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Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (approximately 75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LID mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control mice) and abnormal glucose clearance after insulin injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their control littermates. Thus, the high levels of circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID mice. In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues. [ABSTRACT FROM AUTHOR]

Activation of the sympathetic nervous system is a compensatory mechanism which initially provides support for the circulation in the face of a falling cardiac output. It has been recognized for some time that chronic elevation of sympathetic outflow with the consequent increase in plasma norepinephrine, is counterproductive to improving cardiac function. Indeed, therapeutic targeting to block excessive sympathetic activation in heart failure is becoming a more accepted modality. The mechanism(s) by which sympathetic excitation occurs in the heart failure state are not completely understood. Components of abnormal cardiovascular reflex regulation most likely contribute to this sympatho-excitation. However, central mechanisms which relate to the elaboration of angiotensin II (Ang II) and nitric oxide (NO) may also play an important role. Ang II has been shown to be a sympatho-excitatory peptide in the central nervous system while NO is sympatho-inhibitory. Recent studies have demonstrated that blockade of Ang II receptors of the AT1 subtype augments arterial baroreflex control of sympathetic nerve activity in the heart failure state, thereby predisposing to a reduction in sympathetic tone. Ang II and NO interact to regulate sympathetic outflow. Blockade of NO production in normal conscious rabbits was only capable of increasing sympathetic outflow when accompanied by a background infusion of Ang II. Conversely, providing a source of NO to rabbits with heart failure reduced sympathetic nerve activity when accompanied by blockade of AT1 receptors. Chronic heart failure is also associated with a decrease in NO synthesis in the brain as indicated by a reduction in the mRNA for the neuronal isoform (nNOS). Chronic blockade of Ang II receptors can up regulate nNOS expression. In addition, exercise training of rabbits with developing heart failure has been shown to reduce sympathetic tone, decrease plasma Ang II, improve arterial baroreflex function and increase nNOS expression in the central nervous system. This review summarizes a large number of studies which have concentrated on the mechanisms of sympatho-excitation in heart failure. It now seems clear that one mechanism which is important in regulating sympathetic outflow in this disease state depends upon a central interaction between Ang II and NO at the cellular and nuclear levels. [ABSTRACT FROM AUTHOR]

Investigates the role of the area postrema in mediating the enhancement in baroreflex function in response to angiotensin II type 1 receptor blockade in rabbits with pacing-induced congestive heart failure (CHF). Effectiveness of area postrema lesions; Baroreflex function in normal and CHF rabbits.

Studies the effects of nitric oxide on baroreflex control of heart rate and renal nerve activity in conscious rabbits. Surgical preparations; Implantation of renal sympathetic nerve recording electrodes; Sinoaortic denervation; Experimental protocols; Data analysis.

Investigates the effect of the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole on the baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in the rabbit. Influence of blockade of neuronal NO synthase on baroreflex control of HR; Role of endogenous brain NO in decreasing the baroreflex control of HR.

Clarifies the role of endogenous angiotensin II (ANG II) on baroreflex control of heart rate both in normal, conscious rabbits and conscious rabbits with pacing-induced heart failure. Sympathetic nerve activity; Arterial pressure; Suggestion of a role for ANG II in regulating cardiac sympathetic outflow in heart failure.