SOme stuff:
J Vasc Surg. 1999 Jun;29(6):1097-103.
Propionyl-L-carnitine dilates human subcutaneous arteries through an endothelium-dependent mechanism.
Cipolla MJ1, Nicoloff A, Rebello T, Amato A, Porter JM.
Author information
Abstract
PURPOSE:
The vasoactive effects of propionyl-L-carnitine (PLC) on human arteries, including endothelial and smooth muscle cell influences, were studied.
METHODS:
Small (less than 200 microm) subcutaneous fat arteries (n = 19), obtained from human patients undergoing vascular surgery, were dissected and mounted in an arteriograph system that allowed measurement of lumen diameter and control of transmural pressure. To investigate the role of the endothelium, arteries were compared intact, intact and in the presence of either 0.3 mmol/L nitro-L-arginine (an inhibitor of nitric oxide synthesis) or 10 micromol/L indomethacin (an inhibitor of prostaglandin synthesis), or denuded of endothelium. After a 1-hour equilibration at a pressure of 50 mm Hg, arteries were precontracted 50% with an intermediate concentration of norepinephrine, and clinically relevant concentrations of PLC (0.1 to 100 micromol/L) were cumulatively added to the bath while the lumen diameter was continually measured.
RESULTS:
Intact arteries dose-dependently dilated to PLC, with the half maximal dilation occurring at 2.9 +/- 1.2 micromol/L, increasing diameter 91% +/- 5% at 100 micromol/L. In contrast, PLC had significantly less effect on deendothelialized arteries, increasing diameter only 24% +/- 11% at 100 micromol/L (P <.01 vs. intact). This indicates the endothelial dependency of this compound. Blockade of nitric oxide did not inhibit this vasodilation, with the half-maximal response occurring at 8.6 +/- 7 micromol/L, increasing diameter 85% +/- 8% at 100 micromol/L ( P >.05 vs. intact). However, this vasodilation was significantly diminished in the presence of indomethacin, which dilated arteries only 53% +/- 18% at 100 micromol/L (P <.01 vs. intact; P >.05 vs. denuded).
CONCLUSION:
PLC is an endothelium-dependent vasodilator, the mechanism of which is partially mediated by prostaglandin synthesis, not nitric oxide. The beneficial effects of this compound may, in part, be related to vasodilation and enhanced blood flow.
PMID:
10359944
Basic Res Cardiol. 2000 Apr;95(2):75-83.
Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions.
Calvani M1, Reda E, Arrigoni-Martelli E.
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Abstract
This review focuses on the regulation of myocardial fatty acids and glucose metabolism in physiological and pathological conditions, and the role of L-carnitine and of its derivative, propionyl-L-carnitine. Fatty acids are the major oxidation fuel for the heart, while glucose and lactate provide the remaining need. Fatty acids in cytoplasm are transformed to long-chain acyl-CoA and transferred into the mitochondrial matrix by the action of three carnitine dependent enzymes to produce acetyl-CoA through the beta-oxidation pathway. Another source of mitochondrial acetyl-CoA is from the oxidation of carbohydrates. The pyruvate dehydrogenase (PDH) complex, the key irreversible rate limiting step in carbohydrate oxidation, is modulated by the intra-mitochondrial ratio acetyl-CoA/CoA. An increased ratio results in the inhibition of PDH activity. A decreased ratio can relieve the inhibition of PDH as shown by the transfer of acetyl groups from acetyl-CoA to carnitine, forming acetylcarnitine, a reaction catalyzed by carnitine acetyl-transferase. This activity of L-carnitine in the modulation of the intramitochondrial acetyl-CoA/CoA ratio affects glucose oxidation. Myocardial substrate metabolism during ischemia is dependent upon the severity of ischemia. A very severe reduction of blood flow causes a decrease of substrate flux through PDH. When perfusion is only partially reduced there is an increase in the rate of glycolysis and a switch from lactate uptake to lactate production. Tissue levels of acyl-CoA and long-chain acylcarnitine increase with important functional consequences on cell membranes. During reperfusion fatty acid oxidation quickly recovers as the prevailing source of energy, while pyruvate oxidation is inhibited. A considerable body of experimental evidence suggests that L-carnitine exert a protective effect in in vitro and in vivo models of heart ischemia and hypertrophy. Clinical trials confirm these beneficial effects although controversial results are observed. The actions of L-carnitine and propionyl-L-carnitine cannot be explained as exclusively dependent on the stimulation of fatty acid oxidation but rather on a marked increase in glucose oxidation, via a relief of PDH inhibition caused by the elevated acetyl-CoA/CoA ratio. Enhanced pyruvate flux through PDH is beneficial for the cardiac cells since less pyruvate is converted to lactate, a metabolic step resulting in the acidification of the intracellular compartment. In addition, L-carnitine decreases tissue levels of acyl moieties, a mechanism particularly important in the ischemic phase.
PMID:
10826498
Vasc Med. 1997;2(2):77-81.
Carnitines increase plasma levels of adenosine and ATP in humans.
Capecchi PL1, Laghi Pasini F, Quartarolo E, Di Perri T.
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Abstract
In order to help to clarify the mode of action of carnitine derivatives, plasma levels of adenosine, ATP and inosine were evaluated following the infusion of 0.75, 0.50 and 0.25 mg/kg/min propionyl-L-carnitine (PLC) for 30 min in patients affected with peripheral arterial disease. Moreover, the effects of 0.75 mg/kg/min acetyl-L-carnitine (ALC) and L-carnitine (LC) were studied in the same conditions. Finally, the activity of 7.5 mg/kg/min PLC administered for 3 min was also evaluated. PLC and ALC produced a significant increase in plasma levels of adenosine and ATP, whereas LC induced less relevant changes. The administration of the compounds did not affect the adenosine/inosine ratio. Peak plasma levels of adenosine preceded in any case those of ATP. The possibility can be suggested that the pharmacological activity of PLC, ALC, and LC may be mediated, at least in part, by an interference with the endogenous purine system. Since these effects may be related to physiological mechanisms of tissue protection, new pharmacological perspectives for the compounds may arise.
PMID:
9546959
Ann N Y Acad Sci. 2004 Nov;1033:79-91.
Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review.
Ferrari R1, Merli E, Cicchitelli G, Mele D, Fucili A, Ceconi C.
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Abstract
Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent remodeling of the left ventricle. Propionyl-L-carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.
PMID:
15591005