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Biomedical subjects

R Paoletti

Publications and source records attributed to R Paoletti.

At least 127 records · Page 7Linked to original sources
PubMed1988

Calcium antagonists and low density lipoprotein receptors.

The effect of different calcium antagonists on receptor-mediated LDL catabolism by human cells in culture was investigated. The calcium antagonists have been recently classified in six types, based on their pharmacological activities. The three types selective for the slow calcium channels (types I, II, and III), and the nonselective type IV have been investigated in respect to LDL metabolism. Calcium antagonists of type I (verapamil-related compounds) and type III (diltiazem) induce an increase of receptor-mediated uptake of human LDL. In contrast, calcium antagonists of type II (nifedipine-related compounds) and type IV (flunarizine) are inactive. Verapamil and diltiazem stimulate LDL receptor activity in normal fibroblasts, in fibroblasts obtained from a hypercholesterolemic type IIa heterozygous patient, in the human hepatoma cell line HepG2, but not in receptor-negative cells. The stimulatory effect depends on drug concentrations in the culture medium. Cycloheximide and alpha-amanitin prevent the stimulating effect of calcium antagonists on LDL uptake. The possible mechanisms of this action of calcium antagonists and the relationship between the in vitro stimulation of LDL receptor activity and the in vivo inhibition of lipid deposition in the arterial wall elicited by calcium antagonists are discussed. Calcium antagonists may exert part of their antiatherosclerotic activity by counteracting the inhibition of receptor-mediated lipid metabolism induced by calcium deposition in the cellular components of the arterial walls.

Calcium↗
PubMed1988

Effect of derivatives of trapidil on the expression of LDL receptors.

The influence of trapidil and some of its derivatives (AR 12456, AR 12463, AR 12465) on the LDL receptor mediated uptake and degradation of 125 I-LDL by human skin fibroblasts (HSF) and human hepatic cells (HEP G2) was investigated. AR 12456 enhanced the uptake and degradation of 125 I-LDL in HEP G2, but inhibited this pathway in HSF. When this drug was preincubated with HEP G2 cells, and then the incubation medium was transferred to HSF, a stimulation of specific LDL pathway occurred also in this cell line. Trapidil, AR 12463 and AR 12465 were inactive under the same experimental conditions. These findings suggest that a metabolite of AR 12456 might be responsible for the enhanced expression of LDL receptors in human cells.

Antihypertensive Agents↗
PubMed1986

[Neuromediator changes during cerebral aging. The effect of Ginkgo biloba extract].

Ginkgo biloba extract exerts a specific effect on the noradrenergic system and on beta-receptors. No variation was found in alpha 2-receptors and serotonin uptake. These findings provide the first evidence of central effects of a drug acting on cerebral ageing, connected specifically to reactivation of the noradrenergic system in the cerebral cortex.

Aging↗
PubMed1986

[Vascular and neuronal mechanisms of calcium antagonists. Significance in neurological therapy].

Calcium-channel entry blockers are drugs with different chemical properties and a common pharmacological characteristic. Calcium is very important in many physiological mechanisms and could be involved in neuronal damage following cerebral ischemia. Thus, calcium-channel blockers agents could be of interest in medical treatment of cerebrovascular diseases, headache and subarachnoid hemorrhage. Calcium-channel blockers seem to have a direct protective role against neuronal ischemic damage and/or a direct action on cerebral vessels. Some clinical experiences have suggested a protective role of nimodipine in the prevention of ischemic complications related to cerebral vasospasm after subarachnoid hemorrhage.

Blood-Brain Barrier↗
PubMed1986

Dietary interventions in north Karelia, Finland and south Italy. Modification of thromboxane B2 formation in platelets of male subjects only.

The effects of dietary interventions, based on changes of total fat, saturated fatty acids and cholesterol contents and of the polyunsaturated/saturated (P/S) fatty acid ratio of the diet, were studied in normal male and female subjects, living in North Karelia, Finland, and South Italy. In North Karelia the increase of P/S ratio (from 0.15 to 1.2) of the diet for a 6-week period resulted in reduced thromboxane B2 (TxB2) production by collagen-stimulated platelets only in male subjects, whereas plasma total, LDL and HDL cholesterol were reduced in both sexes. After a 6-week return to the original diet, plasma lipid levels were restored in all subjects. In the South Italy study, changes in platelet TxB2 production were observed only after return to the original diet in male subjects. Total and LDL cholesterol were significantly increased during the dietary intervention and returned toward baseline levels after switch back to the original diet. These data indicate that the increase of the P/S ratio in the diet reduces platelet TxB2 formation only in men.

Adult↗
PubMed1986

Calcium antagonists and low density lipoproteins metabolism by human fibroblasts and by human hepatoma cell line HEP G2.

The effect of Ca2+ antagonists (CA) on the receptor-mediated low density lipoprotein pathway has been investigated "in vitro" in human skin fibroblasts (HSF) and in human hepatoma cell line Hep G2. The specific binding and internalization of human 125I-labeled LDL are dose-dependently increased in HSF by CA of the verapamil series (verapamil, anipamil, gallopamil, ronipamil, and diltiazem), but neither by CA of the dihydropyridine series (nifedipine, nitrendipine) nor by flunarizine. BAY K 8644, a Ca2+ agonist, elicited an opposite effect. In the presence of the tested CA, LDL degradation is either unaffected (lower concentrations) or inhibited (higher concentrations). 125I-LDL uptake is stimulated also in fibroblasts from type IIa hypercholesterolemic patients, heterozygous for defective expression of LDL receptor. The enhanced cellular uptake of 125I-LDL was prevented by cycloheximide and by alpha-amanitin. CA of the verapamil series including diltiazem retained their effect in human hepatoma cell line Hep G2, a model proposed for hepatic metabolism of LDL. Our studies show that a) CA stimulate the high affinity binding and internalization of LDL in HSF and in human hepatoma cell line Hep G2; b) this stimulation involves DNA transcription and new protein synthesis; c) this effect is specific to one subgroup of Ca2+ antagonists (the verapamil class only).

Amanitins↗
PubMed1986

Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.

A study in vitro of specimens of human aortic and common carotid arteries was carried out to determine the feasibility of direct measurement (i.e., not from residual lumen) of arterial wall thickness with B mode real-time imaging. Measurements in vivo by the same technique were also obtained from common carotid arteries of 10 young normal male subjects. Aortic samples were classified as class A (relatively normal) or class B (with one or more atherosclerotic plaques). In all class A and 85% of class B arterial samples a characteristic B mode image composed of two parallel echogenic lines separated by a hypoechoic space was found. The distance between the two lines (B mode image of intimal + medial thickness) was measured and correlated with the thickness of different combinations of tunicae evaluated by gross and microscopic examination. On the basis of these findings and the results of dissection experiments on the intima and adventitia we concluded that results of B mode imaging of intimal + medial thickness did not differ significantly from the intimal + medial thickness measured on pathologic examination. With respect to the accuracy of measurements obtained by B mode imaging as compared with pathologic findings, we found an error of less than 20% for measurements in 77% of normal and pathologic aortic walls. In addition, no significant difference was found between B mode-determined intimal + medial thickness in the common carotid arteries evaluated in vitro and that determined by this method in vivo in young subjects, indicating that B mode imaging represents a useful approach for the measurement of intimal + medial thickness of human arteries in vivo.

Adult↗
PubMed1986

Aspirin inhibits platelet 12-hydroxy-eicosatetraenoic acid formation.

The effects of aspirin on platelet 12-hydroxyeicosatetraenoic acid (12-HETE) formation were studied after administration to humans in platelet-rich plasma (PRP) and in vitro in human PRP and in washed platelets (WPs). Healthy volunteers were given orally either single or repeated (1 week) daily doses (20 and 500 mg) of aspirin. Two hours after a single 20 mg aspirin dose, 12-HETE formation by PRP was significantly inhibited. With the highest aspirin dose used (500 mg), the inhibition of 12-HETE formation was more pronounced and long lasting. Thromboxane B2 (TXB2) synthesis was significantly inhibited at 2 hours with the lowest dose. At the 500 mg dose, platelet aggregation was significantly reduced, and TXB2 formation was almost completely suppressed for at least 24 hours. The degree of inhibition of 12-HETE formation at 2 hours after 1 week of daily treatment (20 and 500 mg) was similar to that achieved at 2 hours after the single dose. As far as TXB2 and platelet aggregation are concerned, the effect of 20 mg aspirin was cumulative. In vitro studies show that aspirin (0.25 to 3 mmol/L concentration) significantly inhibits 12-HETE formation in PRP, but not in WPs, suggesting that plasma is required for the aspirin effect on lipoxygenase products. These results indicate that aspirin, even at low doses, not only affects the platelet cyclooxygenase activity but also exerts reversible inhibition of 12-HETE formation, both in vitro and ex vivo. These data may help to further elucidate the role of hydroxyacids in the anti-inflammatory and antipyretic action of aspirin.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1985

Pathological significance of the thromboxane-prostacyclin hypothesis.

Disturbances in the balance between the production of thromboxane A2 by the platelets and that of prostacyclin by the vessel wall may play a major role in disease and be a target for therapeutic agents. Acetylsalicylic acid, given in small doses, may inhibit the production of thromboxane A2 without affecting that of prostacyclin. Even if it reduces prostacyclin synthesis, the drug is beneficial as an antithrombotic agent, possibly because it has actions not related to inhibition of cyclooxygenase. Dazoxiben not only inhibits the production of thromboxane A2 by platelets, but also facilitates that of prostanoids, in part by diverting endoperoxides to the blood vessel wall and to leukocytes. Although reduced production of prostacyclin may contribute to the etiology of atherosclerosis, the blood vessel wall of hypercholesterolemic animals exhibits an increased production of prostacyclin. The latter has been given successfully in patients with accelerated turnover of platelets or with peripheral vascular disease. However, its very short t1/2 limits its practical use. The availability of stable prostacyclin derivates, such as ZK 36374, may bypass this problem.

Animals↗