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PubMed2004

Identification of a nicotinic acid receptor: is this the molecular target for the oldest lipid-lowering drug?

Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia, producing a desirable normalization of a range of cardiovascular risk factors. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a Gi-type G protein-coupled receptor, resulting in the inhibition of adipocyte lipolysis, may contribute. This review describes the identification of this elusive receptor, and outlines the evidence suggesting that this may be the molecular target for the clinical effects of nicotinic acid.

Animals↗

PubMed1981

[Metabolic changes in the liver as affected by nicotinic acid].

The author carried out a dynamic study on the metabolic changes in liver under the influence of nicotinic acid, administered singly by intramuscular injection in a dose of 2mM/kg of body weight. She examined at the 1th, 3th, 6th and 24th hour the changes in the levels of nicotine-amide coenzymes (NAD, NAD-H and NADP), adenine nucleotides (ATP, ADP and AMP), the metabolic lactate and pyruvate and the enzymes LDH, MDH, GOT and GPT. The obtained data were compared with those of the control groups, treated with saline and killed at the same intervals as the experimental animals. Furthermore she made also a comparison with an intact group, presented as O group, whose values served as basal. The obtained data showed that after application of the nicotinic acid (NA) complex metabolic changes occurred in liver, due to its basic effects-stimulation of biosynthesis of nicotinamide coenzymes and inhibition of lipolysis in the fatty tissue. Most probably the effect on the biosynthesis of NAD was primary, which showed later substantial regulatory influence both on lipolysis in the fatty acid and on the metabolization of mobilizing lipids on behalf of the liver. Parallel occurring metabolic processes in the aorta and in the vascular wall in general, stimulation of the biological oxidation and bioenergetics formed the whole antilipolytic and antiarteriogenic action of nicotinic acid.

Adenine Nucleotides↗

PubMed2005

Calcium signalling by nicotinic acid adenine dinucleotide phosphate (NAADP).

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a recently described Ca2+ mobilizing messenger, and probably the most potent. We briefly review its unique properties as a Ca2+ mobilizing agent. We present arguments for its action in targeting acidic calcium stores rather than the endoplasmic reticulum. Finally, we discuss possible biosynthetic pathways for NAADP in cells and candidates for its target Ca2+ release channel, which has eluded identification so far.

Animals↗

PubMed1992

A comparison of acipimox and nicotinic acid in type 2b hyperlipidaemia.

The side effect profiles and lipid lowering efficacy of nicotinic acid (1 g three times daily) and its analogue acipimox (250 mg three times daily) in type 2b hyperlipidaemia were compared in a double-blind placebo controlled study. In the nicotinic acid group (n = 7) at 12 weeks there were significant reductions (P less than 0.05) with respect to placebo (n = 9) in total cholesterol (median and range) 6.6 mmol l-1 (4.8-8.4) vs 8.8 mmol l-1 (7.5-9.5), triglyceride 1.4 mmol l-1 (0.5-4.6) vs 2.8 mmol l-1 (1.5-9.5) and apoprotein B 88.6 mg dl-1 (62.1-114) vs 121.9 mg dl-1 (88.0-170.7). In contrast there was no significant alteration in lipids in the acipimox group (n = 12). Nicotinic acid was associated with a high incidence of side effects, principally cutaneous flushing, while acipimox was well tolerated by all patients.

Adult↗

PubMed1981

Effect of supplemental dietary chromium or nicotinic acid on carbohydrate metabolism during basal, starvation, and refeeding periods in poults.

A series of experiments were conducted with turkey poults to ascertain the effects of supplemental chromium or excess of nicotinic acid on growth and carbohydrate metabolism. A 23% protein starter diet was selected to emphasize the effect of chromium under basal, starvation for 48 hr, and refeeding periods. Thirty percent protein diets were also used to determine if the effects were compounded by protein levels. Supplemental chromium (20 ppm) significantly increased (P less than .05) weight at 3 weeks of age of poults consuming 23% protein diets, while an additional 250 ppm of nicotinic acid had little effect on poult weight at 3 weeks (P greater than .05). Supplemental chromium did not increase (P greater than .05) feed consumption of poults consuming both 23 and 30% protein diets. Supplemental chromium increased liver glycogen at 3 weeks of age and following refeeding after the 48 hr fast (P less than .05). Blood glucose was significantly affected by starvation-refeeding (P less than .05) but was not affected by either chromium or nicotinic acid. Supplemental chromium increased (P less than .01) active glycogen synthetase, while nicotinic acid increased (P less than .01) active phosphorylase at both protein levels. Synthetase was not decreased by starvation but was increased (P less than .01) by refeeding regardless of protein level fed. Phosphorylase was not affected by a starvation-refeeding regimen. Chromium supplementation increased in the vitro incorporation of (14C) glucose into glycogen during basal, starvation and refeeding periods (P less than .01), again, regardless of protein level.

Animal Feed↗

PubMed1968

Plasma lipids and urinary excretion of catecholamines in man during experimentally induced emotional stress, and their modification by nicotinic acid.

33 male volunteers were studied in the morning after fasting overnight. 11 (the control group) were allowed to sit comfortably for three consecutive 2-hr periods, no stressors or treatment being introduced. The remaining 22 were divided into two groups, each being exposed to standardized, emotional stressors during the second of the three 2-hr periods. The subjects in one of these groups were each given a total dose of 3 g of nicotinic acid during the first 3 hr of the experiment, whereas the other group received no treatment. Stress was accompanied and followed by increased levels of free fatty acids and triglycerides in arterial plasma, by an increase in catecholamine excretion, and a rise in heart rate and systolic and diastolic blood pressure. No such increases were seen in the control group. The stress-induced rise in free fatty acids was inhibited by nicotinic acid, and the triglyceride rise was turned into a fall. The stressor-induced increase in catecholamine excretion was not significantly affected by nicotinic acid, neither were the increases in heart rate and blood pressure. The hypothesis is discussed, from a qualitative as well as a quantitative viewpoint, that there is a direct relationship between the increased concentration of free fatty acids accompanying emotional stress in man and the eventual development of the stress hyperlipoproteinemia.

Adipose Tissue↗

PubMed2006

Evaluation of the safety and tolerability of prolonged-release nicotinic acid in a usual care setting: the NAUTILUS study.

OBJECTIVE: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid (niacin; Niaspan) in an usual care setting with patients receiving treatment for dyslipidaemia in Germany: the multiceNtre, open, uncontrolled sAfety and tolerability stUdy of a modified-release nicoTinic acId formuLation in sUbjects with dySlipidaemia and low HDL-cholesterol (NAUTILUS). RESEARCH DESIGN AND METHODS: This was a multicentre, open-label, 15-week study. Eligible patients had a diagnosis of dyslipidaemia with lipids inadequately controlled by 4 weeks of diet treatment. Additionally, patients had low HDL-cholesterol (< 1.03 mmol/L [< 40 mg/dL]) in men and < 1.29 mmol/L [< 50 mg/dL] in women), and had triglycerides < 9.03 mmol/L (< 800 mg/dL). Exclusion criteria included uncontrolled diabetes (HbA(1C) > 9%), significant hepatic, vascular or renal disease. The target dose was 2000 mg once daily. MAIN OUTCOME MEASURES: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid [incidence of adverse events (AE) and serious AE] in the overall population (the safety population). Efficacy parameters (lipid parameters) were also measured in the intent-to-treat population. RESULTS: A total of 566 patients were recruited, mostly with metabolic syndrome (39.4%), mixed hypercholesterolaemia (31.6%), isolated low HDL-cholesterol and markedly elevated cardiovascular risk for other reasons (10.8%), and primary hypercholesterolaemia (8.8%), according to NCEP/ATP III guidelines. The target dose was achieved by 65% of patients. Flushing was the most common side-effect (42%), as expected, and 9.7% withdrew for flushing. Other drug-related AEs occurred at low frequency (18.6%), and 8.7% withdrew for an AE other than flushing. Most AEs were mild or moderate in severity. Serious AEs considered possibly related to treatment occurred in three patients (0.5%); all resolved following treatment withdrawal. There was no hepatotoxicity or serious muscle AE. CONCLUSIONS: Prolonged-release nicotinic acid was well tolerated, and these results support its use in the management of patients at elevated cardiovascular risk due to low HDL-cholesterol.

Adult↗

PubMed1976

Nicotinic acid reduction of plasma volume loss after thermal trauma.

Intravenous administration of nicotinic acid to the anesthetized dog prior to thermal trauma reduced plasma loss at 10 minutes after burn from 7 milliliters per kilogram to less than 2 millimeters per kilogram. During the next 50 minutes plasma loss was the same in treated and untreated animals. An additional dose of nicotinic acid 30 minutes after burn prevented this further loss.

Animals↗

PubMed2005

Crystal structure of nicotinic acid mononucleotide adenylyltransferase from Pseudomonas aeruginosa in its Apo and substrate-complexed forms reveals a fully open conformation.

The enzyme nicotinic acid mononucleotide adenylyltransferase (NaMN AT; EC 2.7.7.18) is essential for the synthesis of nicotinamide adenine dinucleotide and is a potential target for antibiotics. It catalyzes the transfer of an AMP moiety from ATP to nicotinic acid mononucleotide to form nicotinic acid adenine dinucleotide. In order to provide missing structural information on the substrate complexes of NaMN AT and to assist structure-based design of specific inhibitors for antibacterial discovery, we have determined the crystal structure of NaMN AT from Pseudomonas aeruginosa in three distinct states, i.e. the NaMN-bound form at 1.7A resolution and ATP-bound form at 2.0A as well as its apo-form at 2.0A. They represent crucial structural information necessary for better understanding of the substrate recognition and the catalytic mechanism. The substrate-unbound and substrate-complexed structures are all in the fully open conformation and there is little conformational change upon binding each of the substrates. Our structures indicate that a conformational change is necessary to bring the two substrates closer together for initiating the catalysis. We suggest that such a conformational change likely occurs only after both substrates are simultaneously bound in the active site.

Amino Acid Sequence↗

PubMed2004

Are the effects of nicotinic acid on insulin resistance precipitated by abnormal phosphorous metabolism?

Nicotinic acid is a unique cholesterol modifying agent that exerts favorable effects on all cholesterol parameters. It holds promise as one of the main pharmacological agents to treat mixed dyslipidemia in metabolic syndrome and diabetic patients. The use of nicotinic acid has always been haunted with concerns that it might worsen insulin resistance and complicate diabetes management. We will discuss the interaction between phosphorous metabolism and carbohydrate metabolism and the possibility that worsening of insulin resistance could be related to a drug induced alteration in phosphorous metabolism, and the implications of that in medical management of diabetes and metabolic syndrome patients with mixed dyslipidemia.

Journal Article↗

PubMed1995

"Essential" phospholipids versus nicotinic acid in the treatment of patients with type IIb hyperlipoproteinemia and ischemic heart disease.

In patients with moderate, dietary noncorrigible hyperlipoproteinemia type IIb and ischemic heart disease, treatment with nicotinic acid is limited by the side effects of the drug. In 100 patients, 6-month treatment with nicotinic acid (n = 50) or "essential" phospholipids (EPL); Lipostabil, manufacturer: Rhône-Poulenc Rorer) (n = 50) indicated comparable efficacy for both substances: Significant (p < .001) reductions of serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride values were similar in both groups, while nicotinic acid increased high-density lipoprotein (HDL) cholesterol significantly (p < .01) better than Lipostabil. A detailed analysis of ultracentrifugal lipoprotein profiles, hydroperoxide concentrations in LDL, and cholesterol-accepting properties of HDL in a small number of Lipostabil- and nicotinic acid-treated patients revealed favorable shifts in the lipoprotein profile, significant (p < .05) reductions of LDL hydroperoxides, and favorable increases of the most antiatherogenic HDL2b subfraction only in the Lipostabil-treated group. Clinically, both medications reduced the intensity and number of angina pectoris attacks per week (p < .05), but only Lipostabil-treated patients significantly (p < .05) increased their working capacity in the veloergometric test. Since in the nicotinic acid-treated group dropouts (nine patients, eight related to the drug) and side effects [14] exceeded those in the Lipostabil-treated group (two dropouts not related to the drug, no side effects), it is suggested that Lipostabil is a preferable alternative in the treatment of patients with moderate, dietary noncorrigible hyperlipoproteinemia IIb and ischemic heart disease.

Cholesterol, HDL↗

PubMed1975

The effects of nicotinic acid upon postburn plasma volume loss.

The effects of intravenously injected nicotinic acid upon postburn plasma volume loss have been studied in the anesthetized dog. Results of this study have shown that two hours after a third degree flame burn over 40 per cent of the surface area, approximately 12 milliliters per kilogram of plasma are lost to the extravascular spaces. If untreated, this loss will increase to 16 milliliters per kilogram at four hours postburn and 19 milliliters per kilogram at six hours postburn. Treatment of the dogs with nicotinic acid beginning two and one-half hours postburn will reduce the plasma extravasation to 13 milliliters per kilogram four hours postburn and to 11 milliliters per kilogram at six hours postburn. In general, the decrease in cardiac output observed after thermal trauma paralleled the loss of plasma volume. In the untreated dogs, this decrease continued with time postburn, but in the treated dogs, the decrease in cardiac output leveled off during the first two hours after beginning treatment and started what appeared to be a slow return toward control levels in the next two hour period.

Animals↗

PubMed1983

Inhibition of adenylate cyclase and stimulation of a high affinity GTPase by the antilipolytic agents, nicotinic acid, acipimox and various related compounds.

In hamster adipocyte ghosts, the influence of the antilipolytic agents, nicotinic acid, 5-methyl-pyrazine-2-carboxylic acid 4-oxide (acipimox) and various related compounds, was studied on adenylate cyclase and low Km GTPase activities. As shown before for hormonal factors and nicotinic acid, the new drug, acipimox, inhibited adenylate cyclase by a GTP-dependent process, which was amplified by sodium ions; half-maximal inhibition occurred at about 10 mumol/l acipimox. For the various compounds studied, the following rank order of potency in inhibition of adenylate cyclase was obtained, nicotinic acid greater than 3-carboxy-5-methylpyrazole greater than acipimox greater than 3-carboxy-5-methylisoxazole; 6-hydroxynicotinic acid and beta-pyridylcarbinol had no effect up to 300 mumol/l. In the same membrane system the antilipolytic drugs increased GTP hydrolysis by stimulation of a low Km GTPase as shown before for antilipolytic hormones. The potency order of the antilipolytic agents studied was identical for GTPase stimulation and adenylate cyclase inhibition. The data suggest that the antilipolytic drugs studied act on adipocyte adenylate cyclase via membrane-bound receptors in a hormone-like manner and that stimulation of a high affinity GTPase is involved in the mechanism of adenylate cyclase inhibition by these agents.

Adenylyl Cyclase Inhibitors↗

PubMed2002

Opposite effects of nicotinic acid and pyridoxine on systemic prostacyclin, thromboxane and leukotriene production in man.

The effects of nicotinic acid (2500 mg orally during 12 hr) and pyridoxine (300 mg orally twice daily for seven days) on the excretion of urinary 2,3-dinor-6-ketoprostaglandin F1alpha, 11-dehydrothromboxane B2 and leukotriene E4, the markers of systemic prostacyclin, thromboxane A2 and cysteinyl leukotriene production, respectively, were investigated in healthy male volunteers (n=6-8). Nicotinic acid increased 11-dehydrothromboxane B2 and leukotriene E4 excretions to 2.6- and 2.0 times the initial values (P<0.05), respectively. In the volunteers treated with pyridoxine, 11-dehydrothromboxane B2 and leukotriene E4 excretions were decreased to 70% (P<0.05) and 65% (P<0.01) of the initial values, respectively, but the excretion of 2,3-dinor-6-ketoprostaglandin F1alpha was increased 1.7 times (P<0.01). The results suggest that nicotinic acid increases thromboxane and leukotriene synthesis which may not be beneficial for patients with cardiovascular diseases or asthma. In contrast, the increase in prostacyclin production and the inhibition in thromboxane and leukotriene synthesis by pyridoxine might be beneficial in disorders where the production of prostacyclin is decreased and the formation of thromboxane and cysteinyl leukotrienes is enhanced.

6-Ketoprostaglandin F1 alpha↗

PubMed2001

Identification, characterization, and crystal structure of Bacillus subtilis nicotinic acid mononucleotide adenylyltransferase.

The nadD gene, encoding the enzyme nicotinic acid mononucleotide (NaMN) adenylyltransferase (AT), is essential for the synthesis of NAD and subsequent viability of the cell. The nadD gene in Bacillus subtilis (yqeJ) was identified by sequence homology with other bacterial nadD genes and by biochemical characterization of the gene product. NaMN AT catalyzes the reversible adenylation of both NaMN and the nicotinamide mononucleotide (NMN) but shows specificity for the nicotinate. In contrast to other known NMN ATs, biophysical characterizations reveal it to be a dimer. The NaMN AT crystal structure was determined for both the apo enzyme and product-bound form, to 2.1 and 3.2 A, respectively. The structures reveal a "functional" dimer conserved in both crystal forms and a monomer fold common to members of the nucleotidyl-transferase alpha/beta phosphodiesterase superfamily. A structural comparison with family members suggests a new conserved motif (SXXXX(R/K)) at the N terminus of an alpha-helix, which is not part of the shared fold. Interactions of the nicotinic acid with backbone atoms indicate the structural basis for specificity.

Amino Acid Sequence↗

PubMed1990

Effects of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2 and HDL3 in hyperlipoproteinaemia.

Nicotinic acid was given in a 4-g daily dose for 6 weeks to 41 weight-stable patients of mean age (+/- SD) 52 +/- 9 years, with type IIa, type IIb or type IV hyperlipoproteinaemia (HLP), in order to study its effects on serum cholesterol concentrations of high density lipoprotein (HDL) subfractions HDL2 and HDL3. The triglyceride and cholesterol levels of serum very low density (VLDL) and low density (LDL) lipoproteins decreased during treatment (P less than 0.001). Serum HDL and HDL2 cholesterol levels increased by 37% and 135%, respectively. These changes were positively correlated (r = 0.93; P less than 0.001). There was no significant change in mean serum HDL3 cholesterol concentration. A negative correlation existed between changes in HDL3 and HDL2 cholesterol levels (r = -0.54; P less than 0.001). Multiple stepwise linear regression analyses revealed that the initial HDL3 cholesterol predicted more than 30% of the increase in HDL2 cholesterol. Changes in the concentrations of HDL2 and HDL3 cholesterol after 6 weeks of drug treatment were not related to the type of HLP, neither were these effects of nicotinic acid correlated with changes in VLDL or LDL lipid levels. The concept has previously been proposed, on the basis of in vitro data, that HDL2 is formed from HDL3 particles in the blood. Our results suggest that, in man, this reaction is stimulated in vivo by prolonged nicotinic acid therapy.

Adult↗

PubMed1975

The sources of plasma cyclic AMP: studies in the rat using isoprenaline, nicotinic acid and glucagon.

The effects of intravenous administration of isoprenaline, glucagon and nicotinic acid on plasma concentrations of cyclic AMP in rats are described. In order to determine the relative importance of the liver as a source of extracellular cyclic AMP, the effects of the hormones were investigated in intact and functionally hepatectomised rats. The results showed that hepatectomy did not prevent an isoprenaline-stimulated increase in plasma cyclic AMP concentrations, although glucagon was without effect on plasma nucleotide concentrations in this group of animals. It is suggested that the liver is essential for the action of glucagon but that isoprenaline can increase plasma cyclic AMP concentrations in hepatectomised animals by increasing extrahepatic release of the nucleotide. Since inhibition of adipose tissue lipolysis with nicotinic acid did not prevent an isoprenaline or glucagon-stimulated increase in plasma cyclic AMP concentrations, adipose tissue is discounted as a major source of plasma cyclic AMP.

Adipose Tissue↗

PubMed1983

Occurrence of molybdenum in the nicotinic acid hydroxylase from Clostridium barkeri.

Molybdenum, assayed by atomic absorption spectrometry, copurifies with the selenium-containing nicotinic acid hydroxylase from Clostridium barkeri. Fluorescence spectral studies on the enzyme indicate the presence, along with flavin, of another component. The fluorescence spectra of this component obtained after the aerobic denaturation of the nicotinic acid hydroxylase are similar to the fluorescence properties reported for the "pterin-like" cofactor from xanthine oxidase and several other molybdoproteins. Nicotinic acid hydroxylase from C. barkeri contains molybdenum, selenium, iron, acid-labile sulfur, and flavin with the occurrence of a "pterin-like" cofactor also a likely component.

Bacterial Proteins↗