Alessandro Chinellato

Evaluation of the prescription and utilization patterns of statins in an Italian local health unit during the period 1994–2003

ObjectivesThe prescription pattern of statins in the Local Health Unit (LHU) of Treviso (northern Italy) over a 10-year period was evaluated, with the aim of evaluating the persistence with and adherence to therapy.MethodsData on 21,393 subjects who received at least one prescription for statins during the period between January 1, 1994 and December 31, 2003 were retrieved from the LHU database in order to track the pharmacological history of individual patients. The data included age, sex, drug formulation, strength, number of drug packages prescribed, and prescription date. The adopted indicators for drug utilization included the Defined Daily Dose (DDD), the Received Daily Dose (RDD), and a surrogated Prescribed Daily Dose (sPDD), extrapolated from available prescription data. An Adherence to Therapy Index (ATI) was calculated from the ratio between the amount of drug actually prescribed and the amount of sPDD. Based on the ATI, patients were grouped into non-adherent, poor-adherent, and good-adherent groups. The distribution of adherence level among patient-age classes and statin-prescribed patients in primary or secondary prevention was evaluated.ResultsAll drug-utilization indicators showed an increase in statin use over the study period in terms of both the number of prescribed patients and the sPDD. Persistence with and adherence to therapy remained low, with a 50% discontinuation rate in the first year, and persistent patients did not follow the therapy regularly. Patients in secondary prevention were the most adherent to their drug regimen, although only 41% of these had a good compliance.ConclusionsOur findings suggest an increase in statin use which is, however, accompanied by poor patient persistence with and adherence to statin therapy.

Dual effect of ATP and UTP on rat atria: which types of receptors are involved?

The effects of adenine compounds and UTP were examined in electrically driven rat left atria.ATP, ADP, AMP, adenosine and UTP caused a dual inotropic effect: first a rapid decrease in contractility, and second an increase in contractile tension. α,β-Methylene ATP caused an increase in contractile tension only, whereas 2-methylthio-ATP only induced a negative inotropic effect. 1,3-Dipropyl-8-cyclopentylxanthine inhibited the negative effects of ATP and adenosine, whereas 3,7-dimethyl-l-propargylxanthine did not influence the effects of ATP. Suramin but not reactive blue 2 antagonized the positive inotropism induced by ATP and α,β-methylene ATP. Suramin also abolished the positive inotropic effect induced by UTP.These results demonstrate that ATP may induce negative inotropism directly by an action on A1-adenosine receptors and positive inotropism by an action on P2x-purinoceptors. UTP induces a positive inotropic effect mediated by Suramin-sensitive receptors.

P2x-purinoceptors in the heart: actions of ATP and UTP.

Positive inotropic effects of ATP and UTP (1 microM - 1mM) were studied in isolated rat and guinea pig cardiac tissues. The potency order obtained was ATP>UTP in both species, suggesting possible interaction with P2X-purinoceptors. Binding studies using [(3)H]alpha,beta-methylene ATP as marker of P2X-purinoceptors revealed two receptor sites: one high-, the other low-affinity, in atria and ventricles from rat and guinea pig. Both ATP and UTP were found to bind high-affinity sites of [(3)H]alpha,beta-methylene ATP. The effects of various calcium inhibitors such as nifedipine, dantrolene, ryanodine and TMB-8 on positive inotropic effects induced by ATP and UTP were also studied. The results suggest that ATP and UTP may increase inotropism by interaction with P2X-purinoceptors by means of a calcium-dependent mechanism.

Effect of cholesterol-supplemented diet in heritable hyperlipidemic Yoshida rats: functional and morphological characterization of thoracic aorta

In this study we have considered the possibility of inducing vascular damage in Yoshida Pittsburg (YOS) rat, an inbred strain which has endogenous hyperlipidemia without vascular atherosclerotic damage. Cholesterol-enriched diet (4% cholesterol plus 1% cholic acid and 0.5% thiouracil) was administered to YOS rats, in order to induce atherogenesis. The results indicate that, despite significant increase in serum (about 2-fold) and aortic tissue cholesterol (about 6-fold), no morphological damage occurred. A reduction in acetylcholine-mediated relaxation (of about 37%) was observed. No inhibition of ATP- or sodium nitrite-induced relaxation, or of contraction induced by norepinephrine was seen. Serum triglyceride concentration did not vary after administration of a cholesterol-enriched diet. Our results suggest that in heritable hyperlipidemic Yoshida rat, after 2 months of cholesterol-enriched diet, despite increased serum cholesterol levels, no atheromatous plaque developed on the aortic wall. Impaired vascular function and reductions in the response to acetylcholine were related to changed endothelial cell function. Administration of a high cholesterol diet to YOS rat may represent a new model of mixed endogenous and exogenous hyperlipidemia that can resemble many human dislipidemic diseases and therefore may become a useful tool for the study of isolated endothelial dysfunction.

Effect of Age on Rabbit Aortic Responses to Relaxant Endothelium-Dependent and Endothelium-Independent Agents

The aim of this study was to evaluate the effects of aging on endothelium-dependent and endothelium-independent relaxation of rabbit thoracic aorta from New Zealand white rabbits aged 4-6 and 7-12 months. The contractile response to noradrenaline (NA) decreased with increasing age, but NA [EC50] did not vary significantly. Acetylcholine (Ach)-induced relaxation of aortic rings precontracted with NA [EC50] did not change significantly with increasing age. The relaxation induced by ATP of aortic rings, precontracted with NA [EC50], was significantly greater in young than in adult rabbits. This difference between young and adult animals became more evident in aortic rings deprived of endothelium: in adult animals, the ATP-induced relaxation of aortic rings with endothelium was significantly greater than in the rings without endothelium. The endothelium-independent relaxation by sodium nitrite (NaNO2) at lower concentrations was significantly greater in young than in adult rabbit aortic rings precontracted with NA [EC50]. Concluding, the age-induced changes in vascular response in male New Zealand white rabbits are related to an impaired mechanism at smooth muscle level.

Aortic response to relaxing agents in Watanabe heritable hyperlipidemic (WHHL) rabbits of different age

Serum and aortic tissue cholesterol levels in parallel with aortic relaxation to endothelium-dependent and independent drugs were determined in Watanabe heritable hyperlipidemic (WHHL) rabbits in comparison with New Zealand (N.Z.) normocholesterolemic rabbits, aged 4-14 months. Serum cholesterol was elevated (626 +/- 99 mg/100 ml) in 4-6-month-old WHHL rabbits and significantly lower in 12-14-month-old animals (344 +/- 51 mg/100 ml). Cholesterol infiltration in thoracic aorta was high in young WHHL compared with N.Z. rabbits (0.88 +/- 0.3 mg/100 mg fresh tissue vs. 0.08 +/- 0.003 mg/100 mg, respectively) and it did not vary with age. In N.Z. rabbits, serum and aortic cholesterol levels were low from 4 to 14 months of age. The aortic relaxation to acetylcholine (0.03-3 microM) on EC50 noradrenaline precontracted rings was similar in 4-6-month-old WHHL and N.Z. rabbits of the same age. In WHHL rabbits, the relaxation to acetylcholine was significantly reduced in 7-11- (-35% at maximum) and in 12-14-month-old rabbits (-40% at maximum). In N.Z. rabbits the response to acetylcholine was not modified in the 3 age groups. The relaxation to ATP (30 microM to 3 mM) was reduced by age both in N.Z. and in WHHL rabbits, but in 12-14-month-old WHHL rabbits the maximal relaxing response was significantly more elevated than in age-matched N.Z. rabbits (50.1 +/- 2.5% vs. 35.1 +/- 3.2%, respectively). The aortic relaxation to NaNO2 (10 microM to 3 mM) was reduced by age both in N.Z. and in WHHL rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Purine- and nucleotide-mediated relaxation of rabbit thoracic aorta : common and different sites of action

Abstract— The mechanisms of the relaxant effect of purines and pyrimidines in New Zealand rabbit isolated aorta were investigated at endothelial and smooth muscle cell levels. Endothelium‐mediated relaxation by ATP was only partially inhibited by the P2‐purinoceptor antagonist suramin (0·1 Mm). The pyrimidine UTP produced vasodilation by acting at the endothelial level and relaxation was not antagonized by suramin (0·1 Mm). This effect was not mediated by P2 purinoceptors, indicating that UTP, like ATP to a certain extent, produces relaxation via an endothelium nucleotide (N) pyrimidinoceptor. ATP, ADP, AMP, adenosine, 5′‐N‐ethylcarboxamidoadenosine (NECA) and inosine were all active as relaxants on smooth muscle. The NECA relaxant effect was not antagonized by P1‐purinoceptor antagonists 3,7‐dimethyl‐1‐propargylxanthine (50 μm) or 1,3‐dipropyl‐8‐(2‐amino‐4‐chlorophenyl)xanthine (5 μm), excluding a P1‐mediated effect. P2‐related activity was excluded because adenosine‐mediated relaxation was not antagonized by suramin (0·1 Mm). UTP was ineffective as a relaxant at smooth muscle level, thus excluding the presence of muscular nucleotide (N) pyrimidinoceptor and suggesting a P3 purinoceptor. The rank order of potency of this muscle purinoceptor was NECA > adenosine > ATP ≅ ADP ≅ AMP ≅ inosine.

Pharmacological characterization of endothelial cell nitric oxide synthase inhibitors in isolated rabbit aorta

Different receptors mediating the release of endothelium-derived nitric oxide (EDNO) have been identified at endothelial level. In the present study we aimed to characterise, on rabbit aorta by means of pharmacological tools, the generation of EDNO by receptors located on endothelial cell membrane (M3, P2u, P2y) and by direct activation of Ca2+ entry into the endothelial cell. Four vasodilating drugs were tested (acetylcholine, UTP, A23187 and 2-methyl-thio-ATP); they were active only if the endothelial layer was intact, suggesting that they act through endothelial receptors. The effect of different nitric oxide synthase (NOS) inhibitors (0.1 mM: L- and D-NAME, L-NMMA, L-NIO and 7-NI) was investigated on NO-mediated relaxation induced by the relaxants in vessels with intact endothelium. NOS inhibitors differently affected relaxation mediated by the vasoactive drugs in isolated rabbit aorta. Reversibility of the inhibition by using a fixed concentration of L-arginine (0.1 mM) was different depending on the relaxing drug and NOS-inhibitor. The data obtained support the coexistence in aortic vessel of more than one endothelial cell NOS isoform, each provided with different receptor coupling.

Heparin: Pharmacological potentials from atherosclerosis to asthma

1. Heparin belongs to a family of polysaccharide species, whose best known property is, undoubtedly, anticoagulant activity. However, heparin has many other pharmacological effects, particularly on the cardiovascular system. 2. The therapeutic use of chronically inhaled heparin has been suggested as prophylaxis in atherosclerosis. 3. Heparin, physiologically stored in mast cells of the respiratory system, has also been recently studied in the prevention of immunological and non-immunological asthmatic attacks. 4. Experimental findings and new hypotheses of heparin action in asthma and atherosclerosis are discussed.

Endothelial nucleotide-mediated aorta relaxation in aged Watanabe heritable hyperlipidemic rabbits.

Summary: We investigated the activity of muscarinic and purinergic endothelial receptors during atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbit aorta. Experiments were performed on isolated thoracic aorta from WHHL rabbits aged 1 and 2.5 years. The relaxant response to acetylcholine (ACh) was progressively reduced with aging, being almost completely abolished in 2.5-year-old rabbits. The relaxant effect of ATP was not affected by the P2-purinoceptor antagonist suramin, thus excluding any involvement of relaxant P2y purinoceptors in both considered ages. The pyrimidine UTP, acting on nucleotide (P2U ) receptors, produced concentration-dependent relaxation in 1-year-old WHHL rabbit aorta only in the presence of endothelium; relaxation was reduced in older animals. In 1-year-old WHHL rabbits, the endothelium-dependent relaxant effect of UTP was not antagonized by suramin, but was by the inhibitors of nitric oxide (NO) effect, methylene blue (MB) and L-NG-nitroarginine methyl ester (L-NAME), suggesting involvement of NO in the UTP-mediated relaxation. Morphological data from electron microscopy observations indicated the presence of typical atherosclerotic lesions and extensive dystrophic changes in endothelial cells, gradually evolving at 1 and 2.5 years of age. The present data suggest that progressive atherosclerosis differentially affects the activity of endothelial receptors: The most precociously altered is the P2y-purinoceptor, followed by an impairment of the muscarinic and finally of the P2U-purinoceptor.