Roger Corder

Health: Endothelin-1 synthesis reduced by red wine

Statistical evidence of reduced coronary heart disease in areas of high wine consumption has led to the widespread belief that wine affords a protective effect. Although moderate drinking of any alcohol helps to reduce the incidence of coronary heart disease, there is no clear evidence that red wine confers an additional benefit. Here we show that red wines strongly inhibit the synthesis of endothelin-1, a vasoactive peptide that is crucial in the development of coronary atherosclerosis. Our findings indicate that components specific to red wine may help to prevent coronary heart disease.

Oenology: red wine procyanidins and vascular health.

Regular, moderate consumption of red wine is linked to a reduced risk of coronary heart disease and to lower overall mortality, but the relative contribution of wines alcohol and polyphenol components to these effects is unclear. Here we identify procyanidins as the principal vasoactive polyphenols in red wine and show that they are present at higher concentrations in wines from areas of southwestern France and Sardinia, where traditional production methods ensure that these compounds are efficiently extracted during vinification. These regions also happen to be associated with increased longevity in the population.

Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF

1 We have compared the receptors mediating the contractions of rings of rat thoracic aorta or rabbit pulmonary artery and rat stomach strips in response to the endothelin/sarafotoxin (ET/SX) family of peptides and to those mediating endothelium‐dependent vasodilatations within the isolated perfused mesentery of the rat. To discriminate ETA receptors from ETB receptors we have used the criteria that ET‐1 is more active than SX6c on ETA receptors, and that the ET/SX peptides are equiactive on ETB receptors. We have also assessed the effects of the ETA receptor‐selective antagonist BQ‐123, and the non‐selective ET receptor antagonist PD 142893 on the responses of each preparation to the ET/SX peptides. 2 ET‐1‐induced constrictions of the rat thoracic aorta (EC50 3 × 10−10m), a prototypic ETA receptor‐mediated response, or isolated perfused mesentery of the rat were antagonized by BQ‐123 (10−5 m) or PD 142893 (10−5 m). SX6c did not constrict either the rat isolated perfused mesentery or the rat thoracic aorta. Thus, ETA receptors mediate these constrictions. 3 ET‐1 and SX6c were approximately equipotent in constricting rabbit pulmonary artery rings (EC50s 3–6 × 10−10 m). Neither BQ‐123 (10−5 m) nor PD 142893 antagonized the contractions induced by ET‐1. These effects suggest mediation by ETB receptors but PD 142893 (10−5 m) did give a 3 fold antagonism of constrictions induced by SX6c. 4 SX6c was more potent than ET‐1 in contracting the rat stomach strip (threshold concentrations 10−10 and 3 × 10−10 m). Contractions to ET‐1 or SX6c were unaffected by BQ‐123 (10−5 m), again indicative of ETB receptor‐mediated events. PD 142893 (10−5 m) was ineffective against ET‐1 but produced a 3 fold antagonism of SX6c. 5 In the rat isolated perfused mesentery ET‐1 or SX6c (0.3–300 pmol) were equipotent in producing dose‐related vasodilatations that were unaffected by BQ‐123 (10−6 m), indicative of an ETB receptor‐mediated response. In contrast to the other ETB‐mediated responses, PD 142893 (10−6 m) strongly antagonized these vasodilatations. 6 Thus, ETA receptors mediate constrictions of the rat thoracic aorta and rat isolated perfused mesentery whereas ETB receptors mediate constrictions of the rabbit pulmonary artery and rat stomach strip and endothelium‐dependent dilatations within the mesentery. However, within the group of ETB receptor‐mediated responses, endothelium‐dependent vasodilatations are sensitive to PD 142893, whereas contractions of the isolated smooth muscle preparations are not. Thus, the receptor present on the endothelium responsible for the release of nitric oxide in response to the ET/SX peptides is most probably different from that present on smooth muscle that mediates BQ‐123‐insensitive contractions.

Osteoprotegerin as a Predictor of Coronary Artery Disease and Cardiovascular Mortality and Morbidity

Osteoprotegerin (OPG) is a glycoprotein that acts as a decoy receptor for receptor activator of nuclear factor kappaB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand. The OPG/RANKL/receptor activator of nuclear factor kappaB axis plays an important regulatory role in the skeletal, immune, and vascular systems. The protective role of OPG, in animal models, against vascular calcification has not been replicated in human trials; moreover, increased OPG levels have been consistently associated with the incidence and prevalence of coronary artery disease. There seems to be some dichotomy in the role of OPG, RANKL, and tumor necrosis factor-related apoptosis-inducing ligand in atherosclerosis and plaque stability. In this review, we integrate the findings from some of the important studies and try to draw conclusions with a view to gaining some insight into the complex interactions of the OPG/RANKL/receptor activator of nuclear factor kappaB axis and tumor necrosis factor-related apoptosis-inducing ligand in the pathophysiology of atherosclerosis.

Increased volume of epicardial fat is an independent risk factor for accelerated progression of sub-clinical coronary atherosclerosis

BACKGROUND Epicardial adipose tissue (EAT), a metabolically active visceral fat depot surrounding the heart, has been implicated in the pathogenesis of coronary artery disease (CAD) through possible paracrine interaction with the coronary arteries. We examined the association of EAT with metabolic syndrome and the prevalence and progression of coronary artery calcium (CAC) burden. METHODS CAC scan was performed in 333 asymptomatic diabetic patients without prior history of CAD (median age 54 years, 62% males), followed by a repeat scan after 2.7±0.3 years. CAC progression was defined as >2.5mm(3) increase in square root transformed volumetric CAC scores. EAT and intra-thoracic fat volumes were quantified using a dedicated software (QFAT), and were examined in relation to the metabolic syndrome, baseline CAC scores and CAC progression. RESULTS Both epicardial and intra-thoracic fat were associated with metabolic syndrome after adjustment for conventional cardiovascular risk factors, but the association was attenuated after additional adjustment for body mass index. EAT, but not intra-thoracic fat, showed significant association with baseline CAC scores (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.04-1.22, p=0.04) and CAC progression (OR 1.12, 95% CI 1.05-1.19, p<0.001) after adjustment for conventional measures of obesity and risk factors. CONCLUSION EAT volume measured on non-contrast CT is an independent marker for the presence and severity of coronary calcium burden and also identifies individuals at increased risk of CAC progression. EAT quantification may thus add to the prognostic value of CAC imaging.

Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Abnormal elevation of hepatic gluconeogenesis is central to the onset of hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). Metformin corrects hyperglycaemia through inhibition of gluconeogenesis, but its mechanism of action is yet to be fully described. SIRT1 and GCN5 (listed as KAT2A in the MGI Database) have recently been identified as regulators of gluconeogenic gene expression through modulation of levels and activity of the coactivators cAMP-response element binding protein-regulated transcription coactivator 2 (TORC2 or CRTC2 as listed in the MGI Database) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha or PPARGC1A as listed in the MGI Database). We report that in db/db mice, metformin (250 mg/kg per day; 7 days) increases hepatic levels of GCN5 protein and mRNA compared with the untreated db/db mice, as well as increases levels of SIRT1 protein and activity relative to controls and untreated db/db mice. These changes were associated with reduced TORC2 protein level and decreased gene expression and activation of the PGC1alpha gene target phosphoenolpyruvate carboxykinase, and lower plasma glucose and insulin. Inhibition of SIRT1 partially blocked the effects of metformin on gluconeogenesis. SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD(+). Moreover, levels of GCN5 were dramatically reduced in db/db mice compared with the controls. This indicates that loss of GCN5-mediated inhibition of gluconeogenesis appears to constitute a major mechanism for the onset of abnormally elevated hepatic glucose production in db/db mice. In conclusion, induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin. In addition, these data identify induction of hepatic GCN5 as a potential therapeutic strategy for treatment of T2DM.

A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy

Summary Untreated streptozotocin-diabetic (7 weeks duration) rats showed reductions (all p < 0.01; percentages in brackets) in motor and sensory nerve conduction velocity (MNCV; 14 %, SNCV; 17 %) and in sciatic nerve contents of nerve growth factor (NGF; 57 %), substance P (SP; 53 %) and neuropeptide Y (NPY; 39 %). Treatment with a γ-linolenic acid-α-lipoic acid conjugate (GLA-LA; 35 mg · day–1· rat–1) attenuated (p < 0.05) these reductions to MNCV (8 %), SNCV (5 %), NGF (19 %), SP (23 %), NPY (20 %), such that the values in GLA-LA-treated diabetic rats did not differ significantly from those of control non-diabetic animals. Treatment with alpha-lipoic acid alone at 100 mg/kg i. p. was without effect on these variables except for NGF (33 % reduction, p < 0.05) and treatment with the antioxidant, butylated hydroxytoluene (1.5 % dietary supplement) did not affect any deficits. These data show that GLA-LA is effective in improving both electrophysiological and neurochemical correlates of experimental diabetic neuropathy. [Diabetologia (1998) 41: 839–843]

A Physiological Role for Neuropeptide Y in Regulating the Estrogen/Progesterone Induced Luteinizing Hormone Surge in Ovariectomized Rats

To test the hypothesis that neuropeptide Y (NPY) is involved in the regulation of the estrogen/progesterone-induced luteinizing hormone (LH) surge in ovariectomized rats, we passively immunized animals against NPY by administering purified immunoglobulins raised against the peptide directly into the central nervous system. Ovariectomized rats were prepared with an intracerebroventricular (i.c.v.) guide cannula and an intravenous catheter prior to experimentation. On day 1 of the experiment the animals received a 5-microliters i.c.v. injection of a highly specific immunoglobulin against NPY (NPY-ab) and a 50-micrograms injection of estradiol benzoate. The antibody injection was repeated on days 2 and 3 of the experiment. On day 3, animals received a 2.5-mg injection of progesterone. Control animals were treated in exactly the same fashion except that a nonspecific control immunoglobulin was injected i.c.v. rather than the NPY-ab. As expected, the steroid-primed animals treated with the control antibodies exhibited large surges in LH secretion approximately 4 h following the progesterone injection. Concentrations rose from 4.2 +/- 1.0 to 27.9 +/- 9.9 ng/ml. In marked contrast, the NPY-ab-treated animals demonstrated no increase in LH concentrations. Baseline values were 3.1 +/- 0.3 ng/ml and remained unchanged (maximum concentrations were 3.8 +/- 1.9 ng/ml) following the progesterone injection. These results demonstrate that hypothalamic NPY plays a role in mediating the estradiol/progesterone-induced gonadotropin surge and suggests that this neuropeptide plays a physiological role in normal ovulatory surges of LH and FSH.

Incomplete inhibition of the pressor effects of endothelin‐1 and related peptides in the anaesthetized rat with BQ‐123 provides evidence for more than one vasoconstrictor receptor

1 The effects of the ETA receptor antagonist, BQ‐123 on blood pressure changes induced by various members of the endothelin (ET)/sarafotoxin (SX) peptide superfamily were investigated in the anaesthetized rat. 2 ET‐1 (1 nmol kg−1, i.v. bolus) induced a sustained increase in mean arterial pressure (MAP, maximum increase 44 ± 3 mmHg). Intravenous injection of BQ‐123 at 0.2, 1.0 or 5.0 mg kg−1 5 min before ET‐1 inhibited the pressor response by 18, 50 and 61%, respectively. The ET‐1 pressor response was inhibited by 75% when the peptide was given 60 min after the start of a 120 min i.v. infusion of BQ‐123 (0.2 mg kg−1 min−1). 3 In addition to ET‐1, BQ‐123 (1 mg kg−1, i.v. bolus) attenuated the pressor responses to big ET‐1 (1 nmol kg−1, i.v., bolus, maximum increase in MAP: 68 ± 7 mmHg), ET‐3 (3 nmol kg−1, i.v., bolus, maximum response: 30 ± 3 mmHg), SX6b (1 nmol kg−1, i.v., bolus, maximum response: 41 ± 5 mmHg) and SX6c (1 nmol kg−1, i.v., bolus, maximum response: 24 ± 4 mmHg) by 65, 60, 88 and 50%, respectively. 4 With the exception of big ET‐1, all the peptides used in this study induced an initial transient depressor response (–32 ±3 mmHg, n = 18). Although BQ‐123 (1 mg kg−1, i.v., bolus) did not affect the absolute magnitude of the fall in MAP, the ETA receptor antagonist significantly prolonged the depressor responses induced by ET‐3 and SX6b. 5 Thus, BQ‐123 attenuates the pressor, but not the depressor effects of ET‐1, big ET‐1, ET‐3, SX6b and SX6c. Complete inhibition of the pressor responses could not be achieved, suggesting that a component of the pressor response is not mediated via the ETA receptor.

Dexamethasone treatment increases neuropeptide Y levels in rat hypothalamic neurones

Immunoreactive glucocorticoid receptors (GR) have previously been demonstrated in neuropeptide Y (NPY) neurones of the rat hypothalamus. To determine whether NPY synthesis is influenced by glucocorticoids, the effect of dexamethasone (DEX) on the levels of immunoreactive NPY in rat hypothalamic neurones was investigated in vivo and in vitro. Daily injections of DEX (0.1 mg/day) for 5 days increased the NPY content of the mediobasal hypothalamus in female rats by 117% (p less than 0.002). Primary cultures of hypothalamic neurones were also sensitive to the effect of glucocorticoids. Intracellular NPY levels were significantly increased (p less than 0.001) compared to control values by 151%, 222% and 268% when cultures were maintained in a defined serum free medium containing DEX 10(-9), 10(-8) and 10(-7) M respectively.