Biomedical subjects
Publications and source records attributed to G Tonolo.
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A significantly different prevalence in the Gly40Ser variant of the glucagon receptor gene in a small group of essential hypertensive patients compared with normotensive probands was described in a Caucasian population. It has been postulated that this variant may exacerbate the antinatriuretic effect of high plasma insulin levels commonly seen in hypertensive subjects, leading to volume expansion and rise in blood pressure level. The aim of this study was to evaluate the prevalence of the Gly40Ser variant in a population of 404 non-insulin-dependent diabetic patients of Sardinian origin. No association of the Gly40Ser variant with hypertension was seen in this large population.
Patients with homozygous beta-thalassemia show an abnormal lipoprotein profile. In asymptomatic heterozygotes the lipid pattern is less markedly affected but interestingly related to a diminished cardiovascular risk. The extent and significance of these findings are still a matter of debate and no data are available on lipoprotein(a) plasma levels. Seventy patients with homozygous beta-thalassemia (HT-P), 70 beta-thalassemia trait carriers (TT-C) and 70 sex and age-matched controls were investigated and their plasma lipoprotein profile and apo(a) phenotypes determined. In a subgroup of these same subjects (12 HT-P, 12 TT-C and 24 controls) and in 12 bone marrow-transplanted homozygous beta-thalassemic patients (BMT-P) plasma lipoprotein composition was assessed. HT-P disclosed significantly lower total-cholesterol, LDL-cholesterol, HDL-cholesterol, apo A-I, apo B plasma levels and higher triglyceride concentration than TT-C (-7, -11, -8, -8, -13 and +11%, respectively) or controls (-39, -50, -46, -32, -30 and + 35%, respectively). All lipoprotein subclasses were triglyceride-enriched, while LDLs were also protein-enriched and HDLs protein-depleted. TT-C disclosed a small but significant reduction in apo A-I and apo B plasma levels but only minor lipoprotein abnormalities with respect to the controls. BMT-P lipoprotein composition was intermediate between HT-P and normal subjects. Apo(a) plasma levels did not differ among the groups. A higher prevalence of 'small' apo(a) isoforms was present in HT-P. Within the same 'isoform group', apo(a) plasma levels were significantly lower in HT-P than in TT-C or controls. Since liver cirrhosis is almost always present in HT-P, it is conceivable that an altered hepatic apo(a) synthesis or catabolism due perhaps to diminished apolipoprotein glycation may be involved. In TT-C a partially improved cardiovascular risk profile was apparent (low hematocrit, low LDL-cholesterol and apo B), thus justifying the claim for a low prevalence of ischemic heart disease, but no Lp(a) plasma level modification could be detected.
We have previously shown that the binding of lipoprotein(a) [Lp(a)] to immobilized fibrinogen involves the domain located in kringles IV-5 to IV-8, but not kringle IV-10. In extending those studies to subjects living in Chicago and in the island of Sardinia, we found that about 6% of them had an Lp(a) with Bmax values of 27.7+/-6.0 fmol, which were about 5-8-fold higher than those of controls (3.4+/-2.8 fmol) and in the range of those observed for free apo(a) derived from the Lp(a) of controls (36.6+/-2.9 fmol). This superbinding phenotype was unaffected by age, sex, type of lipid disorder and hypolipidemic agents, and also had a familial incidence. We are currently exploring the hypothesis that this fibrinogen superbinding phenotype is due to conformational changes of apolipoprotein(a) [apo(a)] resulting from the lipid content and composition of the Lp(a) particle and/or sequence anomalies in the kringle domain IV-5 to IV-8.
OBJECTIVE: To study the long-term effects of simvastatin on urinary albumin excretion rate (AER) in normotensive microalbuminuric type 2 diabetic patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: A total of 19 normotensive microalbuminuric hypercholesterolemic type 2 diabetic patients entered a double-blind crossover study for 2 years, receiving either simvastatin (20 mg/day) or placebo (each treatment for 1 year). RESULTS: Simvastatin significantly decreased plasma cholesterol (total and LDL) after 52 weeks of treatment. A concomitant significant decrease of AER (25% from basal) with no significant changes in creatinine clearance was observed during the same period. CONCLUSIONS: Our data are in keeping with the hypothesis that simvastatin might be used as an additional means to preserve renal function in microalbuminuric hypercholesterolemic type 2 diabetic patients.
Contrasting information has been reported concerning the course of renal function in NIDDM with hypertension alone or in association with renal damage. The aim of the present study was to elucidate the course of the glomerular filtration rate (GFR) in hypertensive NIDDM patients during antihypertensive therapy. Furthermore, we compared the effects of ACE inhibitors (cilazapril, Inibace, Roche, Milan, Italy) and Ca(2+)-channel blockers (amlodipine, Norvasc, Pfizer, Rome, Italy). Of the hypertensive NIDDM patients attending the outpatient's clinic of the internal medicine departments of the University of Padova and Sassari, 44 participated in the present study. Of these patients, 26 were normoalbuminuric and 18 microalbuminuric. They were randomly treated with either cilazapril or amlodipine. The target of antihypertensive treatment was a value < 140 mmHg for systolic and 85 mmHg for diastolic blood pressure (BP). Microalbuminuria was defined as an albumin excretion rate (AER) between 20 and 200 micrograms/min. GFR was measured by plasma clearance of 51Cr-labeled EDTA at baseline and every 6-12 months during a 3-year follow-up interval. A significant decrease was observed in the values of GFR, AER, and systolic and diastolic BP in normoalbuminuric and microalbuminuric patients during antihypertensive therapy. The GFR fall in the overall population of NIDDM patients was significantly and inversely related to the decrease of mean BP (diastolic + 1/3 pulse pressure) (r = -0.80, P < 0.0001) but not to that of HbA1c, triglycerides, and BMI. The GFR decline (mean +/- SE) per year in the normoalbuminuric patient was 2.03 +/- 0.66 ml.min-1 x 1.73 m-2 (95% CI 0.92-3.17) during cilazapril and 2.01 +/- 0.71 ml.min-1 x 1.73 m-2 (95% CI 0.82-3.11) during amlodipine therapy. The GFR decline per year in the microalbuminuric patient was 2.15 +/- 0.69 ml.min-1 x 1.73 m-2 (95% CI 0.86-3.89) during cilazapril and 2.33 +/- 0.83 ml.min-1 x 1.73 m-2 per year (95% CI 1.03-3.67) during amlodipine therapy. Cilazapril and amlodipine lowered AER to a similar extent in normoalbuminuric and microalbuminuric patients. No significant changes were observed concerning other clinical and biochemical features between the two antihypertensive therapies and particularly HbA1c, BMI, triglycerides, and cholesterol plasma values. These results support the tenet that arterial hypertension plays a pivotal role in contributing to renal damage in NIDDM, even when AER is normal. However, the degree of BP control, with both cilazapril and amlodipine, can successfully delay the slope of GFR decline in hypertensive NIDDM patients with or without incipient nephropathy.
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Potassium canrenoate (K-Can) prevents hypertension in Milan hypertensive strain (MHS) but not in spontaneously hypertensive rats (SHR). Essential hypertensive patients (HT) may have differential sensitivity to diuretics, since a subgroup of HT insensitive to hydrochlorothiazide (HCTZ) but sensitive to K-Can has previously been found. The aims of this study were: 1) to seek markers of response in essential hypertensive patients selectively sensitive to K-Can: and 2) to test whether selective sensitivity to furosemide may also be demonstrated. After 2 weeks of placebo (P) 50 uncomplicated, mild to moderate HT (46 +/- 9 yrs, mean +/- SD) received K-Can (50 mg/day) for 4 weeks. After 2 more weeks of P, patients received HCTZ (25 mg) and furosemide (25 mg) for 4 weeks each in a single blind crossover design, with 2 weeks P between each treatment. Dosages were doubled after 2 weeks if diastolic blood pressure (DBP) was > 90 mmHg. Responders (R) were those HT whose DBP was < or = 90 mmHg and/or at least 10 mmHg lower than before treatment. Systolic blood pressure (SBP)/DBP was measured every 2 weeks with plasma renin activity (PRA), red blood cell Na(+)-K(+)-Cl- cotransport (COT) and Na(+)-K+ ATPase pump activity measured at the end of the first P period, and serum electrolytes at the end of each period. Four HT dropped out because of low compliance, 6 because of reversible side effects, and 1 because blood pressure was not back to pre-treatment value after the second placebo period.(ABSTRACT TRUNCATED AT 250 WORDS)
We report herein the effects of cyclical variations of endogenous sex steroids during the menstrual cycle on plasma lipids and apolipoproteins (apo) in normal women. We examined 16 normal women (age range 25-36 yr) with normal menstrual cycles of 28-31 days. The study covered the period from the 1st day of a menstrual phase (basal) until the 1st day of the following menstrual phase. During the study all women maintained a normolipidic diet (30% fat). Plasma total cholesterol and low-density-lipoprotein cholesterol were significantly higher than basal in the preovulatory phase until progesterone started to increase in the postovulatory phase [day +8 from luteinizing hormone (LH) surge]. High-density-lipoprotein cholesterol was significantly higher than basal from day -1 to the day after LH surge, whereas plasma apoAI levels were significantly higher from day -8 to day +8 (from LH surge). Plasma apo(a) increased significantly during the luteal phase in four women characterized by a single S4 band and lower basal plasma levels of apo(a). Our results indicate that endogenous female sex steroids have significant effects on the circulating levels of plasma lipids and apolipoproteins, including apo(a). More work needs to be done to elucidate the significance of the observed apo(a) changes, and the different phases of the menstrual cycle must be taken into account when evaluating the lipidic risk profile in premenopausal women.
We compared corticosteroid metabolite excretion rates and patterns in a group of 68 subjects with untreated essential hypertension and a matched group of 48 normotensive control subjects. The ratio of tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone and the ratio of allotetrahydrocortisol to tetrahydrocortisol were significantly higher in the hypertensive group. This is qualitatively similar to the situation found in patients with the syndrome of apparent mineralocorticoid excess or subjects treated with licorice or carbenoxolone where hypertension is known to arise from deficiencies of 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activities. The equivalent ratios for corticosterone metabolites were not different between groups, but total corticosterone metabolite excretion was higher in the hypertensive group. Plasma cortisol levels were lower in hypertensive than in control subjects, but corticosterone levels were higher. This evidence supports a previous suggestion that the activities of these two enzymes may be reduced in essential hypertension, but the contribution of these changes to hypertension is not known.
In a large group of patients with untreated hypertension, excretion rates of tetrahydrocorticosterone (THB), allotetrahydrocorticosterone (alloTHB) and tetrahydro-11-dehydrocorticosterone (THA) were all significantly higher than in a group of matched normotensive controls. Using the sum of these metabolites as an index of corticosterone secretion rate suggests that this variable is also higher. The increase was small (all excretion rates remained within the normal range) and corticosterone has low glucocorticoid and mineralocorticoid potency calling the clinical significance of this finding into question. However, it is possible that in combination with mildly deficient 11 beta-hydroxysteroid dehydrogenase activity such increases in corticosterone levels might affect blood pressure.
Progressive capillary occlusion often leads to severe retinopathy within 15-20 years of the onset of Type 1 (insulin-dependent) diabetes mellitus. Lipoprotein(a), a complex formed by apolipoprotein(a), apo B-100 and lipids, is considered an independent, genetically determined, predictor of cardiovascular disease. It may have antifibrinolytic properties in view of its similarity to plasminogen. To test the hypothesis that circulating lipoprotein(a) is associated with the process that leads to clinically active diabetic retinopathy, we measured the circulating levels of apolipoprotein(a) (which are strictly correlated with those of lipoprotein(a)) in two groups of patients with Type 1 diabetes of at least 15 years duration: 25 with active retinopathy and 27 without clinically detectable retinal lesions. Thirty-eight healthy subjects of the same age and sex served as controls. Serum apolipoprotein(a) was higher in the patients with active retinopathy (36(2-193) U/dl, geometric mean and range) than in those without clinically detectable retinal lesion (17(1-160)) and the control subjects (14(0-115)), p < 0.01 in both cases. The distribution of apolipoprotein(a) levels was skewed to the left, as expected, in the patients without clinically evident retinal lesions and the control groups, but there was a bimodal trend of distribution among those with active retinopathy. The levels of glycated haemoglobin were similar in the two groups of diabetic patients, and no significant differences were found for total and HDL cholesterol, triglycerides or apolipoproteins A1 and B between them and the control subjects. These preliminary results suggest that serum apolipoprotein(a) is elevated in patients with active retinopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
We report herein the effects of long-term intracerebroventricular (icv) dexamethasone in normotensive rats. Dexamethasone (0.002, 0.02, 0.2, and 2.0 micrograms/day) or its vehicle (0 microgram/day, n = 8 each group) was infused icv via subcutaneous miniosmotic pumps (Alzet 2002) for 24 days in male conscious Wistar rats (weight range 190-240 g). Eighteen Wistar rats (weight range 200-230 g) received either vehicle or dexamethasone (0.2 and 2 micrograms/day) subcutaneously (sc) for 24 days. Systolic blood pressure (SBP, tail cuff) and body weight were recorded two times a week in the trained conscious rats. Dexamethasone (0.2 micrograms/day icv) exerted a progressive significant decrease in SBP over 24 days compared with both rats receiving vehicle and to pretreatment values (108 +/- 4 vs. 122 +/- 4 and 120 +/- 2 mmHg, P < 0.01). As previously reported, a significant increase in SBP was observed after 6 days in rats given 2 micrograms/day sc dexamethasone compared with both rats receiving vehicle and to pretreatment values (150 +/- 4 vs. 122 +/- 2 and 120 +/- 2 mmHg, P < 0.01 for both). Thereafter, SBP remained at plateau for the entire experiment. A similar significant decrease in body weight gain with age was observed in rats given icv or sc dexamethasone. Our data suggest that the glucocorticoid receptors exert opposite effects on blood pressure when stimulated at the brain level instead of at the peripheral vascular level.
The contribution of endogenous kinins to the regulation of blood pressure, urinary volume, and renal sodium excretion was evaluated in Wistar rats on high sodium intake by using the new bradykinin receptor antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). Neither Hoe 140 (3 nmol/hr s.c. for 4 weeks) nor its vehicle altered systolic blood pressure (tail-cuff plethysmography) or renal function in rats given saline solution (0.15 mol/L NaCl) to drink ad libitum. Four-week administration of deoxycorticosterone (DOC), combined with high sodium intake and uninephrectomy, increased systolic blood pressure from 127 +/- 3 to 160 +/- 3 mm Hg (p < 0.01). When long-term infusion of Hoe 140 was combined with DOC, high sodium intake, and uninephrectomy, systolic blood pressure rose from 127 +/- 3 to 175 +/- 3 mm Hg (p < 0.01). The hypertensive effect was greater in the Hoe 140 group (48 +/- 4 versus 33 +/- 3 mm Hg in controls, p < 0.05). This difference was confirmed by direct measurement of mean blood pressure (Hoe 140 group, 154 +/- 4 mm Hg; vehicle group, 139 +/- 4 mm Hg; p < 0.05). The antagonist blunted the increase in urinary volume induced by salt load and DOC in uninephrectomized rats, whereas it did not alter the increase in urinary sodium excretion. These results suggest that endogenous kinins do not play a major role in the regulation of normal blood pressure in sodium-loaded rats, whereas they may attenuate the hypertensive effect induced by long-term administration of mineralocorticoids and salt in uninephrectomized rats.
The effects of physiological shifts in plasma atrial natriuretic factor (ANF) concentrations on angiotensin II/aldosterone relationships during changes in sodium status were assessed in 6 conscious beagle dogs. Incremental infusions of angiotensin II (3, 9 and 27ng/kg/min) were administered on three occasions. The animals were studied in sodium replete and deplete states and on a third occasion, again while sodium deplete, with a background constant low-dose infusion of ANF (1.5pmol/kg/min) sufficient to enhance the low endogenous plasma ANF values observed in sodium depletion to match those observed in the sodium replete state. Sodium depletion caused a leftward shift and steepened the slope of the relationship between achieved arterial angiotensin II concentrations and the plasma aldosterone response. This effect was significantly attenuated (approximately 50%) by the low dose ANF infusions which tended to flatten the slope of the angiotensin II/aldosterone curve (ns) and shifted it significantly to the right (p < 0.05). These data suggest subtle shifts in endogenous levels of plasma ANF, accompanying changes in sodium status, are a major contributor to the associated alterations in angiotensin II/aldosterone relationships. Low dose ANF also significantly reduced the effect of angiotensin II on arterial pressures but did not alter natriuresis.
We compared the response of blood pressure (BP) to either K-Canrenoate (K-Can) or hydrochlorothiazide (HCTZ) in 26 mild-to-moderate essential hypertensives in a double-blind, cross-over design over 2 months each. The dose was 12.5 mg o.d. for HCTZ and 50 mg o.d. for K-Can: dosing was doubled after 1 month if seated diastolic BP was > or = 95 mmHg. Eight pts were "selective responder" to the lowest dose of HCTZ (HCTZ-R), and 6 to K-Can (K-Can-R). Seven pts had their high blood pressure controlled by the highest dose of both drugs and 4 were insensitive to both. One pt dropped out during HCTZ for low plasma K+, and 3 during K-Can (nausea and dizziness: 2 pts; plasma creatinine rise: 1 pt). All these side effects were reverted after drug withdrawal. HCTZ-R and K-Can-R differed for PRA (1.4 +/- 0.6 vs 0.8 +/- 0.4 Ang I ng/ml/h, p < 0.05) and Na-K-Cl cotransport (230 +/- 39 vs 372 +/- 24 mumolNa/L RBC/h, p < 0.01). Our data suggest the existence of a subgroup of essential hypertensives surprisingly insensitive to HCTZ, characterized by a "low" PRA and by a Na(+)-K(+)-Cl- cotransport higher than the HCTZ-R. Their selective response to K-Can suggest a peculiar pathogenetic mechanism underlying their high blood pressure.
We describe cases of isolated functioning insulinoma occurring in two members of the same family (father and daughter). The father had a first encapsulated insulinoma diagnosed at 14 years of age and at the age of 33 years he was operated on for a second insulinoma infiltrating the exocrine pancreas with lymph node metastases. The daughter was operated on for an encapsulated insulinoma in the tail of the pancreas when she was 6 years old. No clinical and laboratory signs of other endocrine disturbances have so far been detected in either care or in any other members of the family. Our report suggests the possibility of multiple familial insulinoma, although this is an extremely rare condition. Our data also indicate that insulinomas, even if well controlled by medical treatment, should always be removed by surgery because malignancy cannot be excluded with certainty. Moreover, patients should be closely followed up, as recurrence may develop up to 15 years after surgery.
1. The present study was designed to determine if endogenous kinins are involved in the regulation of arterial blood pressure and renal function in conscious rats given deoxycorticosterone enantate (DOC, 25 mg kg-1, s.c., weekly) or vehicle for two weeks. 2. The bradykinin B2-receptor antagonist, D-Arg[Hyp3,Thi5,D-Tic7,Oic8]- bradykinin (Hoe 140), at a dose of 300 micrograms kg-1, s.c., blocked the hypotensive effect of 300 ng kg-1 bradykinin i.a., but it did not alter the blood pressure lowering action of 300 ng kg-1 acetylcholine or prostaglandin E2. Inhibition of the response to bradykinin persisted up to 6 h after the administration of Hoe 140. 3. Administration of 300 micrograms kg-1 Hoe 140 s.c. four times a day did not alter mean blood pressure, renal blood flow, or renal function in rats given DOC-vehicle. However, it decreased urinary volume by 70% (from 48.2 +/- 3.8 to 14.3 +/- 3.7 ml 24 h-1, P less than 0.01) and urinary secretion of sodium by 54% (from 1.02 +/- 0.05 to 0.47 +/- 0.16 mmol 24 h-1, P less than 0.01) and potassium by 30% (from 2.93 +/- 0.15 to 2.04 +/- 0.15 mmol 24 h-1, P less than 0.05) in DOC-treated rats. Mean blood pressure, glomerular filtration rate and total renal blood flow remained unchanged. 4. Our results suggest that endogenous kinins play a role in the regulation of renal excretion of water and sodium in the presence of elevated levels of DOC.