Abstract-The ability of the dopamine-1 (D 1 )-like receptor to stimulate adenylyl cyclase (AC) and phospholipase C (PLC), inhibit sodium transport in the renal proximal tubule (RPT), and produce natriuresis is attenuated in several rat models of hypertension. Since the inhibitory effect of D 1 -like receptors on RPT sodium transport is also reduced in some patients with essential hypertension, we measured D 1 -like receptor coupling to AC and PLC in cultures of human RPT cells from normotensive (NT) and hypertensive (HT) subjects. Basal cAMP concentrations were the same in NT (nϭ6) and HT (nϭ4). However, the D 1 -like receptor agonist fenoldopam increased cAMP production to a greater extent in NT (maximum responseϭ67Ϯ1%) than in HT (maximum responseϭ17Ϯ5%), with a potency ratio of 105. Dopamine also increased cAMP production to a greater extent in NT (32Ϯ3%) than in HT (14Ϯ3%). has been shown to be a paracrine regulator of sodium transport in humans and in animals during sodium-replete conditions. 1 During states of positive sodium balance, endogenous renal dopamine facilitates sodium excretion caused by a decrease in proximal as well as distal ion and water transport. [1][2][3][4][5] The natriuretic effect of exogenous and endogenous renal dopamine (and dopamine-1 [D 1 ]-like receptor agonists) is impaired in 2 animal models of hypertension. 1 In the spontaneously hypertensive rat (SHR), the impaired natriuretic effect of dopamine and D 1 -like receptor agonists is associated with a decreased ability to inhibit Na ϩ -H ϩ exchanger 1,3,6 and Na ϩ ,K ϩ -ATPase activity in RPT. 3,7,8 The decreased ability of dopamine and D 1 -like receptor agonists to inhibit these transporters has been related to a defective dopaminergic stimulation of second messenger production by adenylyl cyclase (AC), phospholipase C (PLC), and phospholipase A 2 . 6 -10 These phenotypes may be manifestations of a defective gene important in controlling blood pressure, since the defective dopaminergic regulation of RPT transport and sodium excretion cosegregates with hypertension in rats, and disruption of one of the D 1 -like receptor genes (D 1A receptor) in mice produces hypertension. 6 A defective regulation of renal proximal tubule sodium transport by D 1 -like receptors is also present in human essential hypertension. 11,12 We hypothesized that the coupling between a D 1 -like receptor and the G protein/effector enzyme complex may also be defective in some patients with essential hypertension, similar to that seen in animal models of genetic hypertension. Therefore, we compared the effect of dopamine and fenoldopam on AC and PLC activity in human RPT in culture.

Diabetes is known to cause significant alterations in the retinal vasculature. Indeed, diabetic retinopathy is the leading cause of blindness in those of working age. Considerable evidence is emerging that indicates that retinal neurons are also altered during diabetes. Moreover, many types of neuronal deficits have been observed in animal models and patients prior to the onset of vascular compromise. Such clinical tools as the flash ERG, multifocal ERG, colour vision, contrast sensitivity and short-wavelength automated perimetry, all provide novel means whereby neuronal dysfunction can be detected at early stages of diabetes. The underlying mechanisms that lead to neuronal deficits are likely to be broad. Retinal glial cells play an essential role in maintaining the normal function of the retina. There is accumulating evidence that Müller cells are abnormal during diabetes. They are known to become gliotic, display altered potassium siphoning, glutamate and GABA uptake and are also known to express several modulators of angiogenesis. This review will examine the evidence that neurons and glia are altered during diabetes and the relationship these changes have with vascular compromise.

SummaryThe adipocyte-derived hormone leptin is an important regulator of appetite and energy expenditure and is now appreciated for its ability to control innate and adaptive immune responses. We have reported previously that the leptindeficient ob/ob mouse exhibited increased susceptibility to the Gram-negative bacterium Klebsiella pneumoniae. In this report we assessed the impact of chronic leptin deficiency, using ob/ob mice, on pneumococcal pneumonia and examined whether restoring circulating leptin to physiological levels in vivo could improve host defences against this pathogen. We observed that ob/ob mice, compared with wild-type (WT) animals, exhibited enhanced lethality and reduced pulmonary bacterial clearance following Streptococcus pneumoniae challenge. These impairments in host defence in ob/ob mice were associated with elevated levels of lung tumour necrosis factor (TNF)-a, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E2 (PGE2), lung neutrophil polymorphonuclear leukocyte (PMN) counts, defective alveolar macrophage (AM) phagocytosis and PMN killing of S. pneumoniae in vitro.Exogenous leptin administration to ob/ob mice in vivo improved survival and greatly improved pulmonary bacterial clearance, reduced bacteraemia, reconstituted AM phagocytosis and PMN H2O2 production and killing of S. pneumoniae in vitro. Our results demonstrate, for the first time, that leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Further investigations are warranted to determine whether there is a potential therapeutic role for this adipokine in immunocompromised patients.