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Biomedical subjects

A Salvetti

Publications and source records attributed to A Salvetti.

At least 127 records · Page 7Linked to original sources
PubMed1994

Trough:peak ratio of the blood pressure response to angiotensin converting enzyme inhibitors.

SHORT- VERSUS LONG-ACTING ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: Although ACE inhibitors are widely used in the treatment of hypertension, there are few data on trough:peak ratios and the data are contradictory. Part of the explanation for this lies in differences in pharmacological properties. Depending on the kinetics of elimination, the trough:peak ratio of short- and long-acting ACE inhibitors has to be evaluated according to a dose regimen of twice or once a day, respectively, and must take account of the dose used, since long-acting ACE inhibitors appear to have a dose-dependent trough:peak effect. Further explanations for the contradictory trough:peak ratios reported for ACE inhibitors include measurement methods (clinic blood pressure versus ambulatory monitoring) and study design. TROUGH:PEAK RATIO: Data from randomly allocated, placebo-controlled studies indicate that both the short-acting ACE inhibitors captopril and quinapril given twice a day and the long-acting ACE inhibitors enalapril, lisinopril, benazepril and cilazapril given once a day have an acceptable trough:peak ratio (> 50%). The evidence suggests that when chemically different ACE inhibitors with similar kinetics of elimination are administered at equipotent doses, similar trough:peak ratios are obtained.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

[The trough-to-peak ratio in the evaluation of an antihypertensive drug].

The trough-to-peak ratio (T/P) is more and more frequently employed to assess in a simple fashion the duration and the homogeneity of the antihypertensive effect of a drug over a between-dose interval. This paper emphasizes that to provide reliable data T/P should be calculated only when there is a clearcut antihypertensive effect and that other important features are its within-individual reproducibility and an acceptable value (> 50%) in most individual patients. T/P can be assessed by sphygmomanometric measurements obtained at the end of the between-dose interval and at or near the maximal effect of the drug within the dose interval. It is more and more common, however, to assess T/P by ambulatory blood pressure monitoring which, although characterized by a number of limitations (e.g. low reproducibility of blood pressure values within the 24 hours), allows to avoid a parallel placebo group and to simplify the study design. While a high T/P suggests that the dose and the between-dose interval of a drug is capable to provide an adequate therapeutic coverage a low T/P indicates that the therapeutic coverage is insufficient. The posology must then be changed (more frequent and/or greater doses) to avoid an insufficient protection against hypertension.

Antihypertensive Agents↗
PubMed1994

Gene therapy for lysosomal disorders.

Genetic defects of lysosomal hydrolases result in severe storage diseases and treatments based on enzyme replacement have been proposed. In mice lacking beta-glucuronidase, which develop a disease homologous to human mucopolysaccharidosis type VII (MPS VII, sly syndrome), we have used autologous implants of genetically-modified cells for the continuous in vivo production of the enzyme. A retroviral vector containing the human beta-glucuronidase cDNA under the control of the mouse phosphoglycerate kinase promoter was used to infect primary skin fibroblasts, bone marrow cells, or myoblasts from mutant MPS VII animals. The fibroblasts were embedded into collagen lattices and reimplanted into the peritoneal cavity of recipient MPS VII mice. All animals, when analysed 10 to 155 days later, expressed beta-glucuronidase from the vascularised neo-organs that developed after implantation, and accumulated the enzyme in their tissues. A complete disappearance of the lysosomal storage lesions was observed in their liver and spleen. This procedure has been scaled up for long term lysosomal enzyme delivery in dogs. The bone marrow cells were used for partial hematopoietic reconstruction of sublethally irradiated MPS VII mice. Five months after gene transfer, animals in which under 5% of genetically-modified hematopoietic cells were detected in the spleen showed a drastic reduction of lysosomal storage lesions in the liver and spleen. Genetically-modified myoblasts were transplanted into injured muscles, where they participated in the regeneration of a significant proportion of muscle fibers. Enzyme secretion and liver uptake were observed for at least one month.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

What effect does blood pressure control have on the progression toward renal failure?

Since hypertension is associated with nephrosclerosis and an increased progression toward end-stage renal failure, the therapeutic approach to the treatment of hypertension should aim to protect the kidney against damage or to halt the progression toward end-stage renal failure. It appears that compared with systolic and mean blood pressure, the level of diastolic blood pressure is particularly associated with renal damage. In the presence of kidney failure the choice of antihypertensive drug should be made according to pharmacokinetic and pharmacodynamic properties. From the pharmacokinetic point of view, drugs that are eliminated via the biliary route are preferable since no dosage adjustment is required, and those with a favorable trough to peak effect can achieve better blood pressure control by reducing blood pressure variability. Pharmacodynamic properties should include efficacy in lowering blood pressure, beneficial renal effects, and good tolerability. Hence, the dihydropyridine calcium antagonists, which are effective during volume repletion and which counteract vasoconstrictor mechanisms, seem to be particularly effective. There is some suggestion, but no definitive proof, that blood pressure should be lowered well below 140/90 mm Hg; to achieve this, combination therapy frequently must be used. The rationale for combining two or more antihypertensive drugs is based on the knowledge that this combination can exert an additive antihypertensive action while reducing side effects. The combination of an angiotensin converting enzyme inhibitor with a dihydropyridine calcium antagonist may well fulfill these criteria since this combination could enhance both antihypertensive and renal hemodynamic effects in comparison to single-drug treatment and could reduce the side effects of both drugs.

Antihypertensive Agents↗
PubMed1993

Relationship between insulin release, antinatriuresis and hypokalaemia after glucose ingestion in normal and hypertensive man.

1. Insulin simultaneously causes hypokalaemia and antinatriuresis, and it has been suggested that the two effects are tightly coupled. Whether these actions are preserved in patients with essential hypertension is not known. 2. Eight hypertensive patients and eight normotensive control subjects were studied before and after the ingestion of 75 g of glucose. Despite similar glycaemic profiles, the patients showed a hyperinsulinaemic response incremental area 49 +/- 8 versus 27 +/- 6 nmol l-1 3 h, P < 0.04) but a blunted hypokalaemic response (-7 +/- 1 versus -16 +/- 1%, P < 0.001). Both absolute and fractional urinary excretion of sodium and potassium were significantly decreased during glucose-induced hyperinsulinaemia in hypertensive patients as well as in normotensive subjects (P < 0.05 for all changes). 3. To test whether hypokalaemia is required for insulin-induced antinatriuresis, each hypertensive patient received another oral glucose load during which enough potassium chloride was given to clamp the plasma potassium concentration at baseline. Under these conditions, significant insulin-induced antinatriuresis still occurred. In addition, whereas the glycaemic profile was superimposable, the response of the plasma insulin concentration was significantly greater with than without maintenance of the plasma potassium concentration (total area 79 +/- 14 versus 63 +/- 8 nmol l-1 3 h, P < 0.04). 4. We conclude that (a) insulin causes antinatriuresis, antikaliuresis and hypokalaemia under physiological conditions; (b) in hyperinsulinaemic (insulin-resistant) patients with essential hypertension, the antinatriuretic action of insulin is quantitatively preserved; and (c) clamping plasma potassium levels prevents insulin-induced antikaliuresis but not antinatriuresis, and potentiates the insulin secretory response to glucose.

Adult↗
PubMed1993

Long-term preservation of renin-secreting ability by human adult juxtaglomerular tumor cells in explant culture.

Studies on cultured human renin(R)-producing tumors cells are few. In this work the R secretion by a human juxtaglomerular tumor (JGT) in various tissue culture models was evaluated by a new immunoradiometric assay. Freshly isolated JGT cells actively secreted total R (tR; about 70% of which is proR) into the perfusion media of very short-term cultures (tR concentration, 100-400 ng/ml/10(6) cells), independently of factors stimulating or inhibiting R output by normal JG cells. Primary monolayer cultures of the same JGT rapidly lost their tR-secreting capability and died by apoptosis within two months. Conversely, a JGT explant survived for up to 22 months in vitro. During the first year of culture, this explant increased in volume and generated, at 3- to 4-monthly intervals, several self-limited cellular outgrowths, from which it became detached. Meanwhile, tR secretion by the explant decreased very slowly, though its decline was transiently and partly reversed by various combinations of growth factors, hormones, a prostaglandin, and selenous acid added to either a serum-enriched or a synthetic medium. By the 12th month in vitro, tR secretion had faded away. Like the primary monolayers, the various explant outgrowths, once detached, stopped secreting tR and died in a few weeks. Hence, the preservation of a histiotypic relationship and the actions of several mitogenic and/or differentiating agents are essential for the long-term survival and the continuance of R secretion by human JGT cells in vitro.

Adult↗
PubMed1993

Identification of a negative element in the human vimentin promoter: modulation by the human T-cell leukemia virus type I Tax protein.

The vimentin gene is a member of the intermediate filament multigene family and encodes a protein expressed, in vivo, in all mesenchymal derivatives and, in vitro, in cell types of various origin. We have previously demonstrated that the expression of this growth-regulated gene could be trans activated by the 40-kDa Tax protein of HTLV-I (human T-cell leukemia virus type I) and that responsiveness to this viral protein was mediated by the presence of an NF-kappa B binding site located between -241 and -210 bp upstream of the mRNA cap site (A. Lilienbaum, M. Duc Dodon, C. Alexandre, L. Gazzolo, and D. Paulin, J. Virol. 64:256-263, 1990). These previous assays, performed with deletion mutants of the vimentin promoter linked to the chloramphenicol acetyltransferase gene, also revealed the presence of an upstream negative region between -529 and -241 bp. Interestingly, the inhibitory activity exerted by this negative region was overcome after cotransfection of a Tax-expressing plasmid. In this study, we further characterize the vimentin negative element and define the effect of the Tax protein on the inhibitory activity of this element. We first demonstrate that a 187-bp domain (-424 to -237 bp) behaves as a negative region when placed upstream either of the NF-kappa B binding site of vimentin or of a heterologous enhancer such as that present in the desmin gene promoter. The negative effect can be further assigned to a 32-bp element which is indeed shown to repress the basal or induced activity of the NF-kappa B binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1993

Indirect evidence for vascular uptake of circulating renin in hypertensive patients.

To evaluate whether, in the forearm of hypertensive patients with different circulating renin profiles, local beta-adrenergic receptor-induced production of active renin, plasma renin activity, angiotensin I (Ang I), and angiotensin II (Ang II) was or was not related to the renin profile, we studied four groups of patients: 1) hypertensive patients with primary aldosteronism and suppressed circulating plasma renin activity values (0.15 +/- 0.1 ng Ang I/mL per hour; n = 7), 2) essential hypertensive patients with low (0.47 +/- 0.1 ng Ang I/mL per hour; n = 8) circulating plasma renin activity values, 3) essential hypertensive patients with normal (2.48 +/- 0.52 ng Ang I/mL per hour; n = 8) circulating plasma renin activity value, and 4) renovascular hypertensive patients with high circulating plasma renin activity values (4.16 +/- 2.1 ng Ang I/mL per hour; n = 10). Isoproterenol was infused into the brachial artery, and active renin, plasma renin activity, and Ang I and Ang II forearm balance (venous-arterial differences corrected for forearm blood flow by strain-gauge plethysmography) were measured. Despite a comparable vasodilation, beta-adrenergic stimulation failed to release active renin, plasma renin activity, and Ang I and Ang II in primary aldosteronism. It slightly increased them (except for Ang I) in low renin patients but determined a local production in normal renin and renovascular hypertensive patients. The individual increments in plasma renin activity and Ang II release induced by isoproterenol showed a correlation with the renin profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Vasodilation to acetylcholine in primary and secondary forms of human hypertension.

Endothelium-dependent vasodilatation to acetylcholine is reduced in the forearm of essential hypertensive patients. To investigate whether endothelium-dependent vasodilatation is reduced also in secondary hypertension, we evaluated the effects of an intrabrachial infusion of acetylcholine on forearm blood flow (strain-gauge venous plethysmography) in essential hypertensive (n = 12), primary aldosteronism hypertensive (n = 8), and renovascular hypertensive (n = 8) patients and normotensive control subjects (n = 12). To further evaluate the role of a cyclooxygenase-dependent endothelium-derived vasoconstrictor substance, we repeated the infusion of acetylcholine in the presence of indomethacin. The effect of the direct vasodilator sodium nitroprusside was also examined. The vasodilatation to acetylcholine was reduced in essential, primary aldosteronism, and renovascular hypertensive patients compared with normotensive subjects. In contrast, the vasodilatation induced by sodium nitroprusside was similar in all groups of patients and control subjects. In the presence of indomethacin, the vasodilator effect of acetylcholine was increased in essential hypertensive patients but not in normotensive or in secondary hypertensive individuals. These data demonstrate an impairment of endothelium-dependent vasodilation in renovascular and primary aldosteronism hypertensive patients and indicate that a cyclooxygenase-dependent vasoconstrictor mechanism participates in the blunting of endothelium-dependent vasodilation in essential hypertensive patients.

Acetylcholine↗
PubMed1993

The inter-relationship between insulin resistance and hypertension.

Insulin resistance and compensatory hyperinsulinaemia commonly occur in patients with untreated essential hypertension. The coexistence of insulin resistance and hypertension can be viewed as a cause-effect relationship (insulin resistance as a cause of hypertension or vice versa) or as a noncausal association. Insulin can increase blood pressure via several mechanisms: increased renal sodium reabsorption, activation of the sympathetic nervous system, alteration of transmembrane ion transport, and hypertrophy of resistance vessels. Conversely, hypertension can cause insulin resistance by altering the delivery of insulin and glucose to skeletal muscle cells, resulting in impaired glucose uptake. For example, hypertension can impair vasodilation of skeletal muscle as a result of vascular structural changes and rarefaction, and increased response to vasoconstrictor stimuli. Also, the prevalence of muscle type 2b fibres (fast twitch fibres) may contribute to the development of insulin resistance. The common pathogenetic mechanism for both insulin resistance and hypertension could be activation of the sympathetic nervous system. This results in vasoconstriction, and may contribute to the genesis of vascular structural changes and increase the number of fast twitch fibres. Finally, hypertension and insulin resistance can be viewed as a noncausal association, according to the following hypotheses: 1) they may represent 2 independent consequences of the same metabolic disorder (intracellular free calcium accumulation), or 2) insulin resistance is a genetic marker and/or a pathogenetic mechanism of multiple metabolic abnormalities frequently associated with hypertension.

Humans↗
PubMed1993

Organization and expression of intermediate filaments in epithelial cells expressing the HTLV-I Tax protein.

Intermediate filaments (IF) represent major components of the cytoskeletal network. These proteins which are differentially expressed according to the cell type, constitute a dynamic structure which not only contributes to the cell architecture but also defines its state of differentiation. Furthermore, numerous observations have shown that the IF network is altered in cells transformed by tumorigenic viruses. We have previously demonstrated that HTLV-I (human T-cell leukemia virus type I) transformed T cells were characterized by a high level of vimentin transcripts and that the HTLV-I Tax regulatory protein was able to transactivate the vimentin promoter transfected into Jurkat and HeLa cells. To enlarge the scope of this study, we investigated the effects of the Tax protein on the expression and organization of IF of epithelial cells in which the IF network is composed of vimentin and cytokeratin. To this aim, we have developed a model of epithelial cells (HeLa) stably expressing the tax sequences which were introduced by using retrovirus-mediated gene transfer. Half of the Tax expressing HeLa clones were loosely adherent to the culture surface and were displaying remarkable morphological alterations, as ascertained by the presence of round-shaped or spindle-shaped cells. In these cells, expression of this viral protein correlated to a pronounced disruption in the distribution of both the vimentin and the cytokeratin networks, as shown by immunofluorescence and ultrastructural analysis. Indeed, vimentin filaments appeared to be concentrated in discrete spots throughout the cytoplasm, while the cytokeratin filaments appeared to form a dense ring around the nucleus. More importantly, mRNA and protein analysis indicate an enhanced expression of the cytokeratin 7 gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Epithelium↗
PubMed1993

[The rationale for drug combinations in the therapy of arterial hypertension].

The therapeutic goal of antihypertensive drug combination is to improve the hypotensive effect with a possible reduction in incidence and severity of side effects. This goal can be reached by taking into account both pharmacokinetic and pharmacodynamic properties of single antihypertensive drugs. As far as pharmacokinetics is concerned, the rationale is to combine drugs which reach efficient concentrations with low interdose fluctuations and long duration of action. Drug combination with these pharmacokinetic properties allows efficient control of blood pressure with reduction in blood pressure variability and with a favourable trough to peak (T/P) ratio. Moreover these combinations can improve patient compliance to treatment through simplification of the dosing scheme, efficient blood pressure control throughout the dosage interval and reduction of incidence and severity of side effects. The pharmacodynamic rationale requires the combination of drugs with different mechanisms of action, whose biohumoral interactions must exert at least an additive antihypertensive effect and reduce the incidence and severity of side effects of one or of each antihypertensive drug. Finally, dosage should be chosen according to the therapeutic goal as follows: where the hypotensive effect is the primary target, drug doses near the plateau of the dose-response curve must be used, while lower, but effective doses should be used in order to improve tolerability.

Antihypertensive Agents↗
PubMed1993

[Abdominal Doppler ultrasonography in the diagnosis of renovascular diseases. Double-blind prospective study].

Our work was aimed at evaluating the sensitivity and specificity and the positive and negative predictive values of abdominal Doppler US in the diagnosis of renovascular disease. Fifty hypertensive patients (23 men and 27 women) with 100 bilaterally single renal arteries (66 of them normal and 34 stenosed) were studied by means of color (26 cases) and duplex (24 cases) Doppler US. The following US variables were considered in the diagnosis of renal artery stenosis: increased peak systolic velocity in the renal artery, increased ratio between peak systolic velocity in the renal artery and in the aorta, increased parenchymal acceleration time and increased resistive index. Feasibility was 100% for all variables. The general multivariate statistic model of discriminate analysis was used to define three calculation levels, according to: a) duplex vs. color Doppler equipment, b) hemodynamic variables and c) optimal cutoff values. US examinations were performed by a single observer in a double-blind study, before angiography, so as to eliminate interobserver variability. On the whole abdominal Doppler US exhibited optimal specificity and fairly good sensitivity. Specificity increased (94% to 97%) with the use of color Doppler according to the different combinations of variables, but sensitivity remained the same. The calculation including all the Doppler variables increased sensitivity from 73% (with true values) to 93% (with threshold values). The positive predictive value demonstrated that 90% of the renal arteries with increased peak systolic velocity and 100% of those with increased parenchymal acceleration time were stenosed. However, the negative predictive value demonstrated that 15% of the renal arteries with no increase in peak systolic velocity is misdiagnosed as normal. In conclusion, abdominal Doppler US can be used to study renovascular disease patients, but the examination must always be based on different hemodynamic variables and true values.

Double-Blind Method↗
PubMed1992

Atrial natriuretic factor in essential hypertension: echocardiographic and humoral correlates.

Aim of this study was to assess the relationship between plasma concentration of atrial natriuretic factor (ANF) and its two-dimensional echocardiographic (left ventricular mass, left atrium diameter) and humoral (plasma renin and aldosterone) variables in essential hypertension (EH). We evaluated 32 patients with uncomplicated mild to moderate EH and 10 controls. They were studied in the supine position after 7 days of constant dietary sodium intake and were off therapy since at least 3 weeks. ANF values overlapped between EH patients and controls (27.8 +/- 11.5 vs. 19.5 +/- 7.4 pg/ml, p = NS). In EH, no significant correlation was found between ANF values and left ventricular mass (r = 0.29), left atrial diameter (r = 0.04), mean arterial blood pressure (r = 0.26), plasma renin activity (r = 0.00), and aldosterone (r = 0.26). In EH, ANF values overlapped between the 15 patients with hypertrophy and the 17 patients with normal ventricular mass: 30.3 +/- 17 vs. 25.6 +/- 10.6 pg/ms (p = NS). We conclude that there is a substantial overlap in plasma ANF values between mild to moderate uncomplicated EH and controls, and left ventricular hypertrophy is not a major independent stimulus to ANF release in EH.

Adult↗