1. The responses of rabbit urinary bladder to hydrostatic pressure changes and to electrical stimulation have been investigated using both the Ussing chamber and a superfusion apparatus. These experiments enabled us to monitor changes in both ionic transport across the tissue and cellular ATP release from it. 2. The urinary bladder of the rabbit maintains an electrical potential difference across its wall as a result largely of active sodium transport from the urinary (mucosal) to the serosal surface. 3. Small hydrostatic pressure differences produced by removal of bathing fluid from one side of the tissue caused reproducible changes in both potential difference and short-circuit current.The magnitude of these changes increases as the volume of fluid removed increases. 3. Amiloride on the mucosal (urinary), but not the serosal, surface of the membrane reduces the transepithelial potential difference and short-circuit current with an ICÛÑ of 300 nÒ. Amiloride reduces the size of, but does not abolish, transepithelial potential changes caused by alterations in hydrostatic pressure. 4. Field electrical stimulation of strips of bladder tissue produces a reproducible release of ATP.Such release was demonstrated to occur largely from urothelial cells and is apparently nonvesicular as it increases in the absence of calcium and is not abolished by tetrodotoxin. 5. It is proposed that ATP is released from the urothelium as a sensory mediator for the degree of distension of the rabbit urinary bladder and other sensory modalities.

(11)C-metomidate PET-CT is a sensitive and specific noninvasive alternative to AVS in the management of PHA.

Endurance training represents one extreme in the continuum of skeletal muscle plasticity. The molecular signals elicited in response to acute and chronic exercise and the integration of multiple intracellular pathways are incompletely understood. We determined the effect of 10 days of intensified cycle training on signal transduction in nine inactive males in response to a 1-h acute bout of cycling at the same absolute workload (164 +/- 9 W). Muscle biopsies were taken at rest and immediately and 3 h after the acute exercise. The metabolic signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), demonstrated divergent regulation by exercise after training. AMPK phosphorylation increased in response to exercise ( approximately 16-fold; P < 0.05), which was abrogated posttraining (P < 0.01). In contrast, mTOR phosphorylation increased in response to exercise ( approximately 2-fold; P < 0.01), which was augmented posttraining (P < 0.01) in the presence of increased mTOR expression (P < 0.05). Exercise elicited divergent effects on mitogen-activated protein kinase (MAPK) pathways after training, with exercise-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation being abolished (P < 0.01) and p38 MAPK maintained. Finally, calmodulin kinase II (CaMKII) exercise-induced phosphorylation and activity were maintained (P < 0.01), despite increased expression ( approximately 2-fold; P < 0.05). In conclusion, 10 days of intensified endurance training attenuated AMPK, ERK1/2, and mTOR, but not CaMKII and p38 MAPK signaling, highlighting molecular pathways important for rapid functional adaptations and maintenance in response to intensified endurance exercise and training.

Abstract-Hypertension guidelines advise limiting the dose of thiazide diuretics and avoiding combination with ␤-blockade, because of increased risk of diabetes mellitus. We tested whether changes in the 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with a thiazide and could be avoided by switching to amiloride. Two double-blind, placebo-controlled, crossover studies were performed. In study 1 (41 patients), we found that changes in glucose during a 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with bendroflumethiazide. In study 2, 37 patients with essential hypertension received, in random order, 4 weeks of once-daily treatment with hydrochlorothiazide (HCTZ) 25 to 50 mg, nebivolol 5 to 10 mg, combination (HCTZ 25-50 mgϩnebivolol 5-10 mg), amiloride (10 -20 mg), and placebo. Each drug was force titrated at 2 weeks and separated by a 4-week placebo washout. At each visit, we recorded blood pressure and performed a 75-g oral glucose tolerance test. Primary outcome was the difference in glucose (over the 2 hours of the oral glucose tolerance test) between 0 and 4 weeks, when HCTZ and amiloride were compared by repeated-measures analysis. For similar blood pressure reductions, there were opposite changes in glucose between the 2 diuretics (PϽ0.0001). Nebivolol did not impair glucose tolerance, either alone or in combination. There was a negative correlation between ⌬potassium and ⌬2-hour glucose (rϭϪ0.28; PϽ0.0001). In 2 crossover studies, 4 weeks of treatment with a thiazide diuretic impaired glucose tolerance. No impairment was seen with K 1 Outcome trials have shown cardiovascular benefits from the use of thiazides in essential hypertension, which are similar to those achieved with other antihypertensive agents. However, there has been recent recognition that currently used doses are smaller than those used in most of the outcome trials.3-5 The main adverse effects limiting the use of thiazides are metabolic, including hypokalemia, hyponatremia, hyperuricemia, and hyperglycemia.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• In vitro studies have shown that urotensin II is a potent arterial vasoconstrictor.• Previous studies investigating the in vivo cardiovascular actions of intra-arterial administration of urotensin II in humans have provided conflicting results.• The cardiovascular actions of intra-arterial administration of the urotensin II receptor antagonist, urantide, are unknown. WHAT THIS STUDY ADDS• We have shown no in vivo effect of urotensin II or urantide on human forearm resistance vessels.• Previous study discrepancies do not seem to relate to either the age or cardiovascular disease (CVD) status of subjects. AIMS(i) To compare the effects of intra-arterial administration of urotensin II in patients with CVD with healthy volunteers, and (ii) to study the haemodynamic effects of intra-arterial infusion of the urotensin II receptor antagonist, urantide. METHODSTen healthy volunteers and 10 patients with CVD received a dose-ramped brachial artery infusion of urotensin II. A further six healthy male volunteers received a prolonged urotensin II infusion and 11 healthy male volunteers received a dose-ramped infusion of urantide. Forearm blood flow (FBF) was measured every 20 min and blood pressure and heart rate were assessed every 20 min. RESULTSIn healthy volunteers and patients with CVD, intra-arterial infusion of urotensin II had no effect on FBF ratio. A dose-ramped infusion of urantide similarly had no effect on FBF ratio. During dose-ramped infusions of urotensin II and urantide, systolic and mean arterial blood pressure increased significantly. In healthy volunteers, urotensin II and urantide, respectively, increased systolic blood pressure from 133 Ϯ 6 to 137 Ϯ 5 mmHg (P < 0.01) and from 113 Ϯ 4 to 120 Ϯ 4 mmHg (P < 0.01). In patients with CVD, heart rate also significantly increased during dose-ramped infusion of urotensin II from 59 Ϯ 3 to 62 Ϯ 4 bpm (P < 0.05). CONCLUSIONSWe have shown no in vivo effect of urotensin II or urantide on human forearm resistance vessels. Previous discrepancies do not seem to relate to either the age or CVD status of subjects. Changes in systemic cardiovascular haemodynamics during the dose-ramped infusion studies are unlikely to be caused by urotensin II receptor modulation.

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