The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor-alpha (PPARalpha). Here we show that a PPARalpha agonist, ureido-fibrate-5 (UF-5), approximately 200-fold more potent than fenofibric acid, exerts TG-lowering effects (37%) in fat-fed hamsters after 3 days at 30 mg/kg. In addition to lowering hepatic apolipoprotein C-III (apoC-III) gene expression by approximately 60%, UF-5 induces hepatic mitochondrial carnitine palmitoyltransferase I (CPT I) expression. A 3-wk rising-dose treatment results in a greater TG-lowering effect (70%) at 15 mg/kg and a 2.3-fold elevation of muscle CPT I mRNA levels, as well as effects on hepatic gene expression. UF-5 also stimulated mitochondrial [3H]palmitate beta-oxidation in vitro in human hepatic and skeletal muscle cells 2.7- and 1.6-fold, respectively, in a dose-related manner. These results suggest that, in addition to previously described effects of fibrates on apoC-III expression and on peroxisomal fatty acid (FA) beta-oxidation, PPARalpha agonists stimulate mitochondrial FA beta-oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPARalpha agonists.

Tyrphostins are low-molecular-weight synthetic inhibitors of protein tyrosine kinase, which block cell proliferation. Since platelet-derived growth factor (PDGF) is thought to figure prominently in disorders of vascular smooth muscle cells (VSMC), such as atherosclerosis, hypertension, and restenosis, we examined whether tyrphostins would inhibit PDGF-induced mitogenesis in VSMC. In this communication, we demonstrate that tyrphostins with the benzenemalononitrile nucleus inhibited PDGF-dependent growth of VSMC as well as PDGF-dependent DNA synthesis in these cells, with the concentrations for 50% inhibition ranging from 0.04 to 9 microM. Up to 30-fold higher tyrphostin concentrations were required to inhibit serum-stimulated DNA synthesis of VSMC. The effect of the tyrphostins is reversible, since on their removal a normal proliferative response to PDGF was resumed. Tyrphostins also inhibited PDGF-receptor autophosphorylation and PDGF-induced phosphorylation of intracellular substrates, including the phosphorylation of phospholipase C-gamma, with a potency ratio similar to their antimitogenic activity. The expression of c-fos mRNA, a mitogenic nuclear signal, was also reduced in PDGF-stimulated VSMC treated with tyrphostins at concentrations which inhibit PDGF-induced mitogenesis. It is concluded that tyrphostins are potent reversible inhibitors of PDGF-induced mitogenesis which act by inhibiting the tyrosine kinase activity of the PDGF receptor and the subsequent signaling cascade. Tyrphostins may be useful in the study and treatment of VSMC proliferation disorders.

RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.

No abstract

Release of atrial natriuretic factor (ANF) following an elevation in heart rate is thought to be mediated primarily by a change in atrial stretch. To evaluate the direct effect of chronotropic stimulation on ANF release, isolated rat left atria were electrically paced (1-9 Hz) at constant resting tension (0.5-4 g), and the amount of immunoreactive ANF (IRANF) released at each frequency and tension was quantitated with a sensitive radioimmunoassay. Our results show that at controlled resting tensions greater than 1 g, chronotropic stimulation increased IRANF secretion in a manner dependent on the pacing frequency; rapid atrial rates (e.g., 8 and 9 Hz) were necessary to release ANF at tensions of 1 g or less. Resting tension influenced the magnitude of the secretory response to electrical stimulation. Release of IRANF with contraction frequency was transient in nature and, at high frequencies, was associated with a decrease in developed (systolic) tension in accordance with the negative force-frequency relation inherent in the rat heart. When evaluated at a single diastolic tension and pacing frequency, IRANF release was positively correlated with systolic tension. ANF released under in vitro conditions was approximately 3,000 Da, in agreement with the size of the physiologically circulating form. In atria from reserpinized rats, evidence for involvement of catecholamines in chronotropicstimulated ANF release was suggested. The presence of lidocaine (5xlO~4 M) had no effect on rate-induced ANF secretion. Therefore, chronotropic stimulation releases ANF independently of changes in atrial stretch. The magnitude of this response depends on a combination of pacing frequency and diastolic tension. Catecholamine release and sodium transport through channels sensitive to a local anesthetic appear to play a minor role in rate-dependent ANF release in vitro. Release of ANF appears to be influenced by the degree of atrial distension. 5 In addition to atrial stretch, the marked elevation in plasma ANF following episodes of paroxysmal tachycardia in humans, 6 -9 intracardiac pacing in humans and animals, 1011 and increased ANF secretion with repetitive atrial stretch 12 or electrical stimulation 13 in vitro suggest that heart rate may be an additional stimulus for ANF release. Because changes in atrial pressure (distension) are known to accompany alterations in heart rate in vivo and because developed tension is influenced by changes in rate in vitro, results of previous studies associating contraction frequency with ANF release have been unable to Received April 5, 1988; accepted September 28, 1988. provide convincing evidence for a direct effect of heart rate on ANF release. The purpose of these experiments, therefore, was to determine whether atrial rate can influence ANF secretion independently of changes in resting (diastolic) tension. Rat atria were used for these experiments because, in this species, developed (systolic) tension is inversely related to contraction frequency.14 Since diastolic tension influences ANF ...