have been extensively and successfully tested in an ischemic experimental setting of myocardial preservation.
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Material and Methods
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Animal Preparation and Reagents
Hearts were obtained from male Sprague-Dawley (250 to 300 g body weight) rats maintained on a standard laboratory diet. All animals were cared for in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85–23, revised 1985). Endothelium-dependent relaxation was evaluated with a 5-hydroxytryptamine (5-HT) (1 x10-6 mol/L) infusion. Endothelium-independent relaxation was tested with a sodium nitroprusside (SNP) (1 x 10-5 mol/L) infusion. 5-Hydroxytryptamine and SNP were obtained from Sigma Chemicals Ltd.
Perfusion Technique and Protocol
Rats were initially heparinized, anesthetized with pentobarbital, and then decapitated. The chest was immediately opened, and the ascending aorta was isolated, cannulated, and perfused in vivo with a 37°C oxygenated (95% O2, 5% CO2) Krebs Ringer's solution (in millimoles per liter): NaCl, 118.3; KCl, 4.7; MgSO4,1.2; KHPO4,1.22; CaCl2,1.3; NaHCO3,25; glucose,15; pH 7.4. The perfused hearts were excised from the chest and mounted on a modified Langendorff apparatus [19]. By using this harvesting technique, the myocardial ischemia was limited to less than 45 seconds. The perfusion pressure was constant at 80 cm H2O and hearts were paced between 250 to 300 beats/min. A latex balloon was inserted in the left ventricle and inflated to maintain an end-diastolic pressure of 10 mm Hg standardizing experimental conditions. Left ventricular pressure (LVP) and its first derivative (dP/dt) were monitored throughout the experiment. Mean and pulsatile coronary flows were measured using a 2-mm cannulating ultrasonic probe (Transonic Systems, Inc, Ithaca, NY)attached to the aortic cannula. Two studies were conducted simultaneously and all data were recorded on an eight-channel Gould recorder. The 5-HT and SNP were dissolved in sterile water and infused with a Harvard syringe infusion pump 22 (Harvard Apparatus). Calcium-channel blockers were dissolved in Krebs Ringer's solution.
Protocol
After harvesting, hearts were initially stabilized for 30 minutes in the Langendorff apparatus [19] (Fig 1
). At the end of this period, the baseline values for coronary blood flow, LVP, and dP/dt were recorded. The 5-HT was then infused into the aortic cannula for 4 minutes. Absolute increase in coronary flow was measured at the end of this period. A washout period of 30 minutes was then allowed for coronary blood flow to return to baseline values. In a similar fashion, SNP was then infused for 4 minutes, followed by a 30-minute washout period. Subsequently, hearts were pretreated for 10 minutes, with a perfusion of diltiazem, nifedipine, or verapamil as further discussed under the section "Experimental Groups." A pretreatment period of 10 minutes was chosen to simulate a clinical setting of cardioplegic infusion. The coronary blood flow, LVP, and dP/dt variations during calcium antagonists perfusion were measured by comparing data before perfusion to values obtained at the end of the 10-minute perfusion. Hearts were then submitted to a 30-minute warm (37°C) no-flow ischemia (by cross-clamping the aortic cannula) period known to induce a severe endothelial functional damage in this model. The ischemic period was followed by a 45-minute reperfusion with an oxygenated Krebs Ringer's solution. Postischemic baseline values of coronary flow, LVP, and dP/dt were measured at the end of the reperfusion period. Absolute increase in coronary blood flow to 5-HT and SNP were again recorded.
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Fig 1. . Experimental protocol. (CCB = calcium-channel blocker; 5-HT = 5-hydroxytryptamine; SNP = sodium nitroprusside.)
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Experimental Groups
Diltiazem, nifedipine, and verapamil were administered at four different concentrations (10-9, 10-8, 10-7, 10-6 mol/L); n = 6 for each concentration. A control group (n = 6) was exposed to a similar ischemic period without any pretreatment.
Data Analyses
Data are expressed as preservation in percentage of the endothelium-dependent (5-HT) and -independent (SNP) coronary relaxations calculated by the ratio of the absolute increase in coronary blood flow after ischemia-reperfusion over the absolute increase in coronary blood flow before ischemia. Preservation of LVP, dP/dt, and basal coronary blood flow after ischemia-reperfusion are expressed as percentage of preservation of initial (preischemic) values. All data are reported as mean and standard error of the mean (x ± standard error of the mean). For comparison of the treated groups with the control group, statistics were performed using one-way Dunnet's variance analysis. Statistical analysis was considered significant for a p value less than 5%.
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Results
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Baseline Data
Preischemic baseline data are shown in Table 1. No significant differences were observed between the different groups.
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Table 1. . Absolute Baseline Values for Mean Coronary Basal Flow, Left Ventricular Pressure, and First Derivative of Left Ventricular Pressure for Each Group
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Hemodynamic Effects of Calcium-Channel Blockers
Basal coronary blood flow increased significantly in a dose-related mode with all three types of calcium antagonists used (Fig 2). However, the vasodilatory effect of nifedipine was more prominent at low concentrations (10-9 to 10-7 mol/L), whereas at the highest concentration (10-6 mol/L) no significant difference was seen between nifedipine and verapamil. A similar dose-related effect was observed with left ventricular hemodynamic indices (Figs 2B, 2C), although verapamil at an intermediate concentration was found to have the most negative effect on LVP (10-8) and dP/dt (10-8, 10-7 mol/L). Diltiazem was the least myocardial depressive agent and affected ventricular hemodynamics only when infused at the highest concentration (10-6 mol/L). An example of comparative effects of the three calcium-channel blockers at 10-7 mol/L concentration is displayed in Figure 3.
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Fig 2. . Effects of preischemic infusion of the calcium-channel blockers nifedipine (hatched bars), verapamil (white bars), and diltiazem (black bars) on coronary basal flow (CBF), left ventricular pressure (LVP), and the first derivative of left ventricular pressure (dP/dt). Concentrations used were 10-9 to 10-6 mol/L for each of the calcium antagonists. (Dunnet's analysis of variance: *p < 0.05 referred to subgroup of each drug compared with control group and  p < 0.005 referred to in-between group differences for each concentration.)
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Fig 3. . Effects of nifedipine, verapamil, and diltiazem perfusion (arrow indicates perfusion start) on left ventricular pressure (LVP), first derivative of left ventricular pressure (dP/dt), mean coronary flow, and pulsatile coronary flow at the 10-7 mol/L concentration. Recordings show a significant increase in mean and pulsatile coronary flow with all calcium-channel blockers; the maximal flow increase was obtained with nifedipine. The decrease in left ventricular pressure and dP/dt was maximal with verapamil and minimal with diltiazem.
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Postischemic Data (Left Ventricular Pressure, Its First Derivative, and Coronary Blood Flow)
After ischemia-reperfusion LVP and dP/dt were preserved in all pretreated groups (Table 2). Although a trend toward better preservation was observed compared with the control group, statistical significance was only achieved with the higher doses of verapamil (10-7, 10-6 mol/L). Coronary basal flow was constantly and significantly decreased after reperfusion in all hearts pretreated with calcium-channel blockers (Fig 4), whereas sustained increased coronary flow was seen in nonpretreated hearts.
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Table 2. . Postreperfusion Values of Mean Coronary Basal Flow, Left Ventricular Pressure, and First Derivative of Left Ventricular Pressure Expressed as Percentage Preservation of Preischemic Valuesa
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Fig 4. . This figure represents an example of real-time value of coronary flow increase to 5-hydroxytryptamine before (right) and after ischemia-reperfusion (left) at a concentration of 10-9 mol/L. As illustrated, nifedipine and verapamil better preserved endothelium-dependent relaxation than diltiazem at that concentration.
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Endothelium-Dependent Response
The three types of calcium antagonists used improved the preservation of the endothelial-dependent relaxation after ischemia-reperfusion in a dose-dependent fashion. Compared with the control group, preischemic infusion of nifedipine only preserved the endothelial response at the lowest concentration (10-9 mol/L), whereas verapamil was found efficient at all concentrations and diltiazem at the higher doses (10-8 mol/L to 10-6 mol/L) (Fig 5). Increased endothelial preservation with nifedipine and verapamil at the 10-9 mol/L concentration suggests an increased potency of these two agents compared to diltiazem (Fig 6). At intermediate concentrations, verapamil was as efficient as diltiazem (10-8 mol/L and 10-7 mol/L), and at a high concentration (10-6 mol/L), diltiazem was found to be the most efficient (see Fig 5).
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Fig 5. . Percentage of preservation of preischemic value of endothelium-dependent coronary flow increase to 5-hydroxytryptamine for all groups pretreated with the calcium antagonists nifedipine, verapamil, and diltiazem compared with control. Concentrations used were 10-9 to 10-6 mol/L for each calcium-channel blocker. (Dunnet's variance analysis.)
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Fig 6. . Percentage of preservation of preischemic value of endothelium-dependent coronary flow increase to 5-hydroxytryptamine for all groups pretreated with the calcium antagonists nifedipine, verapamil, and diltiazem. Concentrations used were 10-9 to 10-6 mol/L for each calcium-channel blocker. (Dunnet's variance analysis.)
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Endothelium-Independent Response
Compared with control, preservation of the endothelium-independent relaxation to SNP was improved with all calcium antagonist preischemic perfusion regardless of the dose used, although diltiazem at the lowest dose (10-9 mol/L) was not found beneficial (Table 3). No significant difference was noted among the three calcium antagonists.
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Table 3. . Postreperfusion Values of Sodium Nitroprusside-Induced Increase in Coronary Flow, Expressed as Percentage Preservation of Preischemic Values
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Comment
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This study was designed to assess indirectly the coronary artery EDRF release mediated by serotonergic receptors in the isolated rat heart before and after ischemia-reperfusion injury. Agonist-mediated release of EDRF requires an elevation in intracellular calcium [20]. First-generation calcium antagonists (diltiazem, verapamil, and nifedipine) have not been shown to inhibit the release of EDRF [21]. As a matter of fact, in a smooth muscle preparation, relaxations induced by calcium antagonist and EDRF are additive, thus suggesting two independent modes of action on the smooth muscle [22]. Calcium-channel blockers have also been reported to decrease vascular endothelial permeability after ischemia [23]. Our results demonstrate the capacity of first-generation calcium-channel blockers to protect 5-HT–mediated coronary relaxation after ischemia-reperfusion injury in the isolated rat heart model. Verapamil and nifedipine were found more potent than diltiazem. Protective effects of verapamil and diltiazem were observed in a dose-related fashion, whereas protection with nifedipine was effective at the 10-9 mol/L concentration and not at higher doses. Differences in tissue specificity among calcium-channel blockers may explain partially this phenomenon. In a canine model, Selwyn and colleagues [24] have demonstrated similar beneficial effects of lower nifedipine dosage to protect regional myocardial ischemia, whereas higher dosages tended to increase infarct size. Such variability in the relative potencies among calcium-channel blockers to protect the ischemic myocardium was also observed by others and suggest an optimal dosage for each calcium antagonist to induce their maximal cardioprotective effect [25]. In our study, results regarding 5-HT endothelium-dependent preservation suggest that the optimal range for diltiazem is 10-8 mol/L to 10-6 mol/L, 10-9 mol/L to 10-7 mol/L for verapamil, and 10-9 mol/L for nifedipine. Timing for calcium antagonist administration is also important. In vitro, calcium antagonists are more effective in reducing myocardial infarct size when administered before ischemia as opposed to during or after ischemia [26]. Although not the main objective of our study, global heart performance as assessed by LVP and dP/dt was not significantly altered after ischemia possibly attributable to the limitations of our model to detect myocardial damage.
Calcium antagonists have been tested extensively in myocardial protection. Using an ischemic rabbit heart preparation, Wicomb and colleagues [27] demonstrated a close correlation between myocardial and vascular endothelial dysfunctions. Such data may imply comparable ischemic injury mechanisms on the myocardium and the endothelium, which could be halted partially or reduced by calcium-channel blockers. One of the most frequently proposed mechanisms for the beneficial effects of calcium antagonists on the ischemic myocardium is related to their negative inotropic and chronotropic properties, thus decreasing cardiac workload. Although this mechanism appears to be preponderant in vitro, in vivo studies do not corroborate these findings [28]. In the present study, the negative effect obtained on LVP and dP/dt at higher concentrations (10-7 mol/L, 10-6 mol/L) of calcium antagonists did not correlate with the level of endothelial preservation. Aside from these effects on myocardial contractility, calcium antagonists have been implicated as antioxidants [29]. Free radicals are known to induce myocardial and endothelial dysfunction [30]. Noronha-Dutra and colleagues [31], using an endothelial cell culture model, demonstrated that calcium antagonist pretreatment prevents in vivo generation of free radicals induced by adrenaline. Free radicals are mostly generated by the inflammatory response during reperfusion. In a blood-free media as in our experiment, free radicals may be produced during ischemia by conversion of xanthine dehydrogenase to xanthine oxidase, thus contributing to endothelial damage [32]. Increased intracellular calcium during ischemia has also been proposed as a mediator of myocardial injury [33]. Cellular calcium overload has been shown to impair mitochondrial high-energy phosphate synthesis [34] and promote activation of phospholipase A2, thus leading to membrane instability [35]. Calcium antagonists decrease calcium overload during ischemia-reperfusion and as most of them are lipophilic compounds, an unknown intracellular site of action is possible [36].
To optimize cardiac preservation in open heart operations, clinical studies have addressed the beneficial effects of adding calcium antagonists to cardioplegic solutions [37]. Christakis and colleagues [38] found an improved adenosine triphosphate preservation and reduced ischemic injury after addition of diltiazem (150 µg/kg) to crystalloid cardioplegia during elective coronary bypass. Caution was advised in patients with ventricular dysfunction considering the negative inotropic and atrioventricular blockade side effects of diltiazem. These side effects were reported to be dose dependent [38]. However, endothelial dysfunction was never assessed. The dysfunctional endothelium may promote vasospasm and platelet aggregation in the postoperative course. As suggested by our experiment, calcium-channel blockers at very low dosage may protect endothelial function without depressing myocardial hemodynamics. Clinical application in cardioplegia solutions or preservation solutions may ultimately be possible.
In summary, we demonstrated that diltiazem, verapamil, and nifedipine preserve 5-HT-induced coronary vasodilation after ischemia in an isolated rat heart preparation. Such protection is possible with minimal effects on global heart function. Although different hypotheses have been discussed to explain the protective effects of calcium antagonists, the exact mechanism remains unknown. Further studies will be required to substantiate these findings and elucidate the underlying mechanisms.
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Acknowledgments
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This study was supported by the Fonds de Recherche de l'Institut de Cardiologie de Montréal.
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Footnotes
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Address reprint requests to Dr Cartier, Research Center, Montreal Heart Institute, 5000 Belanger St, Montreal, PQ H1T 1C8, Canada.
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References
|
|---|
- Moncada S, Herman AG, Higgs EA, Vale C. Differential formation of prostacyclin (PGX or PG12) by layers of the arterial wall. An explanation for the anti-thrombotic properties of vascular endothelium. Thrombosis Res 1977;11:323–44.[Medline]
- Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;299:373–6.
- Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43:109–41.[Medline]
- Galle J, Mülsch A, Busse R, Bassenge E. Effects of native and oxidized low density lipoproteins on formation and inactivation of endothelium derived relaxing factor. Arterioscler Thromb 1991;11:198–203.[Abstract/Free Full Text]
- Winquist RJ, Bunting PB, Baskin EP, Wallace AA. Decreased endothelium-dependent relaxation in the New Zealand genetic hypertensive rats. J Hypertension 1984;2:536–41.
- Kolb H, Kolb-Bachofen V. Type 1 (insulin-dependent) diabetes mellitus and nitric oxide. Diabetologia 1992;40:796–7.
- Faraci FM, Brian JE. Nitric oxide and the cerebral circulation. Stroke 1994;25:692–703.[Abstract]
- Xin-Liang M, Weyrich AS, Lefer DJ, Lefer AM. Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to the coronary endothelium. Circ Res 1993;72:403–12.[Abstract/Free Full Text]
- DeMey JG, Vanhoutte PM. Anoxia and endothelium-dependent reactivity of the canine femoral artery. J Physiol 1983;335:65–74.[Abstract/Free Full Text]
- Schmid-Schönbein GW. The damaging potential of leukocyte activation in the microcirculation. Angiology 1993;44:45–55.
- Mügge A, Elwell JH, Paterson TE, Hofmayer TG, Heistad DD, Harrison DG. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 1991;69:1293–300.[Abstract/Free Full Text]
- Cartier R, Hollmann C, Dagenais F, Buluran J, Pellerin M, Leclerc Y. Effects of University of Wisconsin solution on endothelium-dependent coronary artery relaxation in the rat. Ann Thorac Surg 1993;55:50–6.[Abstract]
- Kloner RA, Braunwald E. Effects of calcium antagonists on infarcting myocardium. Am J Cardiol 1987;59:84B–94B.[Medline]
- Seitelberger R, Zwölfer W, Huber S, et al. Nifedipine reduces the incidence of myocardial infarction and transient ischemia in patients undergoing coronary bypass grafting. Circulation 1991;83:460–8.[Abstract/Free Full Text]
- DaLuz PL, de Barros LFM, Leite JJ, Pileggi F, DeCourt LV. Effect of verapamil on regional coronary and myocardial perfusion during acute coronary occlusion. Am J Cardiol 1980;45:269–75.[Medline]
- Miller RC, Stoclet JC. Modulation by endothelium of contractile responses in rat aorta in absence and presence of flunarizine. Br J Pharmacol 1985;86:655–61.[Medline]
- Gerritsen ME, Nganele DM, Rodrigues AM. Calcium ionophore (A23187) and arachidonic acid-stimulated prostaglandin release from microvascular endothelial cells: effects of calcium antagonists and calmodulin inhibitors. J Pharmacol Exp Ther 1987;240:837–46.[Abstract/Free Full Text]
- Auch-Schwelk W, Vanhoutte PM. Endothelium-derived relaxing factor(s) and calcium antagonists. Z Kardiol 1989;78:120–3.
- Langendorff O, Nawrocki C. Untersuchgen am überlebenden Saugethierherzen. Pfluger Arch 1935;61:291–332.
- Kikkawa K, Murata S, Nagao T. Endothelium-dependent calcium-induced relaxation in the presence of Ca++-antagonists in the canine depolarized coronary arteries. Br J Pharmacol 1989;98:700–6.[Medline]
- Jayakody RL, Kappagoda CT, Senaratne MPJ, Sreeharan N. Absence of effect of calcium antagonists on endothelium-dependent relaxation in rabbit aorta. Br J Pharmacol 1987,91:155–64.[Medline]
- Vanhoutte PM. Role of calcium and endothelium in hypertension, cardiovascular disease, and subsequent vascular events. J Cardiovasc Pharmacol 1992;19:S6–10.
- Sunnergren KP, Rovetto MJ. Myocyte and endothelial injury with ischemia reperfusion in isolated rat hearts. Heart Circ Physiol 1987;21:H1211–7.
- Selwyn AP, Welman E, Fox K, Horlock P, Pratt T, Klein M. The effects of nifedipine on acute experimental myocardial ischemia and infarction in dogs. Circ Res 1979;44:16–23.[Abstract/Free Full Text]
- Berdeaux A, Kantelip JP, Eschaliera A, Giudicelli JF, Duchene-Marullaz P. Bepridil: hemodynamic and coronary effects on normal and ischemic myocardium in dogs. J Pharmacol 1980;11:391–409.[Medline]
- Flaim SF, Zelis R. Diltiazem pretreatment reduces experimental myocardial infarct size in rat. Pharmacology 1981;23:281–6.[Medline]
- Wicomb WN, Levy JV, Collins GM. Functional integrity of vascular endothelium correlates with myocardial function in stored rabbit hearts. Transplant Proc 1993;25:1639–41.[Medline]
- Henry PD. Comparative pharmacology of calcium antagonists: nifedipine, verapamil and diltiazem. Am J Cardiol 1980;46:1047–58.[Medline]
- Kobayashi A, Yamashita T, Kaneko M, Nishiyama T, Hayashi H, Yamazaki N. Effects of verapamil on experimental cardiomyopathy in the Bio 14.6 Syrian hamster. J Am Coll Cardiol 1987;10:1128–34.[Abstract]
- Kloner RA, Przyklenk K, Whittaker P. Deleterious effects of oxygen radicals in ischemia/reperfusion. Circulation 1989;80:1115–27.[Abstract/Free Full Text]
- Noronha-Dutra A, Steen-Dutra EM, Wooif N. An antioxidant role for calcium antagonists in the prevention of adrenaline mediated myocardial and endothelial damage. Br Heart J 1991;65:322–5.[Abstract/Free Full Text]
- McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159–63.[Abstract]
- Nayler WG, Perry SE, Elz JS, Daly MJ. Calcium, sodium and the calcium paradox. Circ Res 1984;55:227–37.[Abstract/Free Full Text]
- Shine KI, Douglas AM. Low calcium reperfusion of ischemic myocardium. J Mol Cell Cardiol 1983;15:251–60.[Medline]
- Chein KR, Pfau RG, Farber JL. Ischemic myocardial cell injury. Prevention by chlorpromazine of an accelerated phospholipid degradation and associated membrane dysfunction. Am J Pathol 1979;97:505–30.[Abstract]
- Karasawa AS, Kubo K. Protection by benidipine hydrochloride (KW-3049), a calcium antagonist, of ischemic kidney in rats via inhibitions of Ca++-overload, ATP-decline and lipid peroxidation. Jpn J Pharmacol 1990;52:553–62.[Medline]
- Clark RE, Magovern GJ, Christlieb IY, Boe S. Nifedipine cardioplegia experience: results of a 3-year cooperative clinical study. Ann Thorac Surg 1983;36:654–63.[Abstract]
- Christakis GT, Fremes SE, Weisel RD, et al. Diltiazem cardioplegia: a balance of risk and benefit. J Thorac Cardiovasc Surg 1986;91:647–61.[Abstract]
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Top
Abstract
Introduction
