Vitamin B6 (pyridoxine) is a water-soluble vitamin and is present in different types of foods including whole grains, legumes, potatoes, nuts, fish, and poultry . It is an essential vitamin because it is known to participate in numerous enzymatic reactions including protein metabolism, neurotransmitter formation as well as conversion of tryptophan to niacin and homocysteine to methionine . Pyridoxine is converted by all organs of the body to pyridoxal 5-phosphate (PLP) and pyridoxamine, which serve as coenzymes for transaminase reaction . Although supplementation of vitamin B6 and its active metabolite, PLP, has been reported to reduce the complications associated with coronary artery disease, diabetes, hypertension, aging, and neurodegenerative disorders [4–10], the underlying mechanisms are not fully understood. The purpose of this article is to review the role of vitamin B6 and PLP in the prevention of ischemic heart disease and to discuss the cellular and molecular mechanisms of their therapeutic actions. In particular, the status of different risk factors for ischemic heart disease in vitamin B6 deficiency with or without vitamin B6 and PLP treatments will be emphasized. Furthermore, the existing information on the mode and site of action of PLP during the development of cardiac dysfunction in ischemic heart disease will be discussed.
Cardiovascular complications in vitamin B6 deficiency
Vitamin B6 deficiency has been shown to be associated with the development of atherosclerosis and coronary artery disease . It has also been reported to promote atherosclerosis directly as a result of its effects on vascular tissue  or indirectly as a result of the elevation of plasma homocysteine [11, 13]. In this regard, it should be noted that hyperhomocysteinemia is considered to be a well-known risk factor for coronary heart disease, myocardial infarction, and heart failure [14–16]. Several reports have also indicated a relationship among vitamin B6 deficiency, elevated levels of homocysteine, and coronary artery disease [11, 17–23]. Low levels of vitamin B6 or PLP and elevated levels of homocysteine have also been observed in patients with rheumatoid arthritis  and Alzheimer disease . Vitamin B6 deficiency has been shown to affect the antioxidant defense mechanisms in the liver and the heart  and thus can be seen to promote the occurrence of oxidative stress. Low circulating levels of vitamin B6 or PLP have also been reported to be associated with elevated levels of biomarkers for systemic inflammation involving C-reactive proteins and kynurenine [27–29]. Although there is a close relationship among vitamin B6 deficiency, hyperhomocysteinemia, and markers of inflammation with cardiovascular complications, it is not clear if the effects of vitamin B6 deficiency on coronary artery disease are mediated through the elevated levels of homocysteine, C-reactive proteins, or kynurenine. A close analysis of the results in these studies indicates that vitamin B6 deficiency, hyperhomocysteinemia, oxidative stress, and C-reactive proteins may be independent markers of coronary artery disease.
Patients with myocardial infarction were found to have low levels of vitamin B6 [20, 22]. Furthermore, the risk of developing myocardial infarction in patients with degenerative diseases was observed to be markedly reduced upon treatment with vitamin B6 . Vitamin B6 deficiency in pregnant women or in females on anovulatory steroid therapy has also been shown to be associated with hypertension [30, 31]. Rats on vitamin B6-deficient diet were also observed to exhibit hypertension [32, 33]. Because the norepinephrine turnover in hearts of vitamin B6-deficient animals was markedly increased , it has been suggested that hypertension in vitamin B6 deficiency may be mediated through the augmented activity of the sympathetic nervous system. The induction of hypertension due to vitamin B6 deficiency was also reported to be due to an increase in Ca2+ influx in the vascular smooth muscle . The Ca2+-handling abilities of cardiomyocytes obtained from vitamin B6-deficient rats were also examined in the absence and presence of KCl or ATP . In this study, KCl-induced increase in [Ca2+]i was observed to be augmented without any changes in the basal level of [Ca2+]i. Such an increase in [Ca2+]i due to depolarization of cardiomycytes by KCl can be seen to induce intracellular Ca2+ overload in the myocardium and lead to the development of cardiac dysfunction in vitamin B6-deficient rats . Meanwhile, ATP-induced increase in [Ca2+]i in cardiomyocytes from vitamin B6-deficient animals was reduced due to a depression in the number of ATP-binding sites in the sarcolemmal membrane . These alterations in KCl- and ATP-induced increases in [Ca2+]i as well as loss of ATP-binding in vitamin B6 deficiency were reversible upon treatment with vitamin B6 and can be explained on the basis of membrane abnormalities in cardiac membranes of the vitamin B6-deficient animals.
Cardioprotective effects of vitamin B6 and PLP in ischemic heart disease
Several studies have shown that vitamin B6 and its major metabolite, PLP, exert anti-ischemic effects in the heart [1, 9, 21, 22, 37]. PLP has also been reported to reduce ischemic injury to the brain . In a rat model of myocardial infarction, PLP has been demonstrated to reduce infarct size and improve cardiac function [9, 37]. A reduction of the ischemia-reperfusion (I/R) injury and infarct size was also seen in isolated rat hearts [9, 37]. A phase II clinical trial, in which PLP was given to patients undergoing percutaneous coronary intervention, showed a decrease in infarct size 24 h after angioplasty . In 901 high-risk patients undergoing coronary artery bypass graft (CABG) surgery, PLP resulted in a significant decrease in preoperative myocardial infarction but did not affect the prespecified primary end point . A reduction in cardiovascular death and myocardial infarction by PLP in the high-risk patients undergoing CABG was found to be independent of cross clamp time . However, in another study, in which 3023 intermediate- to high-risk patients undergoing CABG were used as subjects, PLP did not show any significant effect on cardiovascular death or non-fatal myocardial infarction [42, 43]. Although the exact reason for the negative results of this study using intermediate- to high-risk patients for CABG [42, 43] is not clear, the clinical studies using high-risk patients for CABG [40, 41] as well as in patients following angioplasty  show a high potential for PLP therapy in ischemic heart disease.
In view of the close association of arrhythmias and mortality in subjects with ischemic heart disease, the beneficial effects of vitamin B6 and PLP on ischemia-induced arrhythmias were tested upon occluding the coronary artery in normal healthy rats [44, 45], and the results are shown in Table 1. Pretreatment of animals for 2 days with PLP, unlike vitamin B6, was observed to delay the onset of arrhythmias upon coronary occlusion. In addition, marked alterations in different electrocardiographic parameters, including ST segment, QTc interval, number of premature ventricular contraction(PVC), and incidence of tachycardia as well as mortality, observed in animals at 1 day after occluding the coronary artery were attenuated by PLP (Table 1). The ineffectiveness of vitamin B6 in modifying the coronary occlusion-induced arrhythmias under this acute experimental setting may be related to insufficient dose or duration of vitamin B6 treatment. To gain information if PLP exerts any direct beneficial effects on the I/R-induced changes in cardiac performance, isolated perfused hearts were subjected to 30 min of global ischemia followed by reperfusion for 30 min . The results in Table 2 show that depressions in left ventricle developed pressure (LVDP), rate of pressure development (+dP/dt), and rate of pressure decay (-dP/dt) as well as increase in left ventricular end diastolic pressure due to I/R injury were reduced by PLP in a dose-dependent manner. Because the sarcoplasmic reticulum (SR), by virtue of its ability to regulate intracellular Ca2+, plays a central role in determining the status of cardiac contraction and relaxation , SR Ca2+-uptake and SR Ca2+-release activities of hearts subjected to I/R injury were examined  with or without PLP treatment. The results in Table 2 indicate that the I/R-induced defects in SR Ca2+ transport were attenuated significantly by PLP treatment. These observations provide evidence regarding the potential use of PLP as a therapeutic intervention for the prevention of ischemic heart disease.
Mechanisms of PLP action in the ischemic heart disease
Despite several studies showing the anti-ischemic effects of vitamin B6 and PLP [19, 20–22, 37], the mechanisms of the PLP effect on the ischemic myocardium are far from clear. Because PLP has been reported to inhibit acetyl-CoA carboxylase , which is known to play an important role in synthesis, elongation, and oxidation of long-chain fatty acids, it can be argued that the beneficial effects of PLP are mediated through the reduction of excessive utilization of fatty acids in the ischemic heart. In fact, different PLP-related compounds have been reported to exert cardioprotective effects on the ischemic myocardium by inducing a shift from fatty acid oxidation toward glucose oxidation . Vitamin B6 compounds, including PLP, have also been shown to prevent the oxygen radical generation and lipid peroxidation caused by oxidative stress  and are thus likely to protect the ischemic myocardium through their antioxidant properties. In view of their inhibitory effect on the sympathetic nervous system [51, 52], vitamin B6 and PLP can also be seen to produce anti-ischemic actions on the heart by reducing the sympathetic system activity and associated adrenoceptor-linked signal transduction mechanisms. In addition, the improvement of cardiac function by vitamin B6 and PLP may be occurring through the protection of endothelium in the ischemic heart because vitamin B6 has been reported to improve the endothelial function in cardiac transplant recipients . Nonetheless, the involvement of purinergic receptor blockade in the beneficial actions of PLP on ischemic myocardium is most likely because suramin and various PLP derivatives such as pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) with purinergic P2 receptor antagonist properties have been reported to prevent I/R injury [54–58]. Thus, vitamin B6 and PLP appear to be acting on multiple sites including acetyl-CoA carboxylase, oxidative stress, sympathetic nerves, endothelium, and purinergic receptors for attenuating different abnormalities in the ischemic heart disease.
Although cardiac dysfunction in the heart due to I/R injury has been suggested to be due to the occurrence of oxidative stress and development of intracellular Ca2+ overload [59, 60], there is evidence to suggest that ATP is released in the extracellular space in the ischemic myocardium [52, 61–63]. The extracellular ATP has been shown to induce Ca2+ influx in cardiomyocytes through the activation of purinergic receptors [64–67] and thus may contribute to the development of intracellular Ca2+ overload and subsequent cardiac dysfunction. These events due to I/R injury are shown in Figure 1where the blockade of purinergic receptors by PLP has been indicated to attenuate the I/R-induced cardiac dysfunction. In view of the therapeutic potential of PLP for the prevention of ischemic heart disease , it seems appropriate to review the evidence for the action of PLP at the purinergic receptors in the myocardium. By using an isolated perfused heart, an extensive study was undertaken to examine if the positive inotropic effect of ATP was attenuated by PLP . It was observed that the time-dependent increases in LVDP, +dP/dt, and -dP/dt by ATP were prevented by pretreatment with PLP. The depressant effect of PLP on ATP-induced increase in LVDP was evident at different concentrations of ATP and was observed to be a concentration-dependent action . Furthermore, the antagonistic effect of PLP on ATP-induced increase in LVDP was of a specific nature because PLP did not affect the isoproterenol-induced increase in LVDP, whereas the ATP-induced increase in LVDP was not affected by propranolol, a well-known β-adrenoceptor blocker . In another set of experiments, PLP was observed to depress the ATP-induced increase in [Ca2+]i without affecting the basal level of [Ca2+]i in adult cardiomyocytes . Because the KCl-induced increase in [Ca2+]i in cardiomyocytes was not affected by PLP, it appears that the effect of PLP on ATP-induced changes in [Ca2+]i was of a specific nature. Furthermore, the depressant effect of PLP on ATP-induced increase in [Ca2+]i was evident at different concentrations of ATP, and PLP produced a dose-dependent inhibitory action on an ATP-induced increase in [Ca2+]i  in cardiomyocytes. It was also observed that PLP reduced the maximal binding of ATP at both the high- and low-affinity sites in the sarcolemmal membrane isolated from the myocardium; this action of PLP was simulated by suramin, a well-known purinergic receptor antagonist . In addition, PLP was observed to depress ATP binding at both high- and low-affinity binding sites in the sarcolemmal membrane in a concentration-dependent manner . These observations provide a compelling evidence that PLP is a specific purinergic receptor antagonist. It is thus evident that the improvement of cardiac function in ischemic heart disease upon treatment with PLP is partly mediated through the blockade of purinergic P2 receptors.
It should be mentioned that PLP was found to exert cardioprotective effects with respect to I/R-induced changes in the rate-pressure product, creatine kinase release, and necrotic area of the isolated rate heart . This cardioprotection by PLP was suppressed by treatment with protein kinase inhibitor (H89) and phospholipase C blocker (U73122), indicating the involvement of P2Y receptor-mediated signal transduction in PLP-induced cardiac preconditioning . Purinergic P2Y antagonists, suramin and Reactive Blue, have also been reported to exert ischemic preconditioning in the rat heart . In control hearts, diadenosine pentaphosphate was observed to produce transient coronary vasoconstriction followed by marked vasodilatation, which are alterations modified by I/R . Furthermore, the vasoconstriction response was inhibited by the blockade of P2X receptors by PPADS, whereas the vasodilatation was attenuated by the P2Y blocker, Reactive Blue in the I/R hearts . The blockade of P2X receptors by PPADS was also found to attenuate the exercise-induced pressor reflex in heart failure  as well as after circulatory occlusion . The activation of cardiac sympathetic afferents, which leads to chest pain and reflex cardiovascular response, by the endogenously released ATP during ischemia was blocked by PPADS . ATP-induced alterations in both the excitatory and the inhibitory neurotransmission to cardiac vagal neurons in the brainstem were also prevented by PPADS [72, 73]. Both suramin and PPADS were observed to attenuate ATP-induced arrhythmias in isolated hearts as well as ATP-induced activation of depolarizing membrane currents and increase in [Ca2+]i in isolated cardiomyocytes . PPADS was also reported to reduce the purinergic receptor-mediated permeation of vascular endothelial cells . On the basis of these observations, it is suggested that the cardioprotective effects of the purinergic receptor blockade by PLP, PPADS, suramin, and Reactive Blue in ischemic heart disease may be occurring at the level of neurons, endothelium, coronary vasculature, and cardiomyocytes.
Although ATP and PLP are considered to be broad-based purinergic P2 receptor agonists and antagonists, respectively, some specific P2X and P2Y receptor agonists and antagonists have been identified. In this regard, α,β-methylene ATP and the N-methanocarba derivative of 2-chloro-AMP (MRS-2339) were found to serve as P2X receptor agonists [52, 76, 77], whereas 2-methylthio-ATP and ATPγS were observed to activate P2Y receptor agonists [78–80]. Meanwhile, compound NF-279 was shown to serve as a selective P2X receptor antagonist , whereas agents such as PPADS, suramin, and Reactive Blue are considered to be P2Y receptor antagonists [69, 74, 82]. Although extensive studies have to be carried out to establish the specificity of these purinergic receptor agonists and antagonists, it appears that PLP and P2Y receptor antagonists may produce beneficial effects in reducing the I/R injury [9, 37, 39, 52, 74]. It is pointed out that novel P2X receptor agonists, MRS-2339 as well as 2-methylthio-ATP, have been found to improve the survival of calsequestrin knockout mice with cardiomyopathy . Accordingly, it has been claimed that P2X receptors may represent an important therapeutic target for the treatment of heart failure . In view of the beneficial effects of PLP and related agents in hypertension, atherosclerosis, stroke, I/R injury, myocardial infarction, and congestive heart failure [10, 11, 21, 37, 39], it is suggested that the development of drugs based on both purinergic P2 receptor agonist and antagonist properties should be encouraged for the prevention and treatment of ischemic heart disease.
Because vitamin B6, unlike PLP, was ineffective in attenuating cardiac abnormalities due to the occlusion of coronary artery under acute experimental conditions, it is likely that the reported beneficial effects of vitamin B6 [20–22] in patients with myocardial infarction may be occurring when a sufficient level of its active metabolite (PLP) is achieved in cardiomyocytes. Such an action can be seen to occur through the alterations in cardiac gene expression because moderate variations in intracellular concentration of PLP have been observed to exert profound modulatory effects on steroid-induced gene expression [83, 84]. In fact, the elevation of intracellular PLP levels have been shown to decrease transcriptional responses to glucocorticoid, progesterone, androgen, or estrogen hormones, whereas vitamin B6 deficiency exhibited enhanced responsiveness to steroid hormones . These gene expression-modulatory effects of PLP were reported to involve the interruption of functional interactions between steroid hormone receptors and the nuclear transcription factor NF1 [83–87]. PLP has been shown to depress the binding of steroid hormone receptor to DNA, inhibit the ATP-stimulated translocation promoter, and serve as a transcriptional coregulator [88–90]. PLP as an active form of vitamin B6 is not only involved in a multitude of reactions including decarboxylation and transamination, it can also inhibit DNA polymerases, and several steroid receptors . From the foregoing discussion on the interaction of purinergic P2 receptor agonists and antagonists, it is evident that PLP acts on purinergic receptors in the cell membrane and intracellularly on the nucleus.
In this article, we have reviewed the existing literature concerning the beneficial effects of vitamin B6 and its metabolite, PLP, in heart disease. We have presented the evidence to show that vitamin B6 may not exert its therapeutic effects in the ischemic heart disease directly but PLP may attenuate the myocardial infarction-induced arrhythmias. The attenuation of cardiac dysfunction due to I/R injury by PLP was associated with the reduction of I/R-induced defects in SR Ca2+-transport activities. Because of the observations that PLP markedly suppressed the action of ATP on cardiac contractile activity, it is evident that this agent may serve as a purinergic receptor antagonist. This view is further attested by findings that the ATP-induced increase in [Ca2+]i in cardiomyocytes, as well as ATP binding at both high- and low-affinity sites in the sarcolemma, was reduced by PLP. Such information supports our contention that the preventive action of PLP in attenuating cardiac complications, associated with ischemic heart disease, may be a consequence of the blockade of purinergic receptors.
The research reported in this article was supported by a grant from the Canadian Institutes of Health Research. The infrastructural support for this project was provided by the St. Boniface Hospital Research Foundation.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. J Am Med Assoc 2002;287:3116–26.
Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc 1993;270:2693–8.
Rogers KS, Mohan C. Vitamin B6 and diabetes. Biochem Med Metab Biol 1994;52:10–7.
Cohen KL, Gorecki G, Silverstein SB, Ebersole JS, Solomon LR. Effect of pyridoxine (vitamin B6) on diabetic patients with peripheral neuropathy. J Am Podiatry Assoc 1984;74:394–7.
Ellis JM, Folkers K, Minadeo M, Van Buskirk R, Xia LJ, Tamagawa H. A deficiency of vitamin B6 is a plausible molecular basis of the retinopathy of patients with diabetes mellitus. Biochem Biophys Res Commun 1991;179:615–9.
Calvaresi E, Bryan JB. Vitamins, cognition and aging: a review. J Gerontol B Psychol Sci Soc Sci 2001;56:P327–39.
Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr 2002;132:1345–56.
Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. J Am Med Assoc 2002;287:3127–9.
Dhalla NS, Sethi R, Dakshinamurti K. Treatment of cardiovascular and related pathologies. US Patent 6,043,259, March 28, 2000.
Dakshinamurti K, Sethi R, Dhalla NS. Treatment of iatrogenic and age-related hypertension and pharmaceutical composition useful therein, United States Patent Number 6,051,587, April 18, 2000.
Rhinehart JF, Greenberg LD. Arteriosclerotic lesions in pyridoxine-deficient monkeys. Am J Pathol 1949;25:481–91.
Murry JC, Fraser DR, Levine CI. The effect of pyridoxine on lysyl oxidase activity in the chick. Exp Mol Pathol 1978;28:301–8.
Tehlivets O. Homocysteine as a risk factor for atherosclerosis: is its conversion to s-adenosyl-L-homocysteine the key to deregulated lipid metabolism. J Lipids 2011;2011:702853.
Gopinath B, Flood VM, Rochtchina E, Thiagalingam A, Mitchell P. Serum homocysteine and folate but not vitamin B12 are predicators of CHD mortality in older adults. Eur J Cardiovasc Prevent Rehab 2011;19:1420–9.
Washio T, Nomoto K, Watanabe I, Tani S, Nagao K, Hirayama A. Relationship between plasma homocysteine and congestive heart failure in patients with acute myocardial infarction. Homocysteine and congestive heart failure. Int Heart J 2011;52:224–8.
Agoston-Coldea L, Mocan T, Gatfosse M, Lupu S, Dumitrascu DL. Plasma homocysteine and the severity of heart failure in patients with previous myocardial infarction. Cardiol J 2011;18:55–62.
Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993;57:47–53.
Herzlich BC. Plasma homocysteine, folate, vitamin B6 and coronary artery disease risk. J Am Coll Nutr 1996;15:109–10.
Serfontein WJ, Ubbink JB, De Villiers LS, Rapley CH, Becker PJ. Plasma pyridoxal-5-phosphate level as risk index for coronary artery disease. Atherosclerosis 1985;55:357–61.
Kok FJ, Schrijver J, Hofman A, Wittman JC, Kruyssen D, Remme WJ, et al. Low vitamin B6 status in patients with acute myocardial infarction. Am J Cardiol 1989;63:513–6.
Ellis JM, McCully KS. Prevention of myocardial infarction by vitamin B6. Res Commun Mol Pathol Pharmacol 1995;89: 208–20.
Chasan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, et al. B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996;15:136–43.
Selhub J, Jacques PF, Bostom AG, Wilson PW, Rosenberg IH. Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. Public Health Rev 2000;28:117–45.
Roubenoff R, Roubenoff RA, Selhub J, Nadeau MR, Cannon JG, Freeman LM, et al. Abnormal vitamin B6 status in rheumatoid cachexia. Association with spontaneous tumor necrosis factor alpha production and markers of inflammation. Arthritis Rheum 1995;38:105–9.
Miller JW, Green R, Mungas DM, Reed BR, Jagust WJ. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology 2002;58:1471–5.
Cabrini L, Bergami R, Florentini D, Marchetti M, Landi L, Tolomelli B. Vitamin B6 deficiency affects antioxidant defences in rat liver and heart. Biochem Mol Biol Int 1998;46:689–97.
Friso S, Jacques PF, Wilson PW, Rosenberg IH, Selhub J. Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation 2001;103: 2788–91.
Chen CH, Lin PT, Liaw YP, Ho CC, Tsai TP, Chou MC, et al. Plasma pyridoxal 5′-phosphate and high-sensitivity C-reactive protein are independently associated with an increased risk of coronary artery disease. Nutrition 2008;24:239–44.
Midttun O, Ulvik A, Ringdal Pedersen E, Ebbing M, Bleie O, Schartum-Hansen H, et al. Low plasma vitamin B-6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation. J Nutr 2011;141:611–7.
Brophy MH, Siiteri PK. Pyridoxal phosphate and hypertensive disorders of pregnancy. Am J Obstet 1975;121:1075–9.
Kleiger JA, Altschuler CH, Krakow G, Hollister C. Abnormal pyridoxine metabolism in toxemia of pregnancy. Ann NY Acad Sci 1969;166:288–96.
Paulose CS, Dakshinamurti K, Packer S, Stephens NL. Sympathetic stimulation and hypertension in the pyridoxine-deficient adult rat. Hypertension 1988;11:387–91.
Lal KJ, Dakshinamurti K, Thilveris J. The effect of vitamin B6 on the systolic blood pressure of rats in various animal models of hypertension. J Hypertens 1996;14:355–63.
Viswanathan M, Paulose CS, Lal KJ, Sharma SK, Dakshinamurti K. Alterations in brainstem alpha 2 adrenoreceptor activity in pyridoxine-deficient rat model of hypertension. Neurosci Lett 1990;111:201–5.
Lal KJ, Dakshinamurti K. Regulation of calcium influx into vascular smooth muscle by vitamin B6. Clin Exp Hypertens 1993;15:489–500.
Dakshinamurti K, Wang X, Musat S, Dandekar M, Dhalla NS. Alterations of KCl- and ATP-induced increase in [Ca2+]i in cardiomyocytes from vitamin B6-deficient rats. Can J Physiol Pharmacol 1998;76:837–42.
Kandzari DE, Dery JP, Armstrong PW, Douglas DA, Zettler ME, Hidinger GK, et al. MC-1 (pyridoxal 5′-phosphate): novel therapeutic applications to reduce ischaemic injury. Expert Opin Investig Drugs 2005;14:1435–42.
Wang CX, Yang T, Noor R, Shuaib A. Role of MC-1 alone and in combination with tissue plasminogen activator in focal ischemic brain injury in rats. J Neurosurg 2005;103:165–9.
Kandzari DE, Labinaz M, Cantor WJ, Madan M, Gallup DS, Hasselblad V, et al. Reduction of myocardial ischemic injury following coronary intervention (the MC-1 to Eliminate Necrosis and Damage trial). Am J Cardiol 2003;92:660–4.
Tardif JC, Carrier M, Kandzari DE, Emery R, Cote R, Heinonen T, et al. Effects of pyridoxal-5′-phosphate (MC-1) in patients undergoing high-risk coronary artery bypass surgery: results of the MEND-CABG randomized study. J Thorac Cardiovasc Surg 2007;133:1604–11.
Carrier M, Emery R, Kandzari DE, Harrington R, Guertin MC, Tardif JC. Protective effect of pyridoxal-5-phosphate (MC-1) on perioperative myocardial infarction is independent of aortic cross clamp time: results from the MEND-CABG trial. J Cardiovasc Surg 2008;49:249–53.
Mehta RH, Alexander JH, Emery R, Ellis SJ, Hasselblad V, Khalil A, et al. A randomized, double-blind, placebo-controlled, multicenter study to evaluate the cardioprotective effects of MC-1 in patients undergoing high-risk coronary artery bypass graft surgery: MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery Trial (MEND-CABG) II–study design and rationale. Am Heart J 2008;155:600–8.
MEND-CABG II Investigators. Efficacy and safety of pyridoxal 5′-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial. J Am Med Assoc 2008;299:1777–87.
Ren B, Lukas A, Shao Q, Guo M, Takeda N, Aitken RM, et al. Electrocardiographic changes and mortality due to myocardial infarction in rats with or without imidapril treatment. J Cardiovasc Pharmacol Ther 1998;3:11–22.
Barta J, Sanganalmath SK, Kumamoto H, Takeda N, Edes I, Dhalla NS. Antiplatelet agents sarpogrelate and cilostazol affect experimentally-induced ventricular arrhythmias and mortality. Cardiovasc Toxicol 2008;8:127–35.
Takeda S, Mochizuki S, Saini HK, Elimban V, Dhalla NS. Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemic-reperfused rat hearts. J Appl Physiol 2005;99:999–1005.
Dhalla NS, Wang X, Beamish RE. Intracellular calcium handling in normal and failing hearts. Exp Clin Cardiol 1996;1:7–20.
Lee WM, Elliot JE, Brownsey RW. Inhibition of acetyl-CoA carboxylase isoforms by pyridoxal phosphate. J Biol Chem 2005;280:41835–43.
Pham V, Zhang W, Chen V, Whitney T, Yao J, Froese D, et al. Design and synthesis of novel pyridoxine 5′-phosphonates as potential antiischemic agents. J Med Chem 2003;46:3680–7.
Kannan K, Jain SK. Effect of vitamin B6 on oxygen radicals, mitochondrial membrane potential, and lipid peroxidation in H2O2-treated U937 monocytes. Free Radic Biol Med 2004;36:423–8.
Cui J, Leuenberger UA, Blaha C, King NC, Sinoway LI. Effect of P2 receptor blockade with pyridoxine on sympathetic response to exercise pressor reflex in humans. J Physiol 2011;589:685–95.
Fu LW, Longhurst JC. A new function for ATP: activating cardiac sympathetic afferents during myocardial ischemia. Am J Physiol Heart Circ Physiol 2010;299:H1762–71.
Miner SE, Cole DC, Evrovski J, Forrest Q, Hutchison S, Holmes K, et al. Pyridoxine improves endothelial function in cardiac transplant recipients. J Heart Lung Transplant 2001;20:964–9.
Lambrecht G, Braun K, Damer M, Ganso M, Hildebrandt C, Ullmann H, et al. Structure-activity relationships of suramin and pyridoxal-5′-phosphate derivatives as P2 receptor antagonists. Curr Pharm Des 2002;8:2371–9.
Millart H, Alouane L, Oszust F, Chevallier S, Robinet A. Involvement of P2Y receptors in pyridoxal-5′-phosphate-induced cardiac preconditioning. Fundam Clin Pharmacol 2009;23: 279–92.
Trezise DJ, Bell NJ, Khakh BS, Michel AD, Humphrey PA. P2 purinoceptor antagonist properties of pyridoxal-5-phosphate. Eur J Pharmacol 1994;259:295–300.
Trezise DJ, Kennedy I, Humphrey PA. The use of antagonists to characterize the receptors mediating depolarization of the rat isolated vagus nerve by alpha, beta-methylene adenosine 5′-triphosphate. Br J Pharm 1994;112:282–8.
Wang X, Dakshinamurti K, Musat S, Dhalla NS. Pyridoxal 5′-phosphate is an ATP-receptor antagonist in freshly isolated rat cardiomyocytes. J Mol Cell Cardiol 1999;31:1063–72.
Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res 2000;47:446–56.
Dhalla NS, Golfman L, Takeda S, Takeda N, Nagano M. Evidence for the role of oxidative stress in acute ischemic heart disease: a brief review. Can J Cardiol 1999;15:587–93.
Burstock G. Purinergic nerves. Pharmacol Rev 1972;24:509–81.
Clemens MG, Forrester T. Appearance of adenosine triphosphate in the coronary sinus effluent from isolated working rat heart in response to hypoxia. J Physiol 1981;312:143–58.
Forrester T, William CA. Release of adenosine triphosphate from isolated adult heart cells in response to hypoxia. J Physiol 1977;268:371–90.
Christie A, Sharma VK, Sheu SS. Mechanism of extracellular ATP-induced increase of cytosolic Ca2+ concentration in isolated rat ventricular myocytes. J Physiol 1992;445:369–88.
De Young M, Scarpa A. ATP receptor-induced Ca2+ transients in cardiac myocytes: sources of mobilized Ca2+. Am J Physiol Cell Physiol 1989;257:C750–8.
Nijjar MS, Hart LL, Panagia V, Dhalla NS. Characterization of ATP-induced elevation in intracellular Ca2+ in rat cardiomyocytes. Cardiovasc Pathobiol 1996;1:152–9.
Saini HK, Elimban V, Dhalla NS. Attenuation of extracellular ATP response in cardiomyocytes isolated from hearts subjected to ischemia-reperfusion. Am J Physiol Heart Circ Physiol 2005;289:H614–23.
Ninomiya H, Otani H, Lu K, Uchiyama T, Kido M, Imamura H. Complementary role of extracellular ATP and adenosine in ischemic preconditioning in the rat heart. Am J Physiol Heart Circ Physiol 2002;282:H1810–20.
Garcia-Villalon AL, Monge L, Fernandez N, Salcedo A, Narvaez-Sanchez R, Dieguez G. Coronary response to diadenosine pentaphosphate after ischaemia-reperfusion in the isolated rat heart. Cardiovasc Res 2009;81:336–43.
Wang HJ, Li YL, Gao L, Zucker IH, Wang W. Alteration in skeletal muscle afferents in rats with chronic heart failure. J Physiol 2010;588:5033–47.
Kindig AE, Hayes SG, Kaufman MP. Purinergic 2 receptor blockade prevents the responses of group IV afferents to post-contraction circulatory occlusion. J Physiol 2007;578:301–8.
Dergacheva O, Wang X, Kamendi H, Cheng Q, Pinol RM, Jameson H, et al. 5HT2 receptor activation facilitates P2X receptor mediated excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguous. Neuropharmacology 2008;54: 1095–102.
Jameson HS, Pinol RA, Mendelowitz D. Purinergic P2X receptors facilitate inhibitory GABAergic and glycinergic neurotransmission to cardiac vagal neurons in the nucleus ambiguous. Brain Res 2008;1224:53–62.
Gurung IS, Kalin A, Grace AA, Huang CL. Activation of purinergic receptors by ATP induces ventricular tachycardia by membrane depolarization and modification of Ca2+ homeostatis. J Mol Cell Cardiol 2009;47:622–33.
Tanaka N, Kawasaki K, Nejime N, Kubota Y, Takahashi K, Hashimoto M, et al. P2Y receptor-mediated enhancement of permeation requires Ca2+-signalling in vascular endothelial cells. Clin Exp Pharmacol Physiol 2003;30:649–52.
Shen JB, Cronin C, Sonin D, Joshi BV, Gongora Nieto M, Harrison D, et al. P2X purinergic receptor-mediated ionic current in cardiac myocytes of calsequestrin model of cardiomyopathy: implications for the treatment of heart failure. Am J Physiol Heart Circ Physiol 2007;292:H1077–84.
Nakamura T, Iwanaga K, Murata T, Hori M, Ozaki H. ATP induces contraction mediated by the P2Y(2) receptor in rat intestinal subepithelial myofibroblasts. Eur J Pharmacol 2011;657:152–8.
Fischer Y, Becker C, Loken C. Purinergic inhibition of glucose transport in cardiomyocytes. J Biol Chem 1999;274:755–61.
Anikina TA, Bilalova GA, Zverev AA, Sitdikov FG. Role of P2X and P2Y receptors in rat myocardial contractility during ontogeny. Bull Exp Biol Med 2007;143:695–8.
Tanaka N, Nejime N, Kubota Y, Kagota S, Yudo K, Nakamura K, et al. Myosin light chain kinase and Rho-kinase participate in P2Y receptor-mediated acceleration of permeability through the endothelial cell layer. J Pharm Pharmacol 2005;57:335–40.
Yao ST, Lawrence AJ. Purinergic modulation of cardiovascular function in the rat locus coeruleus. Br J Pharmacol 2005;145:342–52.
Payne SJ, Brown CA, Benjamin IS, Alexander B. Pyridoxalphosphate-6-azophenyl-2,4-disulphonic acid (PPADS) as a tool for differentiation of P2Y2-receptor-mediated vasorelaxation in guinea pig aorta. Methods Find Exp Clin Pharmacol 2002;24:351–6.
Tully DB, Allgood VE, Cidlowski JA. Modulation of steroid receptor-mediated gene expression by vitamin B6. FASEB J 1994;8:343–9.
Compton MM, Cidlowski JA. Vitamin B6 and glucocorticoid action. Endocr Rev 1986;7:140–8.
Allgood VE, Powell-Oliver FE, Cidlowski JA. The influence of vitamin B6 on the structure and function of the glucocorticoid receptor. Ann NY Acad Sci 1990;585:452–65.
Allgood VE, Powell-Oliver FE, Cidlowski JA. Vitamin B6 influences glucocorticoid receptor-dependent gene expression. J Biol Chem 1990;265:12424–33.
Allgood VE, Cidlowski JA. Vitamin B6 modulates transcriptional activation by multiple members of the steroid hormone receptor superfamily. J Biol Chem 1992;267:3819–24.
Ozyhar A, Kiltz HH, Pongs O. Pyridoxal phosphate inhibits the DNA-binding activity of the ecdysteroid receptor. Eur J Biochem 1990;192:167–74.
Okamoto K, Isohashi F, Ueda K, Sakamoto Y. Properties of an adenosine triphosphate-stimulated factor that enhances the nuclear binding of activated glucocorticoid-receptor complex: binding to histone agarose. Endocrinology 1989;124: 675–80.
Huq MD, Tsai NP, Lin YP, Higgins L, Wei LN. Vitamin B6 conjugation to nuclear corepressor RIP140 and its role in gene regulation. Nat Chem Biol 2007;3:161–5.
Bolander FF. Vitamins: not just for enzymes. Curr Opin Invest Drugs 2006;7:912–5.