Effects of streptozotocin-induced diabetes on heart rate, blood pressure and cardiac autonomic nervous control

Hicks, Kristen; Seifen, Ernst; Stimers, Joseph R.; Kennedy, Richard H.

doi:10.1016/s0165-1838(98)00004-6

Cited by 106 publications

(98 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Long-term telemetry studies, including this one, consistently show stable or reduced BP after induction of type 1 diabetes [14,16,[34][35][36][37]. Recent results indicate that rats with STZ-induced diabetes show salt-resistant BP [16,38] even on a background of hypertension induced by chronic inhibition of nitric oxide synthase (NOS) [38].…”

Section: Discussionmentioning

confidence: 82%

Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake

et al. 2012

View full text Add to dashboard Cite

Aims/hypothesis In early type 1 diabetes mellitus, renal salt handling is dysregulated, so that the glomerular filtration rate becomes inversely proportional to salt intake. The salt paradox occurs in both humans and rats and, with low salt intake, results in diabetic hyperfiltration. We tested whether increased salt intake could reduce the susceptibility to injury of non-clipped kidneys in diabetic rats with pre-existing Goldblatt hypertension. Methods Male Long-Evans rats were made hypertensive and half were then made diabetic. Blood glucose was maintained at ∼20-25 mmol/l by insulin implants. One half of each received only the salt in normal chow (1% by weight) and the other half received added salt in drinking water to equal 2.7% by weight of food intake. Weekly 24 h blood pressure records were acquired by telemetry during the 4-month experiment. Results Systolic blood pressure was not affected by diabetes or increased salt intake, alone or together. Autoregulation was highly efficient in the non-clipped kidney of both intact and diabetic rats. Histological examination showed minor injury in the clipped kidney, which did not differ among groups. The non-clipped kidney showed extensive pressuredependent glomerular and vascular injury in both intact and diabetic rats. Conclusions/interpretation The relationship between pressure and injury was shifted toward lower blood pressure in diabetic rats, indicating that diabetes increased the susceptibility of the kidney to injury despite preservation of autoregulation. The increased susceptibility was not affected by high salt intake in the diabetic rats, thus disproving the hypothesis.

show abstract

Section: Discussionmentioning

confidence: 82%

Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Continuous lines, control; dashed lines, diabetic; dotted lines, diabetic+insulin [35,36] and, more recently, Stebelova et al [37]. Moreover, opposite results on diurnal variations in plasma insulin, leptin, glucocorticoids, growth and thyroid hormones, glucose and fatty acids, as well as on the sympathetic neuronal activity, have been reported by other investigators [38][39][40][41].…”

Section: Discussionmentioning

confidence: 91%

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

et al. 2011

View full text Add to dashboard Cite

Aims/hypothesis It is well documented that melatonin influences insulin secretion mediated by G-protein-coupled melatonin receptor isoforms MT1 and MT2, which are present in rat and human pancreatic islets, as well as in rat insulinoma cells. Recent investigations have proven that hyperinsulinaemic Goto-Kakizaki (GK) rats, which are a rat model of type 2 diabetic rats, and humans have decreased melatonin plasma levels, whereas a streptozotocin-induced rat model of diabetes developed reduced insulin levels combined with increased melatonin levels. Methods Plasma levels of glucose, insulin and melatonin as well as RNA expression of pineal Aanat, Hiomt (also known as Asmt), insulin receptor, adrenoceptor β1 and the clock genes Per1 and Bmal1 (also known as Arntl) were determined in male and female LEW.1AR1-iddm rats as well as in insulin-substituted LEW.1AR1-iddm rats.Results Severe hypoinsulinaemia in diabetic LEW.1AR1-iddm rats was associated with decreased body weight and increased melatonin plasma levels combined with mainly elevated expression of Aanat, Hiomt, pineal insulin receptor and adrenoceptor β1. The changes were normalised by insulin substitution. Diurnal profiles of plasma melatonin and of antagonistic clock genes Per1 and Bmal1 were maintained in diabetic and insulin-substituted rats. Conclusions/interpretation The assumed causal relation between elevated melatonin and reduced insulin levels in LEW.1AR1-iddm rats is supported by the observation that insulin substitution normalised these changes. Further support for this interpretation comes from the observation that in GK rats an increase of plasma insulin was combined with a decrease of plasma noradrenaline (norepinephrine), the most important activator of melatonin synthesis. These relationships between the noradrenergic and insulin pathway support the existence of melatonin-insulin antagonism.

show abstract

“…Diabetic mouse models demonstrate that PKA is overactivated early on in the disease (10,30), and this is accompanied by increased circulating norepinephrine (31). However, there is an eventual decrease in adrenergic sensitivity prior to cardiac FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Humphries

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed ␤-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptorindependent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced ␤-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.Diabetes mellitus carries at least twice the risk of cardiovascular complications such as coronary artery disease, hypertension, and heart failure (1, 2). Diabetes can directly cause heart failure, in the case of diabetic cardiomyopathy, as well as exacerbate other comorbidities (3, 4). The reasons for this are multifaceted and involve both metabolic and mechanical cardiac stresses. Metabolic abnormalities include metabolic inflexibility caused by improper glucose uptake and oxidation and by lipotoxicity induced by lipid overload (5). Diabetes, in common with other forms of heart failure, has impairment of autonomic control and overstimulation of the sympathetic nervous system (6, 7). The etiology of chronic cardiac stimulation in diabetes is characterized by sympathetic enhancement and parasympathetic withdrawal (3, 8). Excess sympathetic stimulation over time causes extensive dysfunction to the ␤-adrenergic pathway, a process that is intimately tied with heart failure (9, 10).Normally, ligand binding to ␤ 1 -receptors activates G s proteins, which stimulate adenylate cyclase to produce cAMP. The primary target of cAMP is cAMP-dependent protein kinase (PKA), 2 a heterotetrameric protein comprised of two catalytic (PKA-C) and two regulatory subunits (either PKA-RI or PKA-RII isoforms). cAMP binds PKA-R subunits and induces the release of PKA-C, which then phosphorylates specific serines and threonines on protein targets in the cytoplasm, myofilaments, sarcoplasmic reticulum, sarcolemma, and nucleus to increase cardiac output, metab...

show abstract

Effects of streptozotocin-induced diabetes on heart rate, blood pressure and cardiac autonomic nervous control

Cited by 106 publications

References 40 publications

Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake

Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Contact Info

Product

Resources

About