Effect of adrenergic receptor blockade on nicotinic acid-induced plasma FFA rebound

Blackard, William G.; Heidingsfelder, Sylvia A.

doi:10.1016/0026-0495(69)90042-0

Cited by 14 publications

(7 citation statements)

References 10 publications

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“…Blackard, Boylen, Hinson, and Nelson (5) and Blackard, Hull, and Lopez-S (6) reported that FFA elevation inhibits HGH release in the monkey and in man. In two other reports, however, no GH increase was seen after FFA depression in monkeys (7) and no inhibition of HGH release by FFA elevation in man (8).…”

Section: Introductionmentioning

confidence: 74%

“…However, practically nothing is known about the lipid metabolism of the hypothalamus, though the FFA concentration of this area has recently been found (in the rat) to be much higher than in other parts of the brain (19). FFA have also been suggested to play a role in postsynaptic membrane permeability in the brain, but these are thought to be derived from brain phospholipids rather than from peripheral sources (20 (7). This supports the view that factors other than HGH are more important for the FFA rebound, but does not exclude its participation in those cases in which the HGH increase occurs early enough before the rebound (24,25).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man

Quabbe¹,

Bratzke²,

Siegers³

et al. 1972

J. Clin. Invest.

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A B S T R A C T The influence of plasma free fatty acid (FFA) concentration on the secretion of human growth hormone (HGH) was investigated. (a) FFA depression was produced by means of a nicotinic acid (NA) infusion for either 1 or 5 hr in the presence of glucoseinduced hyperglycemia. Controls received only saline. (b) FFA depression was also produced by a 90 min NA infusion and then rapid FFA elevation by a lipid-plusheparin (lipid) infusion. This procedure was compared with a similar NA infusion not followed by lipid. (c) FFA elevation was produced either by a lipid or by a norepinephrine (NE) infusion and then HGH secretion was stimulated by insulin-induced hypoglycemia. Each subject in this group received both the lipid and the NE infusion on seperate days as well as two control tests (insulin alone and NE alone).Depression of FFA resulted in an increase of HGH with a lag period of approximately 2 hr. Maximal HGH rise after 1 hr NA infusion was 7.7±1.9 ng/ml and with 5 hr NA infusion 14.3±3.6 ng/ml (both significantly higher than during saline infusion, P < 0.025 and <0.005 respectively) and occurred despite continuous hyperglycemia. Lipid infusion just before the expected HGH increase prevented the HGH response to FFA depression. HGH rise during insulin hypoglycemia (32.2± 6.5 ng/ml) was significantly inhibited by prior FFA elevation whether achieved by lipid infusion (maximum HGH rise 11.4±1.6 ng/ml) or by NE infusion (maximum HGH rise 19.0±6.2 ng/ml).The results are suggestive of a negative feedback loopThe results of this work were presented at the 2nd International Symposium on Growth Hormone, Milan, Italy, 5-7 May 1971. This work was supported by Deutsche Forschungsgemeinschaft.Received for publication 7 February 1972 and in revised form 27 March 1972. between plasma FFA and HGH secretion, of importance for subacute rather than acute changes in the plasma FFA concentration. FFA lack itself seems to be the signal for HGH release despite the lag period between FFA decrease and HGH increase. Glucose and FFA can at least not fully replace each other in their respective influence on HGH release.

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Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man

Quabbe¹,

Bratzke²,

Siegers³

et al. 1972

J. Clin. Invest.

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“…The mechanism of FFA rebound with nicotinic acid remains unknown. It has been suggested that the magnitude of rebound is dependent upon the magnitude of decrease in FFA, and a significant correlation between FFA lowering and rebound has been shown for nicotinic acid (Blackard and Heidingsfelder, 1969;Schwabe et al, 1974). Rebound increase in plasma FFA levels was not observed with CVT-3619, even though FFA concentrations were decreased by similar extent by both CVT-3619 and nicotinic acid, i.e., 54 and 57% from baseline, respectively.…”

Section: Discussionmentioning

confidence: 95%

“…Its use is limited by side effects such as flushing and a post-treatment rebound increase in FFA (McKenny et al, 1994). The suppression of lipolysis by nicotinic acid is followed by a rebound in FFA release, such that the levels of FFA rise above the baseline upon washout of the effect (Pereira, 1967;Blackard and Heidingsfelder, 1969). The rebound has been suggested to be responsible for the paradoxical decrease in insulin sensitivity observed when using large doses of nicotinic acid (Kelly et al, 2000;Poynten et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Dhalla

Santikul²,

Smith³

et al. 2007

J Pharmacol Exp Ther

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Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A 1 adenosine receptor agonists are potent inhibitors of lipolysis. Several A 1 agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619, a novel partial A 1 receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A 1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p Ͻ 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A 1 agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.

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“…The mechanism of NEFA rebound with NA remains unknown. It has been suggested that its magnitude depends on the decrease in NEFA (Blackard and Heidingsfelder, 1969). However, even if an implication of the parasympathetic system has been mentioned, literature did not provide any experimental data to support such hypotheses.…”

Section: Discussionmentioning

confidence: 99%

Nicotinic Acid Decreases Apolipoprotein B100-Containing Lipoprotein Levels by Reducing Hepatic Very Low Density Lipoprotein Secretion through a Possible Diacylglycerol Acyltransferase 2 Inhibition in Obese Dogs

Bloch¹,

Leray²,

Chétiveaux³

et al. 2010

J Pharmacol Exp Ther

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Apolipoprotein B100 (apoB100) is an essential component of very low density lipoprotein (VLDL) and low-density lipoprotein (LDL), both independent markers of cardiovascular risk. Nicotinic acid (NA) is an efficacious drug for decreasing VLDL and LDL, but the underlying mechanisms are unclear. For this purpose, six obese insulin-resistant dogs were given 350 mg/day of NA for 1 week and then 500 mg/day for 3 weeks. Turnover of apoB100-containing lipoproteins was investigated using stable isotope-labeled tracers. Multicompartmental modeling was used to derive kinetic parameters before and at the end of NA treatment. Hepatic diacylglycerol acyltransferase 2 (DGAT2), microsomal triglyceride transfer protein (MTP), hepatic lipase (HL), and adipose lipoprotein lipase (LPL) mRNA expression was also determined. NA treatment decreased plasma triglyceride (TG) (p Ͻ 0.001), VLDL-TG (p Ͻ 0.05), total cholesterol (p Ͻ 0.0001), and LDL cholesterol (p Ͻ 0.05), whereas plasma nonesterified fatty acids were unchanged. The decrease in VLDL-apoB100 concentration (p Ͻ 0.001) was the result of a lower absolute production rate (APR) (p Ͻ 0.001), despite a moderate decrease (p Ͻ 0.05) in fractional catabolic rate (FCR). LDLapoB100 concentration was reduced (p Ͻ 0.05), an effect related to a decrease in LDL APR (p Ͻ 0.05) and no change in FCR. NA treatment reduced DGAT2 expression (p Ͻ 0.05), whereas MTP, HL, and LPL expression was unchanged. Our results suggest that NA treatment reduced VLDL and LDL concentration as a consequence of a decrease in VLDL production.

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Effect of adrenergic receptor blockade on nicotinic acid-induced plasma FFA rebound

Cited by 14 publications

References 10 publications

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Nicotinic Acid Decreases Apolipoprotein B100-Containing Lipoprotein Levels by Reducing Hepatic Very Low Density Lipoprotein Secretion through a Possible Diacylglycerol Acyltransferase 2 Inhibition in Obese Dogs

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Effect of adrenergic receptor blockade on nicotinic acid-induced plasma FFA rebound

Cited by 14 publications

References 10 publications

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man

Antilipolytic Activity of a Novel Partial A1Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Nicotinic Acid Decreases Apolipoprotein B100-Containing Lipoprotein Levels by Reducing Hepatic Very Low Density Lipoprotein Secretion through a Possible Diacylglycerol Acyltransferase 2 Inhibition in Obese Dogs

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Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid