Human obesity is associated with insulin resistance, hyperinsulinemia, and a predisposition to hypertension and vascular disease, the origin of which may lie in impairment of endothelial function. We tested the effects of the thiazolidinedione rosiglitazone on blood pressure and endothelial function in insulin-resistant fatty Zucker rats, which display hypertension and abnormal endothelial cell function. We studied fatty Zucker rats given rosiglitazone maleate (50 micromol/kg diet; n = 8) for 9-12 weeks (treated fatty), untreated fatty rats (n = 8), and lean rats (n = 8) given diet alone. At the end of the study, systolic blood pressure was significantly higher in untreated fatty (147 +/- 5 mmHg) than in lean rats (125 +/- 2 mmHg; P < 0.05), but rosiglitazone treatment prevented the development of hypertension in fatty rats (123 +/- 1 mmHg). Fasting hyperinsulinemia in untreated fatty rats (28.7 +/- 6.0 ng/ml) was significantly lowered by rosiglitazone (7.0 +/- 1.4 ng/ml; P < 0.05 vs. untreated fatty), but remained significantly higher than the levels seen in lean rats (1.5 +/- 0.4 ng/ml; P < 0.01). Mesenteric arteries were studied in a myograph. Maximal acetylcholine chloride (1.1 micromol/l)-induced relaxation of norepinephrine hydrochloride (NE)-induced constriction was impaired in untreated fatty (62.4 +/- 3.4%) vs. lean (74.3 +/- 3.5%; P = 0.01) rats; this defect was partially prevented by rosiglitazone (66.5 +/- 3.0%; P = 0.01 vs. untreated fatty). Insulin (50 mU/l) significantly attenuated the contractile response to NE in lean rats (14.7 +/- 3.3%; P = 0.02); this vasodilator effect of insulin was absent in untreated fatty rats at concentrations of 50-5,000 mU/l, but was partially restored by rosiglitazone (9.7 +/- 2.5% attenuation; P = 0.02 vs. no insulin). Thus, rosiglitazone prevents the development of hypertension and partially protects against impaired endothelial function associated with insulin resistance. These latter effects may contribute to the drug's antihypertensive properties.

SUMMARYWe have assessed the influence of a mild emotional stimulus on arterial blood pressure, heart rate, renal blood flow, plasma resin activity (PRA), and plasma aldosterone concentration in 24 normal subjects, eight of whom had a parent with hypertension, and in IS patients with essential hypertension. A nonverbal IQ test, Raven's Progressive Matrices, was employed as the stimulus. In 11 of the 15 hypertensives, arterial blood pressure rose transiently by 7 mm Hg or more, but in only three of 16 normal subjects (x 2 = 7.23, p < 0.01). Transient moderate increases in heart rate were also more common in the hypertensives (p < 0.01). Renal blood flow rose in 11 of 16 normal subjects and fell in each of the 15 patients with essential hypertension (x* -15.1;/> < 0.005). As opposed to the transient changes in arterial pressure and heart rate, the fall in renal perfusion was sustained. The PRA fell in 10 of the 16 normal subjects with a negative family history and rose In 14 of 15 patients with essential hypertension (p < 0.005). Changes in plasma angiotensin II concentration and in plasma aldosterone were in accord with the changes in PRA, but plasma cortisol did not change. Both the renal vascular response and the change in PRA were intermediate in normal subjects in whom family history was positive for hypertension. For the entire group of 39 subjects there was statistically significant agreement between the direction of the renal vascular response and the directional change in PRA: renal blood flow rose when PRA fell and fell when PRA rose (p < 0.005). We conclude that there is an abnormality in the control of both the renal circulation and of renin release in patients with essential hypertension in response to psychological provocation, and that a similar process is present in some normotensive subjects whose parents have hypertension. (Hypertension 3: 11-17, 1981) KEY WORDS • emotions• familial hypertension renal vasculature • plasma renin activity • plasma aldosterone E SSENTIAL hypertension remains a disease of unknown pathogenesis. As for many processes in which the cause is obscure and which may be exacerbated by stressful circumstances, investigators have repeatedly claimed that psychological, especially emotional, factors play a pathogenetic role -perhaps the key role.1 "' As reviewed recently,*"' this conclusion has lacked credibility to many for a number of reasons: the conclusions were often based on subjective and uncontrolled observations and the stimuli employed were often gross and poorly reproducible. Moreover, the inFrom the

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10–15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the RET oncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant. © 2000 Cancer Research Campaign

To test the hypothesis that the hypertension associated with insulin resistance is secondary to an altered responsiveness of the vasculature to pressor agents, we evaluated the relationship between insulin resistance and pressor responses to angiotensin II (AII) in 21 hypertensive (HT) and 8 normotensive (NT) subjects on both a high (200 meq) and a low (10 meq) sodium diet. When sodium balance was achieved, each supine fasting subject underwent an All infusion at a rate of 3 ng/kg per min for 60 min, with blood pressure monitored every 2 min. On the next day under similar conditions, a euglycemic hyperinsulinemic clamp was performed, with plasma glucose clamped at 90 mg/dl for 120 min. There was no significant relationship between the glucose disposal rate (M) or the insulin sensitivity index (M divided by the mean insulin level [M/I]) and blood pressure response to AII in the NTs, but a highly significant (P < 0.019) negative correlation (r = -0.55) in the HTs. Furthermore, in eight lean HTs whose body mass index was identical to that observed in the NTs, the relationship was even more striking (P < 0.008; r = -0.85). The results on high and low salt diets were similar; however, the M and M/I were significantly increased (P < 0.05) in the NTs but not HTs with sodium restriction.In conclusion, HTs but not NTs display a striking correlation between pressor response to All and insulin resistance. This relationship is independent of the level of sodium intake. Furthermore, sodium intake modifies insulin sensitivity in NTs but not HTs. These results strongly suggest that a primary change in pressor response to vasoactive agents in insulin-resistant subjects can contribute to their elevated blood pressure. (J. Clin. Invest. 1994. 94:2295-2300 Key words: insulin resistance * pressor response a hypertension * sodium intake -angiotensin II

SUMMARY Adrenal and vascular responsiveness to graded doses of angiotensin II (A II) were recorded for seven normal subjects and 12 patients with essential hypertension while in balance on an intake of 200 mEq sodium/100 mEq potassium. Patients with essential hypertension had been previously studied and known to have normal responses of plasma renin activity to sodium restriction and upright posture. A l l was administered for 30 minutes at rates of 0.1, 0.3, 1, and 3 ng/kg per minute and plasma aldosterone responses were assessed 20 and 30 minutes later; blood pressure was monitored at intervals of 1 minute during infusion of A 11 at each rate. A significant increment in plasma aldosterone occurred at an infusion rate of 0.3 ng/kg per minute in patients with hypertension. This change was not seen until the infusion rate reached 1.0 ng/kg per minute in the normotensive control subjects. Even at an A II infusion rate of 1 ng/kg per minute, the increment in plasma aldosterone levels in normotensive subjects (4.2 ± 0.6 ng/dl) was significantly less (P < 0.001) than that in patients with essential hypertension (19 ± 3 ng/dl). In both groups, a significant rise in mean arterial blood pressure occurred at an A II dose of 0.3 ng/kg per minute, but the pressor response of the hypertensive group was significantly greater at the highest infusion rate (3 ng/kg per minute) (P < 0.05). Thus, enhanced adrenal and pressor responsiveness to infused A II was observed in the hypertensive subjects, suggesting a change in A II receptor affinity.ANGIOTENSIN II may play an important role in the control of blood pressure through its vasoconstrictor activity as well as its effects on volume homeostasis exerted through regulation of aldosterone secretion. However, previous studies evaluating adrenal and vascular responsiveness to infused angiotensin II (A II) in hypertensive subjects have yielded conflicting results.1 ' 6 Moreover, recent studies suggest that there may be physiologically important but functionally different receptors for A II on the adrenal cortex and vascular smooth muscle.7 ' 9 An imbalance of the relative responsivenes of these receptors to A II might lead to an imbalance in volume homeostasis or vasoconstrictor activity and thus produce an elevated blood pressure. The present study was designed to compare the relative magnitude of response of blood pressure and aldosterone secretion to graded doses of A II in patients with essential hypertension and normal subjects. MethodsTwelve patients with essential hypertension and seven normotensive control subjects were studied in the Clinical Research Center of the Peter Bent Brigham Hospital. The normotensive subjects (five male, two female) ranged in age from 23 to 38 years. They denied use of drugs and had no evidence of renal, cardiovascular, or endocrine abnormalities on routine screening. Patients with essential hypertension (eight male, four female) ranged in age from 24 to 68 years. The criteria for inclusion of patients with hyperten- sion in the study were as follo...