The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance. Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein-coupled receptors on vascular smooth muscle cells. Receptors that mediate vasoconstriction couple with the G-proteins G(q)-G11 and G12-G13 to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase- and Rho/Rho kinase-mediated signaling pathways, respectively. Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that G(q)-G11-mediated signaling in smooth muscle cells is required for maintenance of basal blood pressure and for the development of salt-induced hypertension. In contrast, lack of G12-G13, as well as of their major effector, the leukemia-associated Rho guanine nucleotide exchange factor (LARG), did not alter normal blood pressure regulation but did block the development of salt-induced hypertension. This identifies the G12-G13-LARG-mediated signaling pathway as a new target for antihypertensive therapies that would be expected to leave normal blood pressure regulation unaffected.

The cortisol rhythm analysis indicated a circadian rhythm pattern for only one premature infant, all others of the neonates showed no circadian or ultradian rhythm in cortisol. Cortisol level of the premature neonates was significantly higher during the first day of the study period at night-time (median: 17.1 nmol/L, IQR=9.7-24.4 nmol/L) than on days 7 (median: 9.6 nmol/L, IQR=4.7-14.6 nmol/L; Tukey-HSD, z=4.12, p<0.001) and 14 (IQR=5.8-13.7 nmol/L; Tukey-HSD, z=2.89, p<0.05). No significant effect of acoustic stimulation was observed on the cortisol concentration and sleep-wake behavior. The activity-sleep rhythm of preterm neonates was dominated by ultradian rhythm patterns with a prominent period length of 4 h (30.5%). Activity frequencies of neonates were also significantly higher overnight on the first study day (mean: 329±185.1 U) than of night seven (mean: 260.2±132.4 U; Tukey-HSD, z=2.50, p<0.05). Quiet-activity patterns increased, whereas high-activity patterns decreased during the observation period. Average sleep time increased significantly during the study time from day 1 to day 7 (Tukey-HSD, z=2.51, p<0.05). In conclusion, premature infants showed higher cortisol levels - without a circadian rhythmicity - and higher activity frequencies in the first days after birth which may reflect an adaptation process of neonates after birth. Cortisol concentrations and the activity patterns were not influenced by music interventions.

Background/Aims: Diabetic retinopathy is characterized by pericyte loss and vasoregression both in the clinic and in animal models. A mild neurodegeneration with loss of ganglion cells is also described in the diabetic retina. Like VEGF-A, Epo is angioprotective and, in high doses, neuroprotective, however, without affecting vessel permeability. This study was to investigate the effect of a long-term suberythropoietic dose of Epo on vascular damage and neurodegeneration in a rat model of diabetic retinopathy. Methods: We administered Epo 3x256 IU/kg body weight/week to streptozotocin-diabetic Wistar rats for up to 6 months. Leukostasis was analyzed by quantitation of CD45 positive cells adherent to the retinal microvasculature. VEGF-A levels were assessed by Elisa at 3 months of treatment. Vasoregression was quantified in retinal digest preparations after 6 months of Epo treatment.Neurodegeneration was analyzed from PAS stained retinal paraffin preparations. Results: Leukostasis was unaffected by treatment with Epo which significantly inhibited the loss of pericyte and the formation of acellular capillaries. Neurodegeneration in the diabetic retina was significantly reduced by Epo treatment. Increased VEGF-A levels in the diabetic retina were normalized by Epo treatment. Conclusions: Suberythropoietic Epo is effective to protect microvascular and neuronal damage in the experimental diabetic retina.