James A. Armitage

Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals?

The incidence of the metabolic syndrome, a cluster of abnormalities focusing on insulin resistance and associated with high risk for cardiovascular disease and diabetes, is reaching epidemic proportions. Prevalent in both developed and developing countries, the metabolic syndrome has largely been attributed to altered dietary and lifestyle factors that favour the development of central obesity. However, population‐based studies have suggested that predisposition to the metabolic syndrome may be acquired very early in development through inappropriate fetal or neonatal nutrition. Further evidence for developmental programming of the metabolic syndrome has now been suggested by animal studies in which the fetal environment has been manipulated through altered maternal dietary intake or modification of uterine artery blood flow. This review examines these studies and assesses whether the metabolic syndrome can be reliably induced by the interventions made. The validity of the different species, diets, feeding regimes and end‐point measures used is also discussed.

Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity.

Obesity and its sequelae may prove to be the greatest threat to human lifestyle and health in the developed world this century. The so called obesity epidemic has seen the incidence of obesity and overweight almost double in Western societies and the trend is mirrored in nations that are transitioning to first world economies. There is no doubt that much of the rise in obesity can be attributed to lifestyle factors such as the excess consumption of energy-dense foods and the decline in physical activity. However, the ‘fetal origins’hypothesis, first proposed by Barker and colleagues and elaborated by several groups over the past 15 years to be termed the ‘Developmental Origins of Adult Health and Disease’ (DOHaD), provides an alternative explanation for the rising rates of obesity. The DOHaD hypothesis states that exposure to an unfavourable environment during development (either in utero or in the early postnatal period) programmes changes in fetal or neonatal development such that the individual is then at greater risk of developing adulthood disease. This chapter discusses the effects of maternal obesity on fetal development and birth outcomes as well as the manner in which DOHaD may contribute to the obesity epidemic.

Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy

Evidence from human and animal studies suggests that maternal nutrition can induce developmental programming of adult hypertension in offspring. We have previously described a model of maternal dietary imbalance in Sprague‐Dawley rats whereby administration of a maternal diet rich in animal lard programmes the development of increased blood pressure, insulin resistance, dyslipidaemia, obesity and mesenteric artery endothelial dysfunction in adult offspring. To further characterize the mechanism of hypertension in this model we have examined vascular and renal structure in adult offspring of Sprague‐Dawley rats fed a control diet (OC) or lard‐rich diet (OHF) during pregnancy and suckling followed by a control diet post‐weaning. To gain further insight, we assessed aortic reactivity and elasticity in an organ bath preparation and renal renin and Na+,K+‐ATPase activity. Plasma aldosterone concentration was also measured. Stereological examination of the aorta in OHF demonstrated reduced endothelial cell volume and smooth muscle cell number compared with OC. Adult OHF animals showed increased aortic stiffness and reduced endothelium‐dependent relaxation. Renal stereology showed no differences in kidney weight, glomerular number or volume in OHF compared with OC, but renin and Na+,K+‐ATPase activity were significantly reduced in OHF compared with controls. Programmed alterations to aortic structure and function are consistent with previous observations that exposure to maternal high fat diets produces systemic vascular changes in the offspring. Despite normal renal stereology, altered renal Na+,K+‐ATPase and renin activity offers further insight into the mechanism underlying the increased blood pressure characteristic of this model.

Exposure to a High-Fat Diet Alters Leptin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 &mgr;g) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: −54%, paraventricular: −69%, and dorsomedial hypothalamus: −65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked “selective leptin resistance” in these animals.

Increased blood pressure later in life may be associated with perinatal n-3 fatty acid deficiency

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Previous work in both animals and humans with high blood pressure has demonstrated the antihypertensive effects of n−3 polyunsaturated fatty acids (PUFA), although it is not known whether these nutrients are effective in preventing hypertension. The predominant n−3 PUFA in the mammalian nervous system, docosahexaenoic acid (DHA), is deposited into synaptic membranes at a high rate during the perinatal period, and recent observations indicate that the perinatal environment is important for the normal development of blood pressure control. This study investigated the importance of perinatal n−3 PUFA supply in the control of blood pressure in adult Sprague-Dawley rats. Pregnant rat dams were fed semisynthetic diets that were either deficient in (DEF) or supplemented with (CON) n−3 PUFA. Offspring were fed the same diets as their mothers until 9 wk; then, half of the rats from each group were crossed over to the opposite diet, creating four groups, i.e., CON-CON; CON-DEF; DEF-DEF, DEF-CON. Mean arterial blood pressures (MAP) were measured directly, at 33 wk of age, by cannulation of the femoral artery. The phospholipid fatty acid profile of the hypothalamic region was determined by capillary gas-liquid chromatography. The tissue phospholipid fatty acid profile reflected the diet that the rats were consuming at the time of testing. Both groups receiving DEF after 9 wk of age (i.e., DEF-DEF and CON-DEF) had similar profiles with a reduction in DHA levels of 30%, compared with rats receiving CON (i.e., CON-CON and DEF-CON). DEF-DEF rats had significantly raised MAP compared with all other groups, with differences as great as 17 mm Hg. DEF-CON rats had raised MAP compared with CON-CON rats, and DEF-DEF rats had higher MAP than CON-DEF rats, despite the fact that their respective fatty acid profiles were not different. These findings indicate that inadequate levels of DHA in the perinatal period are associated with altered blood pressure control in later life. The way in which these long-term effects are produced remains to be elucidated.

Rapid Onset of Renal Sympathetic Nerve Activation in Rabbits Fed a High-Fat Diet

Hypertension and elevated sympathetic drive result from consumption of a high-calorie diet and deposition of abdominal fat, but the etiology and temporal characteristics are unknown. Rabbits instrumented for telemetric recording of arterial pressure and renal sympathetic nerve activity (RSNA) were fed a high-fat diet for 3 weeks then control diet for 1 week or control diet for 4 weeks. Baroreflexes and responses to air-jet stress and hypoxia were determined weekly. After 1 week of high-fat diet, caloric intake increased by 62%, accompanied by elevated body weight, blood glucose, plasma insulin, and leptin (8%, 14%, 134%, and 252%, respectively). Mean arterial pressure, heart rate, and RSNA also increased after 1 week (6%, 11%, and 57%, respectively). Whereas mean arterial pressure and body weight continued to rise over 3 weeks of high-fat diet, heart rate and RSNA did not change further. The RSNA baroreflex was attenuated from the first week of the diet. Excitatory responses to air-jet stress diminished over 3 weeks of high-fat diet, but responses to hypoxia were invariant. Resumption of a normal diet returned glucose, insulin, leptin, and heart rate to control levels, but body weight, mean arterial pressure, and RSNA remained elevated. In conclusion, elevated sympathetic drive and impaired baroreflex function, which occur within 1 week of consumption of a high-fat, high-calorie diet, appear integral to the rapid development of obesity-related hypertension. Increased plasma leptin and insulin may contribute to the initiation of hypertension but are not required for maintenance of mean arterial pressure, which likely lies in alterations in the response of neurons in the hypothalamus.

The role of blood pressure in glaucoma

Although intraocular pressure (IOP) remains an important risk factor for glaucoma, it is clear that other factors can also influence disease development and progression. More recently, the role that blood pressure (BP) has in the genesis of glaucoma has attracted attention, as it represents a clinically modifiable risk factor and thus provides the potential for new treatment strategies beyond IOP reduction. The interplay between blood pressure and IOP determines the ocular perfusion pressure (OPP), which regulates blood flow to the optic nerve. If OPP is a more important determinant of ganglion cell injury than IOP, then hypotension should exacerbate the detrimental effects of IOP elevation, whereas hypertension should provide protection against IOP elevation. Epidemiological evidence provides some conflicting outcomes of the role of systemic hypertension in the development and progression of glaucoma. The most recent study showed that patients at both extremes of the blood pressure spectrum show an increased prevalence of glaucoma. Those with low blood pressure would have low OPP and thus reduced blood flow; however, that people with hypertension also show increased risk is more difficult to reconcile. This finding may reflect an inherent blood flow dysregulation secondary to chronic hypertension that would render retinal blood flow less able to resist changes in ocular perfusion pressure. Here we review both clinical and experimental studies that have attempted to clarify the relationships among blood pressure, OPP and blood flow autoregulation in the pathogenesis of glaucoma.

ACE inhibition salvages the visual loss caused by diabetes

AimsWe consider the nature of retinal dysfunction in streptozotocin rats and assess the functional benefits of administering an angiotensin enzyme inhibitor or an inhibitor of advanced glycation end product formation.MethodsSprague-Dawley rats (n=44) were randomly assigned to control (C=12, Cp=4, Ca=4) and diabetic groups (Streptozotocin, D=24). Diabetes was diagnosed based on a range of physiological and biochemical parameters at 4, 8 and 12 weeks. Streptozotocin animals were administered insulin daily (4 units protophane). Animals were treated with either an Angiotensin Converting Enzyme inhibitor (perindopril, Cp=4, Dp=8) or an inhibitor of advanced glycation end product formation (aminoguanidine, Ca=4, Da=8). Dark-adapted electroretinograms were measured on anaesthetized animals at 12 weeks following streptozotocin treatment. Photoreceptoral and inner retinal responses were extracted, modelled and compared using ANOVA.ResultsStreptozotocin injection increased blood glucose, glycosylated haemoglobin, fluid intake and urine volume, whereas body weight was decreased. Perindopril treatment produced improvements (p<0.05) in all indices, whereas aminoguanidine therapy produced some improvement in blood glucose and water intake. Streptozotocin rats showed losses of photoreceptoral-P3 (−27%), postreceptoral-P2 (−15%) and oscillatory potential (−19%) amplitudes of a similar magnitude. Perindopril therapy returned photoreceptoral and inner retinal function to within control limits. However, aminoguanidine treatment gave no significant functional improvement.ConclusionsOur findings provide evidence for a selective neuropathy in diabetes with a primary photoreceptoral lesion. Treatment with perindopril, an angiotensin converting enzyme inhibitor, ameliorates the neuropathy.

Reversal of Vascular Macrophage Accumulation and Hypertension by a CCR2 Antagonist in Deoxycorticosterone/Salt-Treated Mice

Infiltration of macrophages into the artery wall plays detrimental roles during hypertension by promoting vascular inflammation and endothelial dysfunction, and it occurs via a chemo-attractant action of chemokines on macrophage cytokine receptors. We sought to identify the key chemokine receptors associated with macrophage infiltration into the vascular wall during deoxycorticosterone acetate (DOCA)/salt-induced hypertension in mice and to evaluate the impact of pharmacological inhibition of these receptors on blood pressure and leukocyte accumulation. Mice treated with DOCA/salt for 21 days displayed markedly elevated systolic blood pressure (158±2 versus 114±5 mm Hg in sham group; P<0.0001). Polymerase chain reaction screening via a gene array of 20 chemokine receptors indicated an increased expression of CCR2 in aortas of DOCA/salt-treated mice. Real-time polymerase chain reaction confirmed mRNA upregulation of CCR2 in aortas from DOCA/salt-treated animals and of the CCR2 ligands CCL2, CCL7, CCL8, and CCL12 (all >2-fold versus sham; P<0.05). Flow cytometry revealed 2.9-fold higher macrophage numbers (ie, CD45+ CD11b+ F4/80+ cells) in the aortic wall of DOCA/salt versus sham-treated mice. Intervention with a CCR2 antagonist, INCB3344 (30 mg/kg per day, IP), 10 days after the induction of hypertension with DOCA/salt treatment, reduced the aortic expression of CCR2 mRNA and completely reversed the DOCA/salt-induced influx of macrophages. Importantly, INCB3344 substantially reduced the elevated blood pressure in DOCA/salt-treated mice. Hence, our findings highlight CCR2 as a promising therapeutic target to reduce both macrophage accumulation in the vascular wall and blood pressure in hypertension.

The contribution of cone responses to rat electroretinograms

The contribution of rods and cones to the scotopic electroretinogram (ERG) of small animals is unclear, with a recent report suggesting that the mouse has no cone a‐wave. The present study considered the contribution of cones to the ERG of the rat. Dark‐adapted Long Evans rats (n = 4) had ERG signals collected following a single flash, which stimulated rods and cones (mixed response), or a twin‐flash paradigm (short interstimulus interval, 1 s), which isolated cone responses. Rod signals were derived by digital subtraction of the cone signal from the mixed rod/cone ERG. The rat a‐wave was found to be dominated by rod responses but cone responses contributed substantially (45%) to post‐receptoral waveforms (b‐wave) at higher light levels.