Increased aldosterone levels in a model of type 2 diabetes mellitus.

BACKGROUND: Aldosterone is an important mediator of cardiovascular and renal remodeling. Type II diabetes mellitus leads to renal and cardiac end organ damage. We investigated the renin-angiotensin-aldosterone system in a model of type 2 diabetes mellitus with known diabetic nephropathy and cardiac remodeling, the Zucker Diabetic Fatty rat with and without ACE-inhibition (ZDF and ZDF+ACE-I) and its control, the Zucker Lean (ZDL) rat. METHODS: Male animals were studied from an age of 7-24 weeks. At ages 7, 14, 17, 20, and 23 weeks, urinary excretion of aldosterone-glucuronide and potassium was assessed. ACE-inhibition with ramipril was started orally at week 13 (1 mg/kg/d). At the end of the study rats were sacrificed and plasma aldosterone concentration and plasma renin activity were measured. Aldosterone synthase (CYP11B2) mRNA expression in the adrenals, kidney, heart and adipose tissue was assessed by real-time PCR. Urinary albumin excretion as marker for diabetic nephropathy was measured in metabolic cages and correlated to aldosterone. RESULTS: Plasma aldosterone concentration and aldosterone-glucuronide was significantly elevated in ZDF rats, and significantly reduced by ACE-inhibiton. In contrast, plasma renin activity was significantly reduced in ZDF rats and normalized by ACE-inhibition. The urinary aldosterone correlated significantly to albuminuria. Adrenal CYP11B2 expression was not significantly higher in ZDF rats. CYP11B2 mRNA was not detected in the kidney, heart and adipose tissue. CONCLUSION: In ZDF rats, urinary and plasma aldosterone levels were elevated despite reduced plasma renin activity. The reversible effect of ACE-inhibition shows that the up-regulation of aldosterone must be dependent of the renin-angiotensin-system in this type II diabetes model. The correlation between aldosterone and diabetic nephropathy suggests a clinical relevance of this observation.

Is the response pattern of on- and off-cells in the rostral ventromedial medulla to noxious stimulation independent of stimulation site?

The classification of on- and off-cells in the rostral ventromedial medulla is based on the response pattern to noxious tail heat. It is generally assumed that on- and off-cells respond equally to noxious stimulation anywhere on the body surface, but so far this assumption has not been systematically examined. In the present study the effects of noxious thermal and mechanical stimuli applied to the tail, the extremities and the craniofacial region on the extracellularly recorded activity of 13 on- and 23 off-cells were investigated in lightly anesthetized rats. In 3 out of 13 on-cells and 11 out of 23 off-cells the response pattern evoked by noxious stimulation of the extremities or the craniofacial region differed from the response pattern elicited by noxious tail heat. In comparison with the response pattern to noxious tail heat, stimulation of the extremities or the craniofacial region reproducibly evoked opposite reactions in 2 on- and 9 off-cells and did not change neuronal activity in one on- and 2 off-cells. The results of the present study raise the question of whether the response pattern of on- and off-cells in the rostral ventromedial medulla can be sufficiently predicted by a classification that is exclusively based on the cellular behavior to noxious heat stimulation of the tail.

Are 'neutral cells' in the rostral ventro-medial medulla subtypes of on- and off-cells?

The classification of cells in the rostral ventromedial medulla (RVM) is based on the response pattern to noxious tail heat: on-cell activity increased, off-cell activity decreased, and activity of neutral cells is unaffected by noxious heat tail stimulation. It is generally assumed that on-, off- and neutral cells respond equally to noxious stimulation applied anywhere on the body surface, but so far this assumption has not been systematically examined. In the present study the effects of thermal and mechanical stimuli applied to the tail, the extremities and the orofacial region on the extracellularly recorded activity of 14 neutral cells were investigated in lightly anesthetized rats. Although the neutral cells did not respond to noxious tail heat, all of them responded to most of the other stimuli in an on- or off-manner. Especially cell responses to pinch stimuli applied to the skin of the ear, the forehead and the nose differed from the neutral behavior. The fact that the neutral cells in the present study responded in an off- or on-manner by applying noxious stimuli different from noxious tail heat suggests that these cells are possibly subtypes of on- and off-cells in the RVM.