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 μg) 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.

Arterial compliance, blood pressure, plasma leptin, and plasma lipids in women are improved with weight reduction equally with a meat-based diet and a plant-based diet

Obesity, strongly associated with the risk for coronary heart disease (CHD), is becoming increasingly prevalent. This study was designed to establish first whether systemic arterial compliance (SAC), an index of arterial function, is improved with weight loss and second, whether cardiovascular risk factors that improve with weight loss are reduced equally with lean meat or with an equivalent amount of plant protein in the diet. Thirty-six women, mostly overweight or obess, aged 40 ± 9 years, were allocated nonrandomly to a 16-week parallel-design trial of two equienergetic diets designed to lead to weight loss, with one arm of the study emphasizing red meat and the other soybeans as the major protein source. Body weight, waist and hip circumference, and plasma lipids, glucose, insulin, and leptin levels were measured, and SAC was calculated from ultrasound measurement of aortic flow velocity and aortic root driving pressure. Subjects lost weight (9% of body weight in 16 weeks) and showed decreased plasma total and low-density lipoprotein (LDL) cholesterol (12% and 14%, P < .0001, respectively), triacylglycerol (17%, P < .05), and leptin (24%, P < .01) concentrations. However, lipoprotein(a) [Lp(a)] levels did not change significantly. Mean arterial pressure (MAP) decreased 7% and SAC increased 28% (P < .001 for both). However, only the decrease in arterial pressure correlated significantly with the reduction in the waist to hip ratio (WHR), and the improvement in SAC correlated inversely with the blood pressure reduction (P < .001 for both). Further, weight loss and the metabolic benefits of weight loss occurred equally with the meat-based and plant-based diets. We conclude that moderate weight loss in women leads to a substantial reduction in the cardiovascular risk, including SAC.

Comparison of aspirin and indomethacin pre-treatments on the responses to reduced renal artery pressure in conscious dogs

To examine the role of prostaglandins in physiologically induced renin release, we reduced renal artery pressure within the autoregulatory range in chronically instrumented conscious dogs with aspirin, indomethacin or no pre-treatment. In untreated dogs, reduction of renal artery pressure to 60 mmHg for 90 min produced rises in plasma renin activity (+ 5.4 +/- 1.0 ng ml.-1 hr-1) and mean arterial pressure (+ 17 +/- 2 mmHg) without significant effect on renal blood flow (n = 13). Aspirin pre-treatment (2 X 25-40 mg kg-1 orally) had no effect on the renin, arterial pressure or renal blood flow responses to renal artery pressure reduction (n = 7). In contrast, indomethacin pre-treatment (2 X 2-3 mg kg-1 orally) significantly lessened the increase in plasma renin activity during reduced renal artery pressure (+ 2.0 +/- 0.3 ng ml.-1 hr-1, n = 11). The relative effectiveness of aspirin and indomethacin in inhibiting prostaglandin production in the kidney was then tested in separate experiments by measuring the renal blood flow responses to renal artery injections of arachidonate (5-200 micrograms kg-1). In the doses used above, aspirin markedly attenuated the blood flow response to arachidonate but indomethacin had almost no effect. Both aspirin and indomethacin abolished the hypotensive effect of intravenous arachidonate (0.5 mg kg-1). These results tentatively suggest that indomethacin may not effectively inhibit renal prostaglandin production in conscious dogs at the doses used in these experiments. Thus the reduced renin release in response to lowered renal artery pressure in indomethacin pre-treated dogs may have been due to another, non-prostaglandin action of indomethacin. The results from the aspirin pre-treated dogs suggest that prostaglandins are not involved in the release of renin in response to reduced renal artery pressure in conscious dogs.

Blood pressure modifies retinal susceptibility to intraocular pressure elevation

Primary open angle glaucoma affects more than 67 million people. Elevated intraocular pressure (IOP) is a risk factor for glaucoma and may reduce nutrient availability by decreasing ocular perfusion pressure (OPP). An interaction between arterial blood pressure and IOP determines OPP; but the exact contribution that these factors have for retinal function is not fully understood. Here we sought to determine how acute modifications of arterial pressure will affect the susceptibility of neuronal function and blood flow to IOP challenge. Anaesthetized (ketamine:xylazine) Long-Evan rats with low (~60 mmHg, sodium nitroprusside infusion), moderate (~100 mmHg, saline), or high levels (~160 mmHg, angiotensin II) of mean arterial pressure (MAP, n = 5–10 per group) were subjected to IOP challenge (10–120 mmHg, 5 mmHg steps every 3 minutes). Electroretinograms were measured at each IOP step to assess bipolar cell (b-wave) and inner retinal function (scotopic threshold response or STR). Ocular blood flow was measured using laser-Doppler flowmetry in groups with similar MAP level and the same IOP challenge protocol. Both b-wave and STR amplitudes decreased with IOP elevation. Retinal function was less susceptible to IOP challenge when MAP was high, whereas the converse was true for low MAP. Consistent with the effects on retinal function, higher IOP was needed to attenuated ocular blood flow in animals with higher MAP. The susceptibility of retinal function to IOP challenge can be ameliorated by acute high BP, and exacerbated by low BP. This is partially mediated by modifications in ocular blood flow.

Cortisol, blood pressure, and heart rate responses to food intake were independent of physical fitness levels in women

This research tested the hypothesis that women who had higher levels of physical fitness will have lower hypothalamo-pituitary-adrenal axis (cortisol) and sympatho-adrenal medullary system (blood pressure and heart rate) responses to food intake compared with women who had low levels of physical fitness. Lower fitness (n = 22; maximal oxygen consumption = 27.4 ± 1.0 mL∙kg(-1)·min(-1)) and higher fitness (n = 22; maximal oxygen consumption = 41.9 ± 1.6 mL∙kg(-1)·min(-1)) women (aged 30-50 years; in the follicular phase of the menstrual cycle) who participated in levels of physical activity that met (lower fitness = 2.7 ± 0.5 h/week) or considerably exceeded (higher fitness = 7.1 ± 1.4 h/week) physical activity guidelines made their own lunch using standardised ingredients at 1200 h. Concentrations of cortisol were measured in blood samples collected every 15 min from 1145-1400 h. Blood pressures and heart rate were also measured every 15 min between 1145 h and 1400 h. The meal consumed by the participants consisted of 20% protein, 61% carbohydrates, and 19% fat. There was a significant overall response to lunch in all of the parameters measured (time effect for all, p < 0.01). The cortisol response to lunch was not significantly different between the groups (time × treatment, p = 0.882). Overall, both groups showed the same pattern of cortisol secretion (treatment p = 0.839). Systolic blood pressure, diastolic blood pressure, mean arterial pressure, or heart rate responses (time × treatment, p = 0.726, 0.898, 0.713, and 0.620, respectively) were also similar between higher and lower fitness women. Results suggest that the physiological response to food intake in women is quite resistant to modification by elevated physical fitness levels.

Breaking up prolonged sitting reduces resting blood pressure in overweight/obese adults

Abstract
Aim:
To compare the effect of 7 h of prolonged sitting on resting blood pressure with asimilar duration of sitting combined with intermittent brief bouts of light-intensity or moderate-intensity physical activity.
Methods and results:
Overweight/obeseadults(nZ19;aged45 e65years) were recruited for a randomized three-treatment crossover trial with a one-week washout between treatments: 1) uninterrupted sitting; 2) sitting with 2 min bouts of light-intensity walking at 3.2 km/h every 20 min;and, 3) sitting with 2 min bouts of moderate-intensity walking at between 5.8 and 6.4 km/h every 20 min. After an initial 2 h period seated, participants consumed a test meal (75 g carbohydrate,50 g fat) and completed each condition over the next 5 h. Resting blood pressure was assessed oscillometrically every hour as a single measurement, 5 min prior to each activity bout. GEE models were adjusted for sex, age, BMI, fasting blood pressure and treatment order. After adjustment for potential confounding variables, breaking up prolonged sitting with lightand moderate-intensity activity breaks was associated with lower systolic blood pressure [light:120

1 mmHg (estimated marginal mean

SEM),
P
Z
0.002; moderate: 121

1 mmHg,
P
Z
0.02], compared to uninterrupted sitting (123

1 mmHg). Diastolic blood pressure was also
signi
fi
cantly lower during both of the activity conditions (light: 76

1 mmHg,
P
Z
0.006; moder-
ate: 77

1mmHg,
P
Z
0.03) compared to uninterrupted sitting (79

1 mmHg). No significant between-condition differences were observed in mean arterial pressure or heart rate.
Conclusion:
Regularly breaking up prolonged sitting may reduce systolic and diastolic blood pressure.

Origin of aberrant blood pressure and sympathetic regulation in diet-induced obesity

High fat diet (HFD)-induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin-stimulating hormone (α-MSH) and neuropeptide Y-positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode. After 3 weeks of an HFD (13.3% fat; n=19), rabbits exhibited higher RSNA, mean arterial pressure (MAP), and heart rate compared with control diet-fed animals (4.2% fat; n=15). Intra-VMH injections of a leptin receptor antagonist or SHU9119, a melanocortin 3/4 receptor antagonist, decreased MAP, heart rate, and RSNA compared with vehicle in HFD rabbits (P<0.05) but not in control diet-fed animals. By contrast, α-MSH or neuropeptide Y injected into the VMH had no effect on MAP but produced sympathoexcitation in HFD rabbits (P<0.05) but not in control diet-fed rabbits. The effects of the leptin antagonist, α-MSH, or neuropeptide Y injections into the DMH on MAP or RSNA of HFD rabbits were not different from those after vehicle injection. α-MSH into the DMH of control diet-fed animals did increase MAP, heart rate, and RSNA. We conclude that the VMH is the likely origin of leptin-mediated sympathoexcitation and α-MSH hypersensitivity that contribute to obesity-related hypertension.

Dietary protein level interacts with ω-3 polyunsaturated fatty acid deficiency to induce hypertension

Background : Dietary ω-3 fatty acid deficiency can lead to hypertension in later life; however, hypertension is affected by numerous other dietary factors. We examined the effect of altering the dietary protein level on blood pressure in animals deficient or sufficient in ω-3 fatty acids.

Methods : Female rats were placed on one of four experimental diets 1 week prior to mating. Diets were either deficient (10% safflower oil; DEF) or sufficient (7% safflower oil, 3% flaxseed oil; SUF) in ω-3 fatty acids and contained 20 or 30% casein (DEF20, SUF20, DEF30, SUF30). Offspring were maintained on the maternal diet for the duration of the experiment. At 12, 18, 24, and 30 weeks, blood pressure was assessed by tail cuff plethysmography.

Results : At both 12 and 18 weeks of age, no differences in blood pressure were observed based on diet, however, by 24 weeks hypertension was evident in DEF30 animals; there were no blood pressure differences between the other groups. This hypertension in DEF30 group was increased at 30 weeks, with systolic, diastolic, and mean arterial pressure all elevated.

Conclusions : These results indicate that the hypertension previously attributed to ω-3 fatty acid deficiency is dependent on additional dietary factors, including protein content. Furthermore, this study is the first to plot the establishment of ω-3 fatty acid deficiency hypertension over time.

Mechanisms involved in the renal responses to intravenous and renal artery infusions of noradrenaline in conscious dogs

1. The renal haemodynamic and glomerular filtration rate (G.F.R.) responses to intravenous and intrarenal infusions of noradrenaline were studied in conscious dogs, either with or without prior blockade of angiotensin II formation with teprotide.

2. Infusion noradrenaline by either route resulted in dose-related rises in plasma renin activity.

3. Pretreatment with teprotide reduced the rise in mean arterial pressure and abolished the rise in G.F.R. seen during intravenous infusions of noradrenaline (0.1, 0.2 and 0.4 microgram/kg . min). Noradrenaline also reduced filtration fraction more after teprotide pretreatment.

4. Renal blood flow rose and renal vascular resistance fell in response to I.V. noradrenaline infusions. This renal vasodilatation was unaffected by pretreatment of the dogs with teprotide, indomethacin or DL-propranolol. However after pentolinium pretreatment, I.V. noradrenaline infusion caused a dose-related renal vasoconstriction.

5. Infusion of noradrenaline into the renal artery (0.02, 0.05 and 0.1 microgram/kg . min) resulted in rises in mean arterial pressure and G.F.R. which were abolished by teprotide pretreatment. Filtration fraction rose when noradrenaline was administered alone but fell when it was infused after teprotide treatment.

6. Thus angiotensin II formed as the result of increased renin release acted to maintain G.F.R. and filtration fraction during noradrenaline infusion. In addition, I.V. noradrenaline infusions in conscious dogs caused reflex vasodilatation of the renal vasculature.

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.

Progression of cardiovascular and endocrine dysfunction in a rabbit model of obesity

In rabbits, mean arterial pressure (MAP) increases in response to fat feeding, but does not increase further with progressive weight gain. We documented the progression of adiposity and the alterations in endocrine/cardiovascular function in response to fat feeding in rabbits, to determine whether stabilization of MAP after 3 weeks could be explained by stabilization of neurohormonal factors. Rabbits were fed a control diet or high-fat diet for 9 weeks (n¼23). Fat feeding progressively increased body mass and adiposity. Heart rate (HR) was elevated by week 3 (15±3%) but changed little thereafter. The effects of fat feeding on MAP were dependent on baseline MAP and peaked at 3 weeks. From baseline, MAP p80mmHg, MAP had increased by 8.1±1.3, 4.7±1.7 and 5.6±1.2mmHg, respectively, 3, 6 and 9 weeks after commencing the high-fat diet, but by only 2.6±1.5, 3.0±1.7 and 3.9±1.4mmHg, respectively, in control rabbits. Fat feeding did not increase MAP from a baseline 480mmHg. Plasma concentrations of leptin and insulin increased during the first 3–6 weeks of fat feeding and then stabilized (increasing by 111±17% and 731±302% by week 9, respectively), coinciding with the pattern of changes in MAP and HR. Plasma total cholesterol, triglycerides, renin activity, aldosterone and atrial natriuretic peptide were not significantly altered by fat feeding. Given that the changes in plasma leptin and insulin mirrored the changes in MAP and HR, leptin and insulin may be important factors in the development of hypertensionand tachycardia in the rabbit model of obesity.

Altered responsiveness of the kidney to activation of the renal nerves in fat-fed rabbits

We tested whether mild adiposity alters responsiveness of the kidney to activation of the renal sympathetic nerves. After rabbits were fed a high-fat or control diet for 9 wk, responses to reflex activation of renal sympathetic nerve activity (RSNA) with hypoxia and electrical stimulation of the renal nerves (RNS) were examined under pentobarbital anesthesia. Fat pad mass and body weight were, respectively, 74% and 6% greater in fat-fed rabbits than controls. RNS produced frequency-dependent reductions in renal blood flow, cortical and medullary perfusion, glomerular filtration rate, urine flow, and sodium excretion and increased renal plasma renin activity (PRA) overflow. Responses of sodium excretion and medullary perfusion were significantly enhanced by fat feeding. For example, 1 Hz RNS reduced sodium excretion by 79 ± 4% in fat-fed rabbits and 46 ± 13% in controls. RNS (2 Hz) reduced medullary perfusion by 38 ± 11% in fat-fed rabbits and 9 ± 4% in controls. Hypoxia doubled RSNA, increased renal PRA overflow and medullary perfusion, and reduced urine flow and sodium excretion, without significantly altering mean arterial pressure (MAP) or cortical perfusion. These effects were indistinguishable in fat-fed and control rabbits. Neither MAP nor PRA were significantly greater in conscious fat-fed than control rabbits. These observations suggest that mild excess adiposity can augment the antinatriuretic response to renal nerve activation by RNS, possibly through altered neural control of medullary perfusion. Thus, sodium retention in obesity might be driven not only by increased RSNA, but also by increased responsiveness of the kidney to RSNA.