Objective-The beneficial effect of the natural compound propionyl-L-carnitine (PLC) on intermittent claudication in patients with peripheral arterial disease is attributed to its anaplerotic function in ischemic tissues, but inadequate information is available concerning action on the vasculature. Methods and Results-We investigated the effects of PLC in rabbit hind limb collateral vessels after femoral artery excision, mouse dorsal air pouch, chicken chorioallantoic membrane, and vascular cells by angiographic, Doppler flow, and histomorphometrical and biomolecular analyses. PLC injection accelerated hind limb blood flow recovery after 4 days (PϽ0.05) and increased angiographic quadriceps collateral vascularization after 7 days (PϽ0.001) Histomorphometry confirmed the increased vascular area (PϽ0.05), with unchanged intramuscular capillary density. PLCinduced dilatative adaptation, and growth was found associated with increased inducible nitric oxide synthase and reduced arterial vascular endothelial growth factor and intracellular adhesion molecule-1 expression. PLC also increased vascularization in air pouch and chorioallantoic membrane (PϽ0.05), particularly in large vessels. PLC increased endothelial and human umbilical vascular endothelial cell proliferation and rapidly reduced inducible nitric oxide synthase and NADPH-oxidase 4 -mediated reactive oxygen species production in human umbilical vascular endothelial cells; NADPH-oxidase 4 also regulated NF-B-independent intracellular adhesion molecule-1 expression. Conclusion-Our results provided strong evidence that PLC improves postischemic flow recovery and revascularization and reduces endothelial NADPH-oxidase-related superoxide production. We recommend that PLC should be included among therapeutic interventions that target endothelial function. Key Words: arteriogenesis Ⅲ endothelial function Ⅲ oxidative stress Ⅲ vascular function P eripheral arterial disease (PAD) is the most common clinical consequence of atherosclerosis, affecting Ϸ20% of adults older than age 55 years. 1 Atherosclerotic occlusion of leg arteries induces clinical manifestations, most frequently intermittent claudication. 1,2 Among the functional vascular changes observed with atherosclerosis, endothelial dysfunction plays a major role. 3,4 L-carnitine is a natural amino acid that plays a crucial role in the shuttle mechanism of long-chain fatty acids and in fueling  oxidation. 5 The endogenous L-carnitine pool includes a series of short-chain, medium-chain, and long-chain esters in homeostatic equilibrium. 5,6 Propionyl-L-carnitine (PLC) is a short-chain L-carnitine ester that has been introduced among emerging noninterventional medical regiments that aim to counteract PAD-related adverse effects. 1,2,7 PLC activity is classically related to the anaplerotic function of providing substrates for energy expenditure in ischemic tissues. 1,8 Although some data showed beneficial remodeling after injury, 9 the mechanisms through which PLC influences arterial function remain largely hypot...
The novel Na ϩ /K ϩ -ATPase inhibitor (E,Z)-3-((2-aminoethoxy)-imino)androstane-6,17-dione hydrochloride (PST2744) was characterized for its inotropic and toxic properties. Inhibition potency on dog kidney Na ϩ /K ϩ -ATPase was comparable (0.43 M) to that of digoxin (0.45 M). PST2744 concentration-dependently increased force of contraction in guinea pig atria and twitch amplitude in isolated guinea pig myocytes; in the latter, aftercontractions developed significantly less than with digoxin. Intravenous infusion of 0.2 mg/kg/min PST2744 in anesthetized guinea pigs exerted an immediate and long-lasting inotropic effect (ED 80 of 1.89 Ϯ 0.37 mg/kg) without causing lethal arrhythmias up to a cumulative dose of 18 mg/kg. Conversely, an equieffective infusion of digoxin (0.016 mg/kg/min; ED 80 of 0.32 mg/kg) caused lethal arrhythmias at a cumulative dose of 0.81 mg/kg. At a higher rate (0.4 mg/kg/min), PST2744 induced lethal arrhythmias, with a lethal dose/ED 80 ratio significantly greater than digoxin (20.2 Ϯ 6.3 versus 3.23 Ϯ 0.55, p Ͻ 0.05). Decay of the inotropic effect (t 1/2 , min) was significantly faster for PST2744 (6.0 Ϯ 0.39) than for digoxin (18.3 Ϯ 4.5, p Ͻ 0.05). In anesthetized dogs, PST2744 dose-dependently increased maximum velocity of pressure rise (ϩdP/dt max ) in the range 32 to 500 g/kg i.v. and was safer than digoxin. In conscious dogs with a healed myocardial infarction, PST2744 significantly increased resting values of ϩdP/dt max , left ventricular pressure, and SPB, and increased ϩdP/dt max throughout treadmill exercise while reverting the increase in left ventricular end diastolic pressure seen in control animals. Digoxin significantly decreased basal heart rate, while not affecting the hemodynamic response to exercise. Thus, PST2744 represents a new class of Na ϩ /K ϩ -ATPase inhibitors endowed with inotropic activity comparable with that of digitalis but having greater safety.Improvement of heart failure (HF) treatment remains a major medical challenge for the coming years. Despite achievement of considerable progress during the last two decades, none of the available therapeutic agents is fully satisfactory, and HF remains a disease with a poor prognosis (Kannel, 2000). The goal of ameliorating quality of life, exercise capability, and survival is only partially met by angiotensin-converting enzyme inhibitors, diuretics, vasodilators, glycosides, and -blocking agents, regardless of their being used in combined therapy (Consensus Recommendations for the Management of Chronic Heart Failure, 1999). Therefore, the need still remains for novel drugs able to increase workload tolerance and to reduce morbidity and mortality. Worsening of survival found with chronic administration of inotropic agents that increase intracellular cAMP (phosphodiesterase inhibitors and sympathomimetic amines) (The Xamoterol in Severe Heart Failure Study Group, 1990;Packer et al., 1991;Cohn et al., 1998) and the well known arrhythmogenic effects of cardiac glycosides have led to the general view that drug-i...
Inotropic agents for acute decompensated heart failure are associated with a lack of efficacy or increased mortality. New compounds are needed to support patients with acute exacerbations of heart failure. This study examined the hemodynamic effects of a new inotropic agent (PST-2744) in dogs with chronic ischemic heart failure. Eight mongrel dogs at low risk for postmyocardial infarction (MI) sudden death entered the protocol. Dogs were studied after ischemic left ventricular dysfunction was induced by repeated injections of latex microspheres into the circumflex artery until the ejection fraction reached 35%. Hemodynamic parameters were measured at baseline and peak drug effect (PST-2744 5 microg.kg-1.min-1). In 5 animals, PST-2744 effects were compared with dobutamine. Heart rates, PR intervals and QT intervals were unchanged following PST-2744 administration. PST-2744 increased contractility (+dP/dt) by 56% from 1881 +/- 282 mm Hg/s to 2939 +/- 734 mm Hg/s (P < 0.01). The inotropic effect of PST-2744 was equal to that produced by 5-microg.kg-1.min-1 dobutamine (56% increase in +dP/dt), but peak heart rates were significantly higher with dobutamine (129 +/- 24 bpm PST-2744 versus 160 +/- 6 bpm 5-microg.kg-1.min-1 dobutamine, P < 0.002). No arrhythmias or conduction delays were seen with either compound. PST-2744 is an effective inotropic agent without positive chronotropic effect in subjects with stable moderate left ventricular dysfunction.
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