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PubMed1983

Age related changes in the antilipolytic effects of nicotinic acid in rat adipose tissue.

The effect of nicotinic acid on lipolysis was tested in vitro in adipose tissue from three groups of rats, selected according to age: 6-7 weeks, 10-12 weeks and 16-20 weeks old. Although the changes were not statistically significant, the basal release of free fatty acid (FFA) was increased and glycerol was decreased by nicotinic acid (0.01-1 mM); the drug caused a statistically significant increase in basal FFA: glycerol ratio in a concentration-dependent manner. This ratio also increased with age in the absence of drug. (-)-Noradrenaline (10 microM) and theophylline (3 mM) each stimulated lipolysis. When glycerol release was calculated as a percentage increase, the effects of these drugs became more marked with age. By contrast, the highest absolute rate of induced release occurred in adipose tissue from the youngest rats. The lipolytic effect of 10 microM (-)-noradrenaline was generally unaffected by nicotinic acid except in adipose tissue from the oldest rats when the glycerol release was reduced by 1 mM nicotinic acid, although it did not alter FFA:glycerol ratio. The stimulation of glycerol release induced by 3 mM theophylline was not affected by the presence of nicotinic acid in the youngest rats, but the drug elicited a concentration-dependent antilipolytic effect in adipose tissue from 10-12 weeks old rats, which was even more pronounced in the oldest animals. Lower theophylline concentrations (0.6-1 mM) were also sensitive to nicotinic acid inhibition in the 6-7 weeks old rats. In the presence of theophylline, nicotinic acid had no effect on FFA:glycerol ratio. These data show a direct influence of age on the antilipolytic action of nicotinic acid.

Adipose Tissue↗
PubMed2005

Mixed monolayers involving DPPC, DODAB and oleic acid and their interaction with nicotinic acid at the air-water interface.

The behaviour of binary mixtures involving dipalmitoylphosphatidylcholine (DPPC), dioctadecyldimethylammonium bromide (DODAB) and oleic acid (OA) was investigated at the air-water interface by surface pressure-area (pi-A) measurements and by Brewster angle microscopy (BAM). Thermodynamic analysis indicates for the system DPPC/DODAB miscibility with strong negative deviations from the ideal behaviour, from low to high surface pressures over all the composition range. For systems DODAB/OA and DPPC/OA, thermodynamic analysis and BAM observation indicate miscibility from low to intermediate surface pressures, and phase separation in a limited range of composition at high surface pressures. The interaction of nicotinic acid (NA) with pure lipids and with selected compositions of mixed systems was investigated. Significant positive deviations of pi-A isotherms in the presence of NA indicate attractive interactions between NA and the polar groups of DPPC and DODAB. NA easily penetrates in expanded regimes while it tends to be segregated from condensed regimes in mixed monolayers.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

Fatty acid flow to the duodenum and in milk from cows fed diets that contained fat and nicotinic acid.

Four cows fitted with ruminal and duodenal cannulas were used in a 4 x 4 Latin square design; treatments were arranged in a 2 x 2 factorial. Treatments were 1) low fat diet, no nicotinic acid; 2) low fat diet, 12 g/d of nicotinic acid; 3) high fat diet, no nicotinic acid; and 4) high fat diet, 12 g/d of nicotinic acid. Cows were fed for ad libitum intake diets consisting of 35% alfalfa silage, 15% corn silage, and either 50% low fat concentrate or 40% high fat concentrate (tallow supplied 6.25% of concentrate) and 10% whole raw soybeans (dry matter basis). Intake of gross energy (104 Mcal/d) was not different among treatments. Ruminal and postruminal digestibility of energy was not altered by fat or nicotinic acid. Fatty acid intake and flow to the duodenum were increased by fat but were not affected by nicotinic acid. For all diets, flows to the duodenum of C16:0, C18:0, total C18, and total fatty acids increased, and flows of C16:1, C18:1, C18:2, and C18:3 decreased, compared with their intakes. Biohydrogenation of unsaturated C18 was decreased by fat but was not affected by nicotinic acid. Digestibilities of C18:0, C18:1, C18:2, C18:3, and total fatty acids that flowed to the duodenum were decreased by fat but were not affected by nicotinic acid. The yield of C18:0 in milk was increased, and yields of C6:0 to C16:0 fatty acids were decreased, by fat, but yields were not affected by nicotinic acid.

Animals↗
PubMed2003

PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect.

Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia.

Adipose Tissue↗
PubMed1979

Inhibition of rat and human adipocyte adenylate cyclase in the antilipolytic action of insulin, clofibrate, and nicotinic acid.

Clofibrate (Atromid-S), nicotinic acid, and insulin are known to be potent hypolipidemic and antilipolytic agents. The present study was undertaken to define the mechanism of action of this latter effect on isolated rat and human fat cells. Sodium clofibrate (0.42 mM), nicotinic acid (0.42 mM), and insulin (100 microU/mL) were shown to inhibit norepinephrine-stimulated lipolysis in rat and human adipose cells and this inhibition was associated with a reduction in intracellular 3',5'-cyclic AMP levels. A similar cyclic AMP lowering effect was demonstrated with insulin in the presence of procaine-HCL, which uncouples the adenylate cyclase system from lipolysis. This insulin effect was attributed to inhibition of adenylate cyclase. A direct and significant inhibition of adenylate cyclase in membrane fractions obtained from isolated human adipocytes was demonstrated for all three antilipolytic agents. The common membrane site of action of these agents whereby adenylate cyclase activity is depressed, thus decreasing cyclic AMP production and free fatty acid (FFA) mobilization from adipose stores, implies a central role for the adenylate cyclase system. These findings are consistent with the view that the hypotriglyceridemic effects of clofibrate, nicotinic acid, and insulin may be partly explained by deprivation of FFA substrate for hepatic very low density lipoprotein synthesis.

Adenylyl Cyclase Inhibitors↗
PubMed2005

Applying pattern recognition methods and structure property correlations to determine drug carrier potential of nicotinic acid and analogize to dihydropyridine.

Multivariate methods are utilized to compare nicotinic acid and dihydropyridine as a drug carrier. Nicotinic acid and dihydropyridine form ester groups on 10 beta-lactam antibiotics with an oxymethyl group forming a linkage between the antibiotic and the drug carrier (nicotinic acid or dihydropyridine). Calculated molecular properties are analyzed by self-organizing tree algorithm (SOTA), bivariate regression, cluster analysis, factor analysis, discriminant analysis, hierarchical classification, and principal coordinates analysis. Ten important pharmacological properties for each of the nicotinic acid and dihydropyridine antibiotic derivatives are numerically similar and highly correlated. Calculated molecular properties include molar refractivity, molar volume, parachor, index of refraction, partition coefficient (log P), polarizability, and polar surface area. Dermal permeability coefficients (Kp) for nicotinic acid derivatives are similar to values for dihydropyridine derivatives. Dermal permeabliity coefficients analyzed by hierarchical classification and SOTA analysis were shown to be closely interrelated and highly correlated. Ten properties of the nicotinic acid and dihydropyridine were compared by Passing-Bablok regression analysis and shown to be highly correlated (r=0.9879). Box plot analysis of 10 properties, inclusive of both groups of derivatives, showed narrow ranges in values. Cluster analysis of derivative properties showed the nicotinic acid derivatives to be highly similar to the dihydropyridine derivatives of the same antibiotics. Cluster analysis was performed by single linkage, complete linkage, and centroid linkage. Factor analysis showed the nicotinic acid derivatives to be interrelated and similar to the dihydropyridine derivatives. Discriminant analysis performed on all derivatives formed a single highly cohesive and non-differentiated cluster, demonstrating strong similarity among nicotinic acid and dihydropyridine derivatives. Principal coordinates analysis (determines similarity) of Kp values showed high similarity between the nicotinic acid and dihydropyridine antibiotic derivatives.

Dihydropyridines↗
PubMed1990

Carrier-mediated uptake of nicotinic acid by rat intestinal brush-border membrane vesicles and relation to monocarboxylic acid transport.

The intestinal transport of [14C]nicotinic acid was investigated at 27 degrees C by using brush-border membrane vesicles (BBMV) isolated from the rat small intestine. The osmolarity sensitive uptake by BBMV showed a remarkable overshoot phenomenon in the presence of an inward-directed H+ gradient (pHin = 7.5, pHout = 6.0). In contrast, the imposition of a Na+ gradient ([Na+]in = 0 mM, [Na+]out = 100 mM) had no stimulatory effect on the uptake of [14C]nicotinic acid. The remarkable pH-dependence of the initial uptake showing an increase of the uptake rate with decreasing the extravesicular pH disappeared completely in the presence of a structural analogue, isonicotinic acid, at pH below 6.5. In the presence of a H+ gradient, the initial uptake of [14C]nicotinic acid was saturable with the apparent Kt of 4.43 mM and Jmax of 2.55 nmol/mg protein/15 s. The uptake was increased by the imposition of an inside-positive membrane potential and was significantly inhibited by monocarboxylic acids such as benzoic acid, salicylic acid, acetic acid, propionic acid, valproic acid and L-lactic acids as well as two isomers (isonicotinic acid and picolinic acid). The uptake was not inhibited by nicotinamide, nicotinyl alcohol, D-glucose, p-aminohippuric acid, glycyl-L-proline, succinic acid and an exchange transport inhibitor. From these results it was concluded that nicotinic acid is transported through the intestinal brush-border membrane by a carrier-mediated system and the system can recognize some acidic drugs with a monocarboxylic group. The pH dependent intestinal uptake of nicotinic acid can be ascribed to the proton-coupled and active carrier-mediated transport mechanism rather than a simple diffusion of the undissociated nicotinic acid to follow a pH-partition hypothesis.

Animals↗
PubMed1986

Renal transport and metabolism of nicotinic acid.

Renal metabolism and brush-border transport of nicotinic acid were studied in renal cortical slices and brush-border membrane vesicles exposed to a physiological concentration of vitamin (2.2-3.5 microM). Vesicle transport of [3H]nicotinic acid was found to be Na+ dependent and concentrative. The presence of a Na+ gradient resulted in a fivefold increase in the rate of nicotinic acid uptake over that observed with mannitol and caused a transient nicotinic acid accumulation two- to fourfold above the equilibrium value. The effects of membrane potential, pH, and elimination of Na+-H+ exchange were also studied. Cortical slices and isolated tubules exposed to 2.2 microM [14C]nicotinic acid took up vitamin and rapidly metabolized most of it to intermediates in the Preiss-Handler (J. Biol. Chem. 233: 488-493, 1958) pathway for NAD biosynthesis; little free nicotinic acid was detectable intracellularly. The replacement of Na+ with Li+ in the bathing medium reduced total accumulation of 14C label primarily as a result of reduced nicotinic acid uptake. Cortical tissue concentrated free nicotinic acid only when the involved metabolic pathways were saturated by levels of nicotinic acid far in excess of what occurs in vivo.

Animals↗
PubMed1977

Studies on the mechanism of flush induced by nicotinic acid.

Flush is a common side effect of nicotinic acid therapy in patients. The effect is present as long as the level of nicotinic acid increases in the plasma. The mechanism of flush after nicotinic acid has been studied in the ears of guinea-pigs in vivo. The threshold dose of nicotinic acid (1-3 mg/kg) to raise the skin temperature of the ears and to increase the cyclic AMP level of this tissue was similar. Indomethacin and acetylsalicylic acid which inhibit the synthesis of prostaglandins markedly reduce the duration and intensity of the flush. In isolated slices from guinea-pig ears, nicotinic acid increased the level of cyclic AMP; this effect was inhibited by indomethacin. The stimulating action of prostaglandin E1 on the cyclic AMP level of the ear slices was not inhibited by indomethacin. Since administration to man of both cyclic AMP and prostaglandin E1 produces flush it is suggested that nicotinic acid may induce flush by the formation of some prostaglandin which then increases the formation of cyclic AMP.

Animals↗
PubMed1979

Absorption in rats, dogs, pigs, and humans of nicotinic acid after oral administration of phosphatidyl inositol pentanicotinate hydrochloride (PIN).

Bound nicotinic acid in feces after oral administration of phosphatidyl inositol pentanicotinate (PIN) was determined by chromatographical isolation from acid hydrolysate and UV absorbance of the eluted nicotinic acid. With all species tested, the absorption of nicotinic acid after administration of PIN was found to be incomplete, proportions from 5 to 25% of the amount of nicotinic acid administered with PIN being recovered from feces. Humans absorbed about 75% of the nicotinic acid administered with 700 mg PIN, i.e. 230 mg. It is concluded that the presence of bound nicotinic acid in feces is due to slow absorption of the PIN or slow hydrolysis of the nicotinic acid ester. Rabbit liver homogenate, human blood plasma, and human duodenal juice were found to liberate nicotinic acid from PIN.

Animals↗
PubMed1983

Nicotinic acid and its derivatives: a short survey.

Nicotinic acid is used widely in the treatment of hyperlipoproteinemias and reduces both the cholesterol and the triglyceride concentrations in the plasma. However, very high doses are needed to achieve these therapeutic effects, which is why side effects are common and are particularly known to hinder the compliance of patients. Nicotinic acid derivatives have been developed to overcome this problem. As a result of chemical and galenic retardation, these derivatives lessen the side effects and the necessary doses are considerably reduced in comparison with pure nicotinic acid. However, most of these derivatives are not pure prodrugs, and exert their own synergistic pharmacokinetic and pharmacodynamic effects. In general, when nicotinic acid and its derivatives are used in therapy a desirable modification of the composition of the plasma lipids in the sense of an antiatherosclerotic activity can be expected (reductions of VLDL and LDL and an increase of HDL). Good possibilities for using nicotinic acid in the prevention and remission of atherosclerotic processes arise in connection with the activation of fibrinolysis and the reduction of the tendency toward platelet aggregation. In the light of recent studies on the mechanisms of action of nicotinic acid, an influence on the prostaglandin system has been found, as a result of which an interconnection between its various effects and side effects appears to be possible.

Adipose Tissue↗
PubMed2006

[Pharmacology of niacin or nicotinic acid].

Niacin or nicotinic acid is a soluble vitamin with hypolipidemic properties. Niacin reduces triglycerides (20 50%), LDL-c (5-25%), and raises HDL-c (15-35%). The Coronary Drug Project study showed that the use of niacin was associated with reduction on coronary events and total mortality, and more recently it has been demonstrated that niacin combined with other hypolipidemic drugs can attenuate the progression of coronary atherosclerosis. Niacin appears to reduce the mobilization of free fatty acids from the adipocytes, acting on specific receptors, diminishing the liver formation of triglyceride-rich lipoproteins. There are two forms of niacin, one of rapid absorption (crystalline), more commonly associated with flushing, and another of extended release, recently reported to be better tolerated. The use of niacin can be associated with dyspepsia, increased plasma levels of liver enzymes and also with a modest elevation in glucose and uric acid plasma levels, at least using the extended-release preparation up to 2 g/d.

Delayed-Action Preparations↗
PubMed1999

[Nicotinic acid and nicotinamide].

Nicotinic acid and nicotinamide are called niacin. They are the antipellagra vitamin essential to many animals for growth and health. In human being, niacin is believed necessary together with other vitamins for the prevention and cure of pellagra. Niacin is widely distributed in nature; appreciable amounts are found in liver, fish, yeast and cereal grains. Nicotinamide is a precursor of the coenzyme NAD and NADP. Some of the most understood metabolic processes that involve niacin are glycolysis, fatty acid synthesis and respiration. Niacin is also related to the following diseases: Hartnup disease; blue diaper syndrome; tryptophanuria; hydroxykynureninuria; xanthurenic aciduria; Huntington's disease.

Humans↗
PubMed2005

Prolonged-release nicotinic acid: a review of its use in the treatment of dyslipidaemia.

Prolonged-release (PR) nicotinic acid (niacin) [Niaspan] is an oral, once-daily formulation of the lipid-modifying drug designed to produce less vasodilatory flushing than crystalline immediate-release (IR) nicotinic acid and less hepatotoxicity than previous sustained-release formulations of nicotinic acid.PR nicotinic acid appears to retain the same level of efficacy as crystalline IR nicotinic acid and be better tolerated than older nicotinic acid formulations. Nicotinic acid has beneficial effects on all traditional blood lipid and lipoprotein fractions and is the most effective agent for increasing high-density lipoprotein (HDL)-cholesterol (HDL-C) and reducing lipoprotein(a). The effects of PR nicotinic acid are often additive when used in combination with HMG-CoA reductase inhibitors (statins), making it a useful addition when lipid goals are not achieved with the usual statin monotherapy or when additional correction of a specific lipid abnormality is required. PR nicotinic acid also slows atherosclerotic progression and even appears to produce regression of atherosclerosis in patients on stable statin therapy. PR nicotinic acid is a logical drug choice for treating atherogenic dyslipidaemia commonly associated with type 2 diabetes mellitus and the metabolic syndrome, and has been shown to be effective in patients with diabetes without adversely affecting glycaemic control in the majority of patients. The incidence of vasodilatory flushing with PR nicotinic acid is lower than with IR nicotinic acid and it decreases substantially over time as tolerance develops. To date, there has been no clinically significant hepatotoxicity observed with PR nicotinic acid. Therefore, once-daily PR nicotinic acid appears to maximise the potential benefits of nicotinic acid, while minimising any historical tolerability or safety concerns.

Delayed-Action Preparations↗
PubMedDate not supplied

Enhanced myocardial preservation by nicotinic acid, an antilipolytic compound: mechanism of action.

The cardioprotective effects of an antilipolytic compound, nicotinic acid, on arrested-reperfused myocardium were investigated in the isolated in situ pig heart preparation. Hearts were preperfused for 15 min in the presence of (5-3H)-glucose and (U-14C)-palmitic acid. Half of the hearts were then perfused with 0.08 mM nicotinic acid for an additional 15-min period, while the remaining control hearts received unmodified perfusion. Arrest was then induced in all animals for 2 h using hypothermic K+ cardioplegia, followed by 60 min of normothermic reperfusion. In control hearts, there were significantly greater levels of long-chain acyl Co-A and acyl carnitine and lower levels of membrane phospholipids than in the nicotinic acid group. While nicotinic acid inhibited beta-oxidation during pre-ischemia and reperfusion, it also prevented the degradation of membrane phospholipids. The net result was a reduction of free fatty acid accumulation during arrest and reperfusion in the nicotinic acid group. Glycolysis, as reflected in 3H2O production, was significantly increased by nicotinic acid administration. In the control heart as compared to the nicotinic acid group, the incorporation of 14C-label from palmitate into triglyceride and cholesterol during arrest was enhanced, while incorporation into phospholipids was depressed. The cardioprotective effects of nicotinic acid were demonstrated by decreased release of creatine kinase and improved coronary blood flow, and cardiac contractility in the reperfused myocardium supplemented with nicotinic acid compared to the control group. These results suggest that nicotinic acid significantly protects the arrested-reperfused myocardium by a) preventing elevation of myocardial fatty acid levels, b) stimulating glycolysis by limiting fatty acid oxidation, c) inhibiting degradation of membrane phospholipids, and d) preventing accumulation of fatty acid metabolites with harmful detergent properties.

Animals↗