Sergio Ghione

Visceral Fat in Hypertension: Influence on Insulin Resistance and β-Cell Function

Preferential visceral adipose tissue (VAT) deposition has been associated with the presence of insulin resistance in obese and diabetic subjects. The independent association of VAT accumulation with hypertension and its impact on insulin sensitivity and β-cell function have not been assessed. We measured VAT and subcutaneous fat depots by multiscan MRI in 13 nondiabetic men with newly detected, untreated essential hypertension (blood pressure=151±2/94±2 mm Hg, age=47±2 years, body mass index [BMI]=28.4±0.7 kg · m−2) and 26 age-matched and BMI-matched normotensive men (blood pressure=123±1/69±2 mm Hg). Insulin secretion was measured by deconvolution of C-peptide data obtained during an oral glucose tolerance test, and dynamic indices of β-cell function were calculated by mathematical modeling. For a similar fat mass in the scanned abdominal region (4.8±0.3 versus 3.9±0.3 kg, hypertensive subjects versus controls, P =0.06), hypertensive subjects had 60% more VAT than controls (1.6±0.2 versus 1.0±0.1 kg, P =0.003). Intrathoracic fat also was expanded in patients versus controls (45±5 versus 28±3 cm2, P =0.005). Insulin sensitivity was reduced (10.7±0.7 versus 12.9±0.4 mL · min−1 · kgffm −1, P =0.006), and total insulin output was proportionally increased (64 [21] versus 45 [24] nmol · m−2 · h, median [interquartile range], P =0.01), but dynamic indices of β-cell function (glucose sensitivity, rate sensitivity, and potentiation) were similar in the 2 groups. Abdominal VAT, insulin resistance, and blood pressure were quantitatively interrelated (ρ’s of 0.39 to 0.47, P <0.02 or less). In newly found, untreated men with essential hypertension, fat is preferentially accumulated intraabdominally and intrathoracically. Such visceral adiposity is quantitatively related to both height of blood pressure and severity of insulin resistance, but has no impact on the dynamics of β-cell function.

Arterial hypertension is associated with hypalgesia in humans.

An association between increased blood pressure and hypalgesia has been reported in several studies in animals and in a few reports in humans. We investigated the relationship between hypertension and pain perception by comparing the response to graded electrical stimulation of the tooth pulp, which is thought to represent an exclusively nodceptive system. The test was performed with a commercial tooth pulp tester in a large series of subjects with borderline or established hypertension and in three groups of normotensive controls: volunteers, nonhypertensive patients, and medical students with a well-established or no family history of hypertension. Subjects had to report when they started to feel pulp stimulation (sensory threshold) and when this became painful (pain threshold). Sensory and pain thresholds were obtained as means of the measurements on four healthy, unfilled teeth. Sensory thresholds were significantly higher in subjects with borderline or established hypertension than in two of the three normotensive groups (volunteers and normotensive patients), whereas no significant difference was observed between the two hypertensive groups. The results for the pain threshold were qualitatively similar but less dear and less amenable to statistical analysis because this parameter could not be determined with accuracy in a number of subjects in whom the subjective pain threshold was above the upper range of stimulation of the instrument. The association between Mood pressure levels and pain perception was further confirmed by the highly significant correlation found for the overall data between mean arterial blood pressure and both thresholds. On the other hand, no significant correlation was found with heart rate and no significant effects could be detected by analysis of variance for sex, age, and family history of hypertension. Furthermore, no changes in pain sensitivity were observed in a subgroup of patients studied after 3 months of diuretic or β-blocking treatment or of low salt diet, despite significant reductions of arterial blood pressure. Taken together, our findings provide further confirmatory evidence for an increased tolerance to pain in hypertensive humans and suggest that this may be a feature of arterial hypertension irrespective of the prevailing blood pressure levels.

Impaired insulin action on skeletal muscle metabolism in essential hypertension.

Previous studies have shown that essential hypertension is frequently associated with insulin resistance. The tissues responsible for this metabolic alteration have not been denned. We tested the hypothesis that skeletal muscle is the site of insulin resistance of essential hypertension with the use of the perfused forearm technique. Eight hypertensive (age 42±3 years, body mass index 27±1 kg/m2, intra-arterial mean blood pressure 126±4 mm Hg) and seven normotensive (age 48±3 years, body mass index 26±1 kg/m2, mean blood pressure 95±4 mm Hg) male volunteers were studied. After glucose ingestion (40 g/m2), normal glucose tolerance in the patients was maintained at the expense of a heightened plasma insulin response, suggesting the presence of insulin resistance. During graded, local (intra-arterial) hyperinsulinemia encompassing the physiological range (12-120 milliunits/1), glucose uptake by forearm tissues was significantly (p < 0.03) reduced in the hypertensive subjects as compared with the controls at each of five insulin steps, by 43% on the average. In addition, forearm lactate and pyruvate release were significantly less stimulated in the hypertensive than in the normotensive group (p < 0.01 for both), presumably as a consequence of the decreased glucose influx. Forearm exchange of oxygen, carbon dioxide, lipid substrates (free fatty acids, glycerol, and β-hydroxybutyrate), and potassium were similar in the hypertensive and normotensive groups in the basal state. Insulin had no effect on oxygen consumption, carbon dioxide production, and respiratory quotient in either study group, whereas it stimulated free fatty acids, glycerol, and potassium uptake to the same extent in the hypertensive and normotensive groups. We conclude that the insulin resistance of untreated essential hypertension is present in skeletal muscle, is not secondary to increased fatty substrate use (normal respiratory quotient), and is selective for glucose metabolism. Because forearm substrate oxidation is unaltered, the defect in glucose disposal must predominantly involve glucose conversion into glycogen.

Early Hypertension Is Associated With Reduced Regional Cardiac Function, Insulin Resistance, Epicardial, and Visceral Fat

Mild-to-moderate hypertension is often associated with insulin resistance and visceral adiposity. Whether these metabolic abnormalities have an independent impact on regional cardiac function is not known. The goal of this study was to investigate the effects of increased blood pressure, insulin resistance, and ectopic fat accumulation on the changes in peak systolic circumferential strain. Thirty-five male subjects (age: 47±1 years; body mass index: 28.4±0.6 kg.m−2; mean±SEM) included 13 with normal blood pressure (BP: 113±5/67±2 mm Hg), 13 with prehypertension (BP: 130±1/76±2 mm Hg), and 9 newly diagnosed with essential hypertension (BP: 150±2/94±2 mm Hg) who underwent cardiac magnetic resonance tissue tagging (MRI) and MRI quantitation of abdominal visceral and epicardial fat. Glucose tolerance, on oral glucose tolerance test, and insulin resistance were assessed along with the serum lipid profile. All of the subjects had normal glucose tolerance, left- and right-ventricular volumes, and ejection fraction. Across the BP groups, left ventricular mass tended to increase, and circumferential shortening was progressively reduced at basal, midheart, and apical segments (on average, from −17.0±0.5% in normal blood pressure to −15.2±0.7% in prehypertension to −13.6±0.8% in those newly diagnosed with essential hypertension; P=0.004). Reduced circumferential strain was significantly associated with raised BP independent of age (r=0.41; P=0.01) and with epicardial and visceral fat, serum triglycerides, and insulin resistance independent of age and BP. In conclusion, regional left ventricular function is already reduced at the early stages of hypertension despite the normal global cardiac function. Insulin resistance, dyslipidemia, and ectopic fat accumulation are associated with reduced regional systolic function.

Effects of chronic angiotensin converting enzyme inhibition on glucose tolerance and insulin sensitivity in essential hypertension.

The relation between the renin-angiotensin-aldosterone (RAA) system and carbohydrate metabolism and insulin sensitivity in essential hypertension has not been investigated systematically. Twenty nondiabetic patients (age, 49 +/- 1 years; body mass index (BMI), 26.1 +/- 0.4 kg/m2) with essential hypertension (blood pressure, 155 +/- 3/105 +/- 1 mm Hg) received an oral glucose tolerance test (OGTT) at the end of a 1-month placebo period and again monthly during 3 months of angiotensin converting enzyme (ACE) inhibition (cilazapril, 5 mg/day). Furthermore, a two-step euglycemic insulin clamp was performed after placebo and again at the end of treatment. Blood pressure fell by 7 +/- 4/10 +/- 3 mm Hg (p less than 0.001), while BMI remained stable. On the euglycemic clamp, insulin-mediated (plasma insulin, 470 pM) whole body glucose use averaged 42.5 +/- 1.6 mumol.min-1.kg-1 before and 43.6 +/- 1.9 after ACE inhibition (p = NS). Substrate concentrations and oxidative rates and energy expenditure (as estimated by indirect calorimetry) were not altered by ACE inhibition, either in the fasting state or in response to insulin. In contrast, oral glucose tolerance was significantly (p less than 0.05) improved after treatment (area under OGTT curve (AUC), 240 +/- 24 versus 282 +/- 23 mmol 2 hr.l-1). The latter change was associated with enhanced (+16%, p less than 0.05) insulin responsiveness to glucose (estimated as the insulin AUC divided by the glucose AUC) throughout the 3 months of ACE inhibition. At baseline, both the OGTT and the clamp had a marked hypokalemic effect (mean decrements in plasma potassium of 0.75 +/- 0.05 and 0.92 +/- 0.05 mmol/l, respectively) in association with plasma aldosterone reductions of 30% and 50%. Chronic ACE inhibition caused a further 20% (p less than 0.03) lowering of plasma aldosterone concentrations but attenuated insulin-induced hypokalemia. Plasma sodium, which was unaltered by the pretreatment tests, fell during the posttreatment tests (by 3 mmol/l, p less than 0.001). In the urine, the ratio of the fractional excretion of potassium to that of sodium was decreased by both oral glucose (-22%, p less than 0.01) and ACE inhibition (-21%, p less than 0.001). Higher plasma potassium levels before treatment predicted a better blood pressure response to ACE inhibition (r = 0.60, p less than 0.005).(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin resistance and vasodilation in essential hypertension. Studies with adenosine.

Insulin-mediated vasodilation has been proposed as a determinant of in vivo insulin sensitivity. We tested whether sustained vasodilation with adenosine could overcome the muscle insulin resistance present in mildly overweight patients with essential hypertension. Using the forearm technique, we measured the response to a 40-min local intraarterial infusion of adenosine given under fasting conditions (n = 6) or superimposed on a euglycemic insulin clamp (n = 8). In the fasting state, adenosine-induced vasodilation (forearm blood flow from 2.6 +/- 0.6 to 6.0 +/- 1.2 ml min-1dl-1, P < 0.001) was associated with a 45% rise in muscle oxygen consumption (5.9 +/- 1.0 vs 8.6 +/- 1.7 mumol min-1dl-1, P < 0.05), and a doubling of forearm glucose uptake (0.47 +/- 0.15 to 1.01 +/- 0.28 mumol min-1dl-1, P < 0.05). The latter effect remained significant also when expressed as a ratio to concomitant oxygen balance (0.08 +/- 0.03 vs 0.13 +/- 0.04 mumol mumol-1, P < 0.05), whereas for all other metabolites (lactate, pyruvate, FFA, glycerol, citrate, and beta-hydroxybutyrate) this ratio remained unchanged. During euglycemic hyperinsulinemia, whole-body glucose disposal was stimulated (to 19 +/- 3 mumol min-1kg-1), but forearm blood flow did not increase significantly above baseline (2.9 +/- 0.2 vs 3.1 +/- 0.2 ml min-1dl-1, P = NS). Forearm oxygen balance increased (by 30%, P < 0.05) and forearm glucose uptake rose fourfold (from 0.5 to 2.3 mumol min-1dl-1, P < 0.05). Superimposing an adenosine infusion into one forearm resulted in a 100% increase in blood flow (from 2.9 +/- 0.2 to 6.1 +/- 0.9 ml min-1dl-1, P < 0.001); there was, however, no further stimulation of oxygen or glucose uptake compared with the control forearm. During the clamp, the ratio of glucose to oxygen uptake was similar in the control and in the infused forearms (0.27 +/- 0.11 and 0.23 +/- 0.09, respectively), and was not altered by adenosine (0.31 +/- 0.9 and 0.29 +/- 0.10). We conclude that in insulin-re15-76sistant patients with hypertension, adenosine-induced vasodilation recruits oxidative muscle tissues and exerts a modest, direct metabolic effect to promote muscle glucose uptake in the fasting state. Despite these effects, however, adenosine does not overcome muscle insulin resistance.

Captopril radionuclide test in renovascular hypertension : a european multicenter study

The diagnostic work-up of renovascular hypertension is still controversial. The efficacy of renal scintigraphy with technetium-99m diethylene triamine penta-acetate (DTPA) before and after captopril (scintigraphic captopril test) was evaluated in a multicentre study. All 380 hypertensive patients in the study underwent renal arteriography; 125 had renal arterial stenosis ≥ 70%, and 54 had a technically successful intervention to correct the stenosis. The post-captopril study had a sensitivity of 93% and a specificity of 100% for predicting blood pressure response to intervention, if renal function was normal and a combination of quantitative parameters was applied (individual kidney uptake index < 40%, time to peak activity < 2 min or > 10 min). In the entire population renal artery stenosis ≥ 70% was detected with a sensitivity of 83% and a specificity of 93% if renal function was normal. In patients with abnormal renal function the performance of the test was worse, owing to a lower specificity which could be increased by using only time parameters. The performance of the test was optimal when the post-captopril findings were examined; no improvement was achieved by evaluation of the changes induced by captopril from the baseline. The test can thus be simplified by performing only a post-captopril study for routine use: a negative test would exclude a curable form of renovascular hypertension in > 80% and a positive test would predict it in > 90% of the patients selected for suspicion of the disease. Usefulness of the scintigraphic test for monitoring the clinical results of intervention is suggested by correlating post-intervention outcome with pre- and post-intervention scintigraphic results.

Seasonal influences on blood pressure in high normal to mild hypertensive range.

To investigate the seasonal influences on various arterial blood pressure measurements, 22 subjects in the high normal to mild hypertensive range were examined twice following the same protocol. In one group (13 subjects), measurements were first done in warm conditions and repeated 5-7 months later in cold conditions; in the second group (nine subjects) a reverse sequence was followed. Blood pressure was measured under casual conditions during a hand grip exercise test, mental arithmetic test, and submaximal multistage bicycle exercise test; during the following 24 hours, blood pressure was measured serially with a noninvasive ambulatory blood pressure recorder. Daily outdoor maximum and indoor laboratory temperatures were also obtained. In the cold season, significantly higher values (on the average by 5-10 mm Hg, p less than 0.01) were obtained in both groups for mean diastolic daytime blood pressure. For other measurements, a trend toward higher values in the cold season was observed in both groups, although statistical significance was not obtained in all instances. For nighttime measurements, irrespective of the seasonal sequence, lower values were observed in the second session. Significant correlations were found between the differences in the average daytime ambulatory blood pressures and the corresponding changes of daily maximum outdoor temperatures after 5-7 months. These observations indicate that arterial blood pressure may be strongly influenced by environmental temperature. This phenomenon should be taken into account both in the evaluation of the individual hypertensive patients and in the design and analysis of studies on arterial hypertension, especially when ambulatory blood pressure techniques are employed.

Pain perception and electromagnetic fields

A substantial body of evidence has accumulated showing that exposure to electromagnetic fields (EMFs) affects pain sensitivity (nociception) and pain inhibition (analgesia). Consistent inhibitory effects of acute exposures to various EMFs on analgesia have been demonstrated in most studies. This renders examinations of changes in the expression of analgesia and nociception a particularly valuable means of addressing the biological effects of and mechanisms underlying the actions of EMFs. Here we provide an overview of the effects of various EMFs on nociceptive sensitivity and analgesia, with particular emphasis on opioid-mediated responses. We also describe the analgesic effects of particular specific EMFs, the effects of repeated exposures to EMFs and magnetic shielding, along with the dependence of EMF effects on lighting conditions. We further consider some of the underlying cellular and biophysical mechanisms along with the clinical implications of these effects of various EMFs.

Exposure to a hypogeomagnetic field or to oscillating magnetic fields similarly reduce stress-induced analgesia in C57 male mice

Previous studies have shown that exposure to altered magnetic fields alters analgesic responses in a variety of species, including humans. Here we examined whether deprivation of the normally occurring geomagnetic field also affects stress-induced analgesia, by measuring the nociceptive responses of C57 male mice that were restraint-stressed in a hypogeomagnetic environment (inside a mu-metal box). Stress-induced analgesia was significantly suppressed in a manner comparable to that observed in mice that were either exposed to altered oscillating magnetic fields or treated with the prototypic opiate antagonist naloxone. These results represent the first piece of evidence that a period in a hypogeomagnetic environment inhibits stress-induced analgesia.