P-590: Obesity regulates renal endothelin and endothelin ETA receptor expression in vivo. Differential effects of chronic ETA receptor blockade

ETA receptors have been implicated in obesity-associated hypertension (Hypertension 1999; 33: 1169). We characterized the renal endothelin system in diet-induced obesity and determined the effects of chronic treatment with the ETA antagonist darusentan. C57BL/6J mice were fed a standard diet (control) or a high-fat diet (Harlan TD88137) with or without darusentan (50 mg/kg/d, 30 wk). Total RNA was extracted from whole kidneys and mRNA expression of preproendothelin-1 (ppET-1), ETA receptors, and β-actin were determined by RT-PCR using mouse-specific primers. PCR-products were normalized vs. β-actin or 18S rRNA. Renal ET-1 protein was measured by RIA/HPLC. High fat diet increased body weight by 257% compared to 54% (control diet). Darusentan had no effect on body weight in obese mice (263%) and treatments had no effect on systolic blood pressure. Obesity was associated with upregulation of renal ETA receptors (144±5% vs 100±7%, p<0.05 vs. control) and to a lesser extent, preproendothelin-1 (113±5% vs.100±2%, p<0.05 vs. control). In obese mice chronic darusentan treatment in part prevented the ETA receptor upregulation (126% vs. 144±5%, p<0.05) but had no significant effect on ppET-1 mRNA expression (101±9 vs. 100±2%, n.s.). Renal ET-1 protein increased in obese animals (from 190±18 to 267±19 pg/g tissue, p<0.05 vs. control). This increase was not affected by concomitant darusentan treatment (n.s.). These data for the first time demonstrate that obesity in normotensive rats is associated with upregulation of renal ETA receptor expression suggesting that body weight per se affects ET receptor expression in the kidney. Our data further indicate that in this model ETA receptors control expression of the ETA receptor but not the ppET-1 gene, suggesting autocrine regulation in vivo. These mechanisms might contribute to the pathogenesis of obesity-associated diseases affecting the kidney and/or blood pressur

Left bundle branch block causes relative but not absolute septal underperfusion during exercise

Aims Left bundle branch block (LBBB) often causes septal perfusion defects in radionuclide myocardial perfusion imaging using exercise (Ex) but rarely using vasodilator stress. We studied whether this is due to an underlying structural disease inherent to spontaneous LBBB or whether it is also found in temporary LBBB induced by right ventricular pacing (PM) indicating a functional rather than a structural alteration. Methods and results Regional myocardial blood flow (MBF) at rest and at Ex was measured with(15)O-H(2)O and PET in 10 age-matched healthy volunteers (controls), 10 LBBB patients and 10 PM patients with right ventricular pacing off and on (PM off and PM on). Although at Ex septal MBF tended to be higher in LBBB than in controls (3.04 +/- 1.18 vs. 2.27 +/- 0.72 mL/min/g; P= ns), the ratio septal/lateral MBF was 19% lower in LBBB than in controls (P < 0.05). Similarly, switching PM on at Ex decreased the ratio septal/lateral MBF by 17% (P < 0.005). Conclusion The apparent septal perfusion defect in LBBB is mainly due to a relative lateral hyperperfusion rather than to an absolute septal flow decrease. This pattern seems to be reversibly inducible by right ventricular pacing, suggesting a functional rather than a structural alteratio

Caffeine Impairs Myocardial Blood Flow Response to Physical Exercise in Patients with Coronary Artery Disease as well as in Age-Matched Controls

BACKGROUND: Caffeine is one of the most widely consumed pharmacologically active substances. Its acute effect on myocardial blood flow is widely unknown. Our aim was to assess the acute effect of caffeine in a dose corresponding to two cups of coffee on myocardial blood flow (MBF) in coronary artery disease (CAD). METHODOLOGY/PRINCIPAL FINDINGS: MBF was measured with (15)O-labelled H2O and Positron Emission Tomography (PET) at rest and after supine bicycle exercise in controls (n = 15, mean age 58+/-13 years) and in CAD patients (n = 15, mean age 61+/-9 years). In the latter, regional MBF was assessed in segments subtended by stenotic and remote coronary arteries. All measurements were repeated fifty minutes after oral caffeine ingestion (200 mg). Myocardial perfusion reserve (MPR) was calculated as ratio of MBF during bicycle stress divided by MBF at rest. Resting MBF was not affected by caffeine in both groups. Exercise-induced MBF response decreased significantly after caffeine in controls (2.26+/-0.56 vs. 2.02+/-0.56, P<0.005), remote (2.40+/-0.70 vs. 1.78+/-0.46, P<0.001) and in stenotic segments (1.90+/-0.41 vs. 1.38+/-0.30, P<0.001). Caffeine decreased MPR significantly by 14% in controls (P<0.05 vs. baseline). In CAD patients MPR decreased by 18% (P<0.05 vs. baseline) in remote and by 25% in stenotic segments (P<0.01 vs. baseline). CONCLUSIONS: We conclude that caffeine impairs exercise-induced hyperaemic MBF response in patients with CAD to a greater degree than age-matched controls

Strabisme surso-adducteur décompensé [Decompensated strabismus surso-adductorius]

Strabismus surso-adductorius is a frequent unilateral or bilateral eye movement disorder. Its clinical features include eye elevation with concomitant vertical deviation in adduction, an abnormal head posture from which the patient is unaware (head turned and tilted towards the healthy side), a moderate subjective excyclotorsion, and a positive Bielschowsky head tilt test. Despite its anglo-saxon denomination as "congenital fourth nerve palsy", it is not a paretic disorder. Strabismus surso-adductorius differs from fourth nerve palsy both by etiology and by symptoms. A proper diagnosis is important as neuroradiological examination is mandatory in cases of acquired non-traumatic fourth nerve palsy, whereas decompensated strabismus surso-adductorius can be operated on without any further investigations. Early on, the oculomotor disorder is often well compensated and it does manifest at the adult age. Asthenopia and intermittent vertical diplopia appear as the fusional mechanisms fade out. The best surgical technique for strabismus surso-adductorius is an inferior oblique weakening procedure. In severe cases a combined shortening of the superior oblique tendon may be necessary