The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats.

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.

Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL 49653) and troglitazone on human small arteries in vitro.

BRL 49653 (rosiglitazone) and troglitazone are thiazolidinedione insulin-sensitizing agents, which are undergoing clinical evaluation as treatments for NIDDM. Potential side effects of thiazolidinediones include edema and hemodilution. Although the underlying mechanisms are presently unclear, animal and human studies have demonstrated a vasodilator action of troglitazone, which could in theory cause fluid retention. This in vitro study compared the direct vasodilator effects of troglitazone and BRL 49653 in small arteries (n = 44) from human subcutaneous fat. In arterial rings with a functioning endothelium and preconstricted with norepinephrine (NE; 6 micromol/l), troglitazone (n = 22 vessels), but not BRL 49653 (1-100 micromol/l), caused a concentration-related relaxation (69.4 +/- 5.2% at 100 micromol/l; P < 0.01). In the presence of indomethacin (IM; 10 micromol/l; n = 12), this vasorelaxant effect of troglitazone was abolished (P < 0.01 vs. troglitazone alone) and replaced by enhanced vasoconstriction (58.5 +/- 39.5% over the NE baseline) similar in magnitude to that produced by troglitazone vehicle (ethanol) alone (n = 16; NS vs. ethanol vehicle). By contrast, BRL 49653 (100 micromol/l; n = 22) and an equivalent volume of ethanol alone (n = 12) caused similar degrees of vasoconstriction (18.7 +/- 14.6 and 22.5 +/- 8.0%, respectively; NS). In the presence of IM (10 micromol/l; n = 10), the vasoconstrictor effect of BRL 49653 was enhanced (41.5 +/- 14.4%), although not significantly (NS vs. BRL 49653 alone or ethanol alone). Additional studies in Wistar rat arteries showed a similar vasodilator effect of troglitazone that was not inhibited by L-NAME (100 micromol/l). The alpha-tocopherol moiety alone had no vasorelaxant effect at concentrations up to 300 micromol/l. Thus, in human arterial resistance vessels in vitro, BRL 49653 does not possess the direct, IM-sensitive vasorelaxant action of troglitazone. This vasodilation could, in theory, permit transmission of systemic pressure to the capillary bed.

Partial hypopituitarism and Langerhans cell histiocytosis.

A case of multisystem Langerhans cell histiocytosis with pituitary involvement nearly 20 years after initial presentation. A 48-year-old man had histiocytosis X 22 years ago initially involving the groin; subsequently his external auditory meatus, scalp, gum, mandibular bone, perineum and axilla were involved and treated. The pituitary gland was involved 4 years ago. A thyrotropin-releasing hormone test showed delayed response suggestive of hypothalamic disease. Prolactin levels were normal. A gonadotropin-releasing hormone test showed impaired testosterone and gonadotrophin response in keeping with pituitary disease. A glucagon stimulation test showed an impaired growth hormone response but a normal cortisol increase. MRI pituitary showed an empty sella. There was no evidence of diabetes insipidus. Bone mineral densitometry was normal. He has partial hypopituitarism needing thyroxine and testosterone replacement. He also developed type 2 diabetes mellitus 9 years ago. He is closely monitored for any development of diabetes insipidus and the need for growth hormone supplementation.

Treatment of hypertension in diabetes.

Patients with type I and II diabetes mellitus represent a population at high risk of the cardiovascular, cerebrovascular and renal effects of hypertension. Antihypertensive therapy should be considered for those with blood pressures above 130/85 mmHg with the aim to reduce levels below 125/75 especially for those with microalbummuria or diabetic nephropathy. Hypertension tends to occur on a background of multiple other risk factors. Life-style changes such as increased exercise and reduced salt intake, when combined with medication should improve the blood pressure response. On the currently available data, an Angiotensin Converting Enzyme (ACE) inhibitor, initially as mono-therapy, is the first choice antihypertensive agent in the absence of contraindications. Often dual or triple therapy is required to achieve target blood pressure levels.

The diabetic patient with hypertension.

Hypertension and diabetes co-exist more commonly than would be expected from their individual prevalences. Elevated blood pressure is most commonly due to coexisting essential hypertension, or diabetic renal disease. Early stages of diabetic renal disease can be identified by detecting microalbuminuria. Standard measures of blood pressure are not necessarily raised, but 24-hour ambulatory measures frequently identify a loss of nocturnal drop in blood pressure. Treating hypertension aggressively is important in slowing the inexorable decline in glomerular filtration rate. In diabetes there appears to be no 'J'-shaped relationship between blood pressure and cardiovascular events, thus removing any concern about attaining low blood pressures as long as the patient is asymptomatic. Morbidity and mortality in these patients is usually associated with cardiovascular events, and it is important to assess the effect of drugs on left ventricular hypertrophy and metabolic parameters. Many drugs are effective at lowering blood pressure, but angiotensin-converting enzyme inhibitors may have an additional renoprotective action. alpha-Adrenergic antagonists may improve lipid profiles and calcium antagonists are probably lipid neutral, making these drugs useful alternatives. Dihydropyridine calcium antagonists (eg, nifedipine) may augment protein-uria, and hence non-dihydropyridine calcium antagonists (eg, verapamil, diltiazem) would be preferred. beta-Blockers and thiazide diuretics have the disadvantage of causing a deterioration in glycaemic and lipid profiles, but can be useful on occasions.

Atrial natriuretic peptide in type 2 diabetes mellitus: response to a physiological mixed meal and relationship to renal function.

Relatively few data exist on atrial natriuretic peptide (ANP) characteristics in Type 2 diabetes mellitus (DM). Therefore, plasma immunoreactive ANP concentrations were measured before and for 4 h following the ingestion of a physiological mixed meal in 8 newly diagnosed, normotensive, normoalbuminuric, patients with Type 2 DM and 6 normotensive, non-diabetic controls. In patients with Type 2 DM, basal plasma ANP concentrations were 4.0 +/- 2.0 and not significantly changed following ingestion of the meal, with peak levels of 4.9 +/- 2.8 pmol l(-1). Non-diabetic controls had higher basal plasma ANP concentrations, 8.7 +/- 3.4 pmol l(-1) (p < 0.05), significantly increasing to a peak of 11.9 +/- 6.3 pmol l(-1) at 30 min post meal. Extracellular fluid volume (ECV) was not different between diabetic patients and controls (15877 +/- 2679 vs 13668 +/- 1792 ml3). Glomerular filtration rate (GFR) (isotopic clearance corrected for body surface area) was elevated in diabetic patients (mean +/- SD) 130 +/- 39 vs 98 +/- 10 ml min(-1), p < 0.05). For the DM subjects, basal ANP levels were negatively correlated with GFR (rs - 0.74, p < 0.05) and effective renal plasma flow (ERPF) (rs - 0.8, p < 0.05). We conclude that patients with Type 2 DM demonstrate reduced basal plasma ANP concentrations which are inversely correlated to renal function. In contrast to non-diabetic controls, ANP in Type 2 DM does not rise in response to feeding.