Vitamin C is considered to be a very efficient water-soluble antioxidant, for which several new cardiovascular properties were recently described. The aim of this study was to determine in vivo the effects of a severe depletion of vitamin C on cardiac and vascular variables and reperfusion arrhythmias. For this purpose, we used a mutant strain of Wistar rats, osteogenic disorder Shionogi (ODS). After 15 d of consuming a vitamin C-deficient diet, ODS rats had a 90% decrease in plasma and tissue levels of ascorbate compared with ODS vitamin C-supplemented rats and normal Wistar rats. However, plasma antioxidant capacity, proteins, alpha-tocopherol, urate, catecholamines, lipids, and nitrate were not influenced by the vitamin C deficiency in ODS rats. Moreover, there was no difference between ODS vitamin C-deficient and -supplemented rats in heart rate and arterial pressure. After 5 min of an in vivo regional myocardial ischemia, various severe arrhythmias were observed, but their intensities were not modified by vitamin C in vitamin C-deficient ODS rats. The vascular reactivity, measured in vitro on thoracic arteries, was not altered by ascorbate deficiency in ODS rats. These unexpected results suggest that unidentified compensatory mechanisms play a role in maintaining normal cardiac function and vascular reactivity in vitamin C-deficient rats.

Vitamin C is considered to be a very efficient water-soluble antioxidant, for which several new cardiovascular properties were recently described. The aim of this study was to determine in vivo the effects of a severe depletion of vitamin C on cardiac and vascular variables and reperfusion arrhythmias. For this purpose, we used a mutant strain of Wistar rats, osteogenic disorder Shionogi (ODS). After 15 d of consuming a vitamin C–deficient diet, ODS rats had a 90% decrease in plasma and tissue levels of ascorbate compared with ODS vitamin C–supplemented rats and normal Wistar rats. However, plasma antioxidant capacity, proteins, -tocopherol, urate, catecholamines, lipids, and nitrate were not influenced by the vitamin C deficiency in ODS rats. Moreover, there was no difference between ODS vitamin C–deficient and –supplemented rats in heart rate and arterial pressure. After 5 min of an in vivo regional myocardial ischemia, various severe arrhythmias were observed, but their intensities were not modified by vitamin C in vitamin C–deficient ODS rats. The vascular reactivity, measured in vitro on thoracic arteries, was not altered by ascorbate deficiency in ODS rats. These unexpected results suggest that unidentified compensatory mechanisms play a role in maintaining normal cardiac function and vascular reactivity in vitamin C–deficient rats. J. Nutr. 134: 729–735, 2004.

Spin traps might exert antioxidant cardioprotective effects during myocardial ischaemia-reperfusion where free radicals are thought to be responsible for the occurrence of reperfusion injury. The aim of our study was to investigate the effects of two new alpha-phenyl N-tert-butylnitrone (PBN)-derived beta-phosphorylated nitrones: 2-N-oxy-N-[benzylidène amino] diéthyl propyl-2-phosphate (PPN) and 1-diethoxyphosphoryl-1-methyl-N-[(1-oxido-pyridin-1-ium-4-yl) methylidene] ethylamine N-oxide (4-PyOPN) compared with PBN on (1) the evolution of cardiovascular parameters and (2) the postischaemic recovery. Anaesthetized rats were injected with 120 micro mol/kg of the nitrones or 14 micro mol/kg of amiodarone, used as a reference antidysrhythmic drug. Ischaemia was induced in vivo through ligation of the left anterior descending coronary artery for 5 min followed by 15 min of reperfusion after release. Cardiovascular parameters and occurrence of ventricular premature beats (VPB), ventricular tachycardia (VT) and fibrillation (VF) were recorded throughout the experiment. Under nonischaemic conditions, none of the three spin traps was shown to modify cardiovascular parameters during the 25-min measurement period. Solvent-treated (NaCl 0.9%) animals challenged with ischaemia-reperfusion exhibited 39 +/- 10 VPB, 156 +/- 39 s of VT and 60% mortality caused by sustained VF. Nitrones improved slightly postischaemic recovery, reducing the occurrence of VF and mortality to 33% whereas amiodarone injection totally suppressed rhythm disturbances and mortality. Our study has shown only limited antidysrhythmic cardioprotective effects of PBN-derived beta-phosphorylated nitrones during reperfusion after a regional myocardial ischaemia but also minor antioxidant properties of these spin trapping agents.

Studies from our laboratory have demonstrated rapid ( < 1 min) non-genomic activation of Na+-H+ exchange, K+ recycling, PKC activity and a PKC-dependent Ca2+ entry through L-type Ca2+ channels specifically by mineralocorticoids in distal colon. Aldosterone directly stimulates the activity of the PKCα isoform (but not PKCδ, PKCϵ and PKCζ) in a cell-free assay system containing only purified commercially available enzyme, appropriate substrate peptide, co-factors and lipid vesicles. The primary ion transport target of the non-genomic signal transduction cascade elicited by aldosterone in epithelia is the Na+-H+ exchanger. In isolated colonic crypts, aldosterone produced a PKCα sensitive intracellular alkalinisation within 1 min of hormone addition. Intracellular alkalinisation upregulates an ATP-dependent K+ channel, which is involved in K+ recycling to maintain the electrical driving force for Na+ absorption, while inhibiting a Ca2+ -dependent K+ channel, which generates the charge balance for Cl− secretion. The non-genomic response to aldosterone in distal colon appears to enhance the capacity for absorption while down-regulating the potential for secretion. We have also demonstrated rapid (< 1 min) non-genomic activation of Na+-H+ exchange, K+ recycling, PKCα activity, and a PKCδ- and PKA-dependent Ca2+ entry through di-hydropyridine-blockable Ca2+ channels specifically by 17β-estradiol in distal colon. These rapid effects are female gender specific and are insensitive to inhibitors of the classical estrogen receptor (ER). 17β-Estradiol directly stimulated the activity of both PKCδ and PKCα (but not PKCϵ or PKCζ) in a cell-free assay system. E2 rapidly inhibited basolateral KCa channel activity which would be expected to result in an acute inhibition of Cl− secretion. Physiological concentrations of E2 (0.1–10 nM) reduced both basal and secretagogue-induced Cl− secretion. This anti-secretory effect of E2 is sensitive to PKC inhibition, intracellular Ca2+ chelation, and is female gender specific and insensitive to inhibitors of the classical ER. These observations link rapid non-genomic activation of second messengers with a rapid gender-specific physiological effect in the whole tissue. Aldosterone and E2 differ in their protein kinase signal transduction and both hormones stimulate specific PKC isoforms indicating both common and divergent signalling systems for salt-retaining steroid hormones. The physiological function of non-genomic effects of aldosterone and estradiol is to shift the balance from net secretion to net absorption in a pluripotential epithelium.

Fifty years ago, Hans Ussing described the mechanism by which ions are actively transported across frog skin. Since then, an enormous amount of effort has been invested in determining the cellular and molecular specifics of the transport mechanisms and their regulatory pathways. Ion transport in high-resistance epithelia is regulated by a variety of hormonal and non-hormonal factors. In vertebrates, steroid hormones such as mineralocorticoids, glucocorticoids and estrogens are major regulators of ion and water transport and hence are central to the control of extracellular fluid volume and blood pressure. Steroid hormones act through nuclear receptors to control the transcriptional activity of specific target genes, such as ion channels, ion transporters and ion pumps. These effects are observed after a latency of several hours and can last for days leading to cellular differentiation that allows a higher transport activity. This pathway is the so-called genomic phase. However, in the past 10 years, it has become apparent that steroid hormones can regulate electrolyte and water transport in tight epithelia independently of the transcription of these ion channels and transporters by regulating ion transporter activity in a non-genomic fashion via modulation of various signal transduction pathways. The molecular mechanisms underlying the steroid hormone-induced activation of signal transduction pathways such as protein kinase C (PKC), protein kinase A (PKA), intracellular calcium, intracellular pH and mitogen-activated protein kinases (MAPKs) and how non-genomic activation of these pathways influences epithelial ion transport will be discussed in this review.