Two-year outcome of laparoscopic Roux-en-Y gastric bypass in adolescents with severe obesity: results from a Swedish Nationwide Study (AMOS).

CONTEXT: The prevalence of obesity among adolescents has increased and we lack effective treatments. OBJECTIVE: To determine if gastric bypass is safe and effective for an unselected cohort of adolescents with morbid obesity in specialized health care. DESIGN, SETTING AND PATIENTS: Intervention study for 81 adolescents (13-18 years) with a body mass index (BMI) range 36-69 kg m(-2) undergoing laparoscopic gastric bypass surgery in a university hospital setting in Sweden between April 2006 and May 2009. For weight change comparisons, we identified an adult group undergoing gastric bypass surgery (n=81) and an adolescent group (n=81) receiving conventional care. MAIN OUTCOME MEASUREMENTS: Two-year outcome regarding BMI in all groups, and metabolic risk factors and quality of life in the adolescent surgery group. RESULTS: Two-year follow-up rate was 100% in both surgery groups and 73% in the adolescent comparison group. In adolescents undergoing surgery, BMI was 45.5 ± 6.1 (mean ± s.d.) at baseline and 30.2 (confidence interval 29.1-31.3) after 2 years (P<0.001) corresponding to a 32% weight loss and a 76% loss of excess BMI. The 2-year weight loss was 31% in adult surgery patients, whereas 3% weight gain was seen in conventionally treated adolescents. At baseline, hyperinsulinemia (>20 mU l(-1)) was present in 70% of the adolescent surgery patients, which was reduced to 0% at 1 year and 3% at 2 years. Other cardiovascular risk factors were also improved. Two-thirds of adolescents undergoing surgery had a history of psychopathology. Nevertheless, the treatment was generally well tolerated and, overall, quality of life increased significantly. Adverse events were seen in 33% of patients. CONCLUSIONS: Adolescents with severe obesity demonstrated similar weight loss as adults following gastric bypass surgery yet demonstrating high prevalence of psychopathology at baseline. There were associated benefits for health and quality of life. Surgical and psychological challenges during follow-up require careful attention.

Hedonic and incentive signals for body weight control.

Here we review the emerging neurobiological understanding of the role of the brain's reward system in the regulation of body weight in health and in disease. Common obesity is characterized by the over-consumption of palatable/rewarding foods, reflecting an imbalance in the relative importance of hedonic versus homeostatic signals. The popular 'incentive salience theory' of food reward recognises not only a hedonic/pleasure component ('liking') but also an incentive motivation component ('wanting' or 'reward-seeking'). Central to the neurobiology of the reward mechanism is the mesoaccumbal dopamine system that confers incentive motivation not only for natural rewards such as food but also by artificial rewards (eg. addictive drugs). Indeed, this mesoaccumbal dopamine system receives and integrates information about the incentive (rewarding) value of foods with information about metabolic status. Problematic over-eating likely reflects a changing balance in the control exerted by hypothalamic versus reward circuits and/or it could reflect an allostatic shift in the hedonic set point for food reward. Certainly, for obesity to prevail, metabolic satiety signals such as leptin and insulin fail to regain control of appetitive brain networks, including those involved in food reward. On the other hand, metabolic control could reflect increased signalling by the stomach-derived orexigenic hormone, ghrelin. We have shown that ghrelin activates the mesoaccumbal dopamine system and that central ghrelin signalling is required for reward from both chemical drugs (eg alcohol) and also from palatable food. Future therapies for problematic over-eating and obesity may include drugs that interfere with incentive motivation, such as ghrelin antagonists.

Heart rate variability characteristics of patients with irritable bowel syndrome and associations with symptoms.

BACKGROUND: Disturbed brain-gut interactions are assumed to be of importance for symptom generation in patients with irritable bowel syndrome (IBS). The autonomic nervous system (ANS) is part of the bidirectional brain-gut communication, but previous studies in IBS show diverging results. We aimed to identify subgroups of IBS patients with distinct ANS characteristics differentiating them from healthy controls (HC), and to study associations between ANS status and symptoms. METHODS: Heart rate variability (HRV) was measured in IBS patients and HC (Holter monitoring: supine and standing positions with controlled respiration and ambulatory 24-hour period). Frequency (5 minutes, supine, standing) and time domains (24 hours, day, night) were analyzed. Validated questionnaires were used to measure gastrointestinal and psychological symptoms in patients. Patients and HC were compared on a univariate and multivariate level (principal component analysis [PCA] and orthogonal partial least squares discriminatory analysis (OPLS-DA)). KEY RESULTS: We analyzed 158 IBS patients (Rome III) and 39 HC. Patients differed significantly from HC in HRV parameters during daytime and in standing position. In the PCA, a majority of patients overlapped with HC, but the weighted means differed (P < .01). A subset of patients (n = 30; 19%) with an aberrant global HRV profile was identified through PCA and OPLS-DA; these patients reported more severe symptoms of frequent (P < .05) and loose stools (P = .03), as well as urgency (P = .01). CONCLUSIONS AND INFERENCES: Altered ANS function was demonstrated in patients with IBS, and this might be of particular relevance for symptoms in a subset of the patients.

Sympathetic discharge to mesenteric organs and the liver. Evidence for substantial mesenteric organ norepinephrine spillover.

This study using sampling of blood from the portal vein, in addition to arterial and hepatic sites, to estimate separately spillovers of norepinephrine from mesenteric organs and the liver in seven patients undergoing upper abdominal surgery. Conventional measurements in arterial and hepatic venous plasma provided a measure of net hepatomesenteric NE spillover (403 pmol/ml) that indicated a 13% contribution of these organs to total body spillover of NE into systemic plasma (3,071+/-518 pmol/min). The net hepatomesenteric spillover of NE into systemic plasma was much lower than the spillover of NE from mesenteric organs into portal venous plasma (1,684+/-418 pmol/min). This and the hepatic spillover of NE into systemic plasma (212+/-72 pmol/min) indicated a considerable combined spillover of NE from hepatomesenteric organs (1,896+/-455 pmol/min). The sum of the latter estimate with the difference between total body and net hepatomesenteric NE spillovers provided an adjusted total body spillover of NE into both systemic and portal venous plasma (4,564+/-902 pmol/min). Mesenteric organs made a 37% contribution, and the liver made a 5% contribution to the adjusted total body spillover of NE. Thus, a substantial proportion of total body sympathetic outflow is directed towards mesenteric organs; this is obscured by efficient hepatic extraction of NE (86+/-6%) when measurements are restricted to arterial and hepatic venous plasma.

Autonomic nervous system function predicts the inflammatory response over three years in newly diagnosed ulcerative colitis patients.

BACKGROUND: The autonomic nervous system (ANS) modulates intestinal inflammation in animal models. Human evidence confirming such modulating influence is limited. We aimed to investigate whether ANS function is associated with inflammatory parameters at disease onset, and whether it predicts the evolution of inflammation in patients with ulcerative colitis (UC). METHODS: We prospectively monitored 51 patients from onset of UC for 3 years. Upon remission of the onset flare, ANS activity was assessed by heart rate variability analysis and compared with healthy controls. Inflammatory parameters in blood, stool, and colonic biopsies obtained at onset and during follow-up visits were analyzed. Generalized linear models were used to test cross-sectional associations between ANS activity and inflammatory parameters at onset; linear mixed models were used to test whether ANS function at onset predicted the evolution of inflammation over the following 3 years. KEY RESULTS: Sympathovagal balance was different in UC patients compared to healthy controls, and cross-sectional associated with higher levels of systemic (erythrocyte sedimentation rate [ESR], CRP, TNF-α, IFN-γ) and mucosal inflammation (interleukin-8, IFN-γ) at onset. Conversely, a negative cross-sectional association with parasympathetic activity was found for ESR & TNF-α. Longitudinally, parasympathetic activity at onset predicted systemic (ESR, WBC), but not mucosal inflammation during follow-up. CONCLUSIONS & INFERENCES: This study further strengthens the association between the ANS system and intestinal inflammation previously found in animal models and recently in patients with inflammatory bowel disease. These results may have important implications for the pathogenesis and treatment of UC.

Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders.

BACKGROUND: The etiology of depressive illness has been linked with brain monoaminergic neuronal dysfunction, yet the development of sensitive markers of endogenous depression has proven difficult. METHODS: Using catheters placed in an internal jugular vein, we estimated the release of brain monoamine neurotransmitters in 19 healthy volunteers and in 9 patients with nonbipolar depressive illness refractory to medication at rest and following intravenous desipramine hydrochloride. Venoarterial plasma concentration gradients were used to quantify the amount of neurotransmitters stemming from the brain. Cerebral oxidative metabolism was assessed concurrently from measurements of oxygen and carbon dioxide gas exchange via the process of regional indirect calorimetry. RESULTS: The brains of these patients exhibited reduced venoarterial norepinephrine (4.0 +/- 2.7 nmol/L vs 0.7 +/- 1.3 nmol/L) and homovanillic acid concentration gradients (8.3 +/- 7.8 nmol/L vs 3.1 +/- 1.9 nmol/L), and used an energy source other than glucose. Internal jugular 5-hydroxyindoleacetic acid concentration gradients were not reduced in the patients with depressive illness. While both the reduction in norepinephrine turnover and the defect in cerebral metabolism were normalized following pharmacological blockade of the norepinephrine transporter with desipramine, paradoxically it was the brain's turnover of dopamine that bore a significant relation to the patients' clinical status (r(s) = 0.79, P =.02). The positive nature of this relationship remains difficult to reconcile. CONCLUSIONS: In accordance with the monoamine hypothesis, a deficit in brain norepinephrine and dopamine exists in patients with depressive illness. Moreover, the brains of these patients use an energy source other than glucose, a situation that is normalized following the acute pharmacological blockade of the norepinephrine transporter with the tricyclic antidepressant, desipramine.

Diastolic characteristics and cardiac energetics of isolated hearts exposed to volume and pressure overload.

The relation between diastolic dimensions and systolic function was studied in isolated rat hearts exposed to pressure (primary hypertension) and to volume load (hyperthyroidism). The hearts were arrested in diastole and cardiac dimensions analysed. Cardiac function was determined using an anterograde working heart preparation. Both models of cardiac overload produced significant left ventricular hypertrophy, however with different design. One concentric and one eccentric form of left ventricular hypertrophy were found in the spontaneously hypertensive rat obtained from two different breeders. An even more pronounced form of eccentric left ventricular hypertrophy was seen in hyperthyroid rats. The hearts with an eccentric form of hypertrophy had a higher maximal stroke volume when perfused at a high aortic pressure than those with a concentric form. At a low aortic pressure and hence a limited coronary perfusion cardiac performance was diminished in both types of spontaneously hypertensive rats but remained normal in hyperthyroid rats. Furthermore, oxygen consumption was reduced in all hypertrophied hearts compared with non-hypertrophied hearts. These data therefore suggest (a) that hearts having an eccentric type of hypertrophy may be in a more favourable situation, delivering a higher stroke volume for a given degree of myocardial fibre shortening; and (b) that the development of coronary vascular structural changes in spontaneously hypertensive rats, thereby increasing vascular resistance, leads to a decrease in left ventricular function at a low coronary perfusion pressure, whereas no such reduction was observed in hyperthyroid hearts, probably owing to a normal vascular resistance.

Subarachnoid hemorrhage induced sympathoexcitation arises due to changes in endothelin and/or nitric oxide activity.

OBJECTIVE: The demonstration of the effectiveness of endothelin antagonists and nitric oxide donors in managing vasospasm following subarachnoid hemorrhage is encouraging. Whether such drugs can modify the sympathoexcitation that accompanies this condition remains unknown and was the basis for the present report. METHODS: Subarachnoid hemorrhage was induced in conscious rats by injecting blood via a catheter placed along the surface of the brain and directed towards the circle of Willis. We combined measurements of arterial plasma catecholamines with the spectral analysis of blood pressure variability in order to examine sympathetic nervous activation following subarachnoid hemorrhage. Experiments were performed in untreated animals and in rats following pretreatment with either bosentan or sodium nitroprusside. RESULTS: Indicative of a pronounced sympathoexcitation, the 0.2-0.6 Hz frequency components of blood pressure were markedly elevated following subarachnoid hemorrhage (2.5 +/- 0.5 vs. 8.9 +/- 2.6 mmHg2, P < 0.01). Parallel changes in plasma norepinephrine concentration were observed (1.0 +/- 0.2 vs. 2.4 +/- 0.4 nmol/l, P < 0.01). The subarachnoid injection of saline did not modify blood pressure variability or plasma norepinephrine concentrations. Pretreatment with either bosentan or sodium nitroprusside completely prevented the subarachnoid hemorrhage induced sympathoexcitation. CONCLUSIONS: Experimental subarachnoid hemorrhage is associated with a pronounced activation of the sympathetic nervous system. It would appear that this sympathoexcitation has its roots ensconced in either the release of endothelin or an impairment in nitric oxide mediated vasodilation.

Sympathoadrenal system is critical for structural changes in genetic hypertension.

In spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, we examined tissue and adrenal norepinephrine concentrations, left ventricular (LV) weight, LV weight/body weight ratio (LV/BW), hindquarter resistance properties, ie, perfusion pressures at maximum dilatation and constriction (PPmax, PPmin), and the slope of the methoxamine log dose-PP curve. In series 1, we studied 4-week-old controls (SHRc, WKYc), sympathectomized rats (SX; SHRsx, WKYsx), and SX rats also given prazosin (SXP; SHRsxp, WKYsxp). With SX and SXP, adrenal norepinephrine concentrations increased in both strains, but tissue (LV, muscle, kidney) norepinephrine was depleted. At 4 weeks, LV/BW, PPmin, and PPmax were all greater in SHRc than in WKYc. With SX, these differences between strains remained unchanged, but SXP abolished them completely, indicating the importance of blockade of alpha-adrenergic receptor stimuli of adrenal origin. In SHRc (but not in WKYc), there was evidence of reinnervation after 4 weeks of SX. Hence, in series 2, the SXP period was extended to 8 weeks, and we studied SHRc, WKYc, SHRsxp, and WKYsxp. Systolic blood pressure was already elevated at 4 weeks in SHRc, and by 35 weeks it was 64 mm Hg greater than in WKYc. At 21 and 35 weeks, LV/BW, PPmax, PPmin, and slopes were all greater in SHRc than in WKYc, and the findings suggested greater LV and vascular hypertrophy than at 4 weeks. In SHRsxp hypertension, LV hypertrophy and the vascular changes were completely prevented over the entire 35-week observation period. SXP mainly affected SHR and had few effects on WKY rats. The sympathetic nerves and adrenals are probably the sources of alpha-adrenergic receptor stimulation in young SHR. They account for the development of hypertension and for most of the cardiovascular structural differences between SHR and WKY rats.

Norepinephrine overflow and renin pattern of the individual kidney in patients with unilateral renal artery stenosis.

This study was performed to determine divided renal efferent sympathetic nerve activity from kidneys in seven patients with renin-positive, unilateral renal artery stenosis before and 30 minutes after an acute intravenous dose of 1.25 mg enalaprilat. Renal norepinephrine release was calculated from split renal plasma flow, venoarterial plasma concentration gradients across the kidney, and the fractional extraction of tritiated norepinephrine. All patients had unilateral renin secretion, the affected kidney increasing its plasma renin activity gradient 1.7-fold, whereas no statistically significant change was noted on the contralateral side in response to enalaprilat. Total norepinephrine release to plasma and norepinephrine plasma clearance (assessed by isotope dilution) were similar before and after administration of enalaprilat (approximately 400 ng/min and 1.0 l/min), despite a 26% fall in mean arterial pressure (from 125 mm Hg, p less than 0.01). Heart rate remained unchanged. After enalaprilat, norepinephrine venoarterial difference increased in the renin-secreting kidney (from 264 to 396, SED = 57 pg/ml, p less than 0.05), whereas it increased only slightly in the contralateral kidney (from 149 to 256, SED = 72 pg/ml, NS). Tritiated norepinephrine extraction fell approximately 25% (p less than 0.01) in both kidneys. Thus, renal norepinephrine spillover increased from 49 to 62, SED = 9 ng/min (NS) and from 81 to 129, SED = 17 ng/min (p less than 0.05) from the affected and the contralateral kidney, respectively. Hence, in this relatively small study in patients with renovascular hypertension, no evidence for increased renal nerve activity could be observed in the affected kidney, despite its marked renin production.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular insulin-like growth factor I increases in early renal hypertension.

Increasing interest has been directed toward the possible role of trophically acting molecules as modulators or initiators, or both, of myocardial hypertrophy. The aim of the present study was to investigate the possible role of one such molecule, namely, insulin-like growth factor I, in myocardial hypertrophy developed in response to renal artery stenosis. Two-kidney, one clip Goldblatt hypertension was induced in Wistar rats weighing 180 g, and sham-operated animals were used as controls. Blood pressure was increased as early as 2 days after clipping (133 +/- 4 versus 116 +/- 4 mm Hg, p less than 0.05), and the increase persisted 4 and 7 days after clipping (148 +/- 6 versus 129 +/- 3 mm Hg, p less than 0.01 and 171 +/- 5 versus 139 +/- 3 mm Hg, p less than 0.01, respectively). Left ventricular weight followed a similar pattern (373 +/- 7 versus 350 +/- 8 mg, NS, 415 +/- 11 versus 386 +/- 9 mg, p less than 0.01, and 466 +/- 11 versus 391 +/- 10 mg, p less than 0.01 at 2, 4, and 7 days after clipping, respectively), but no changes in body weight between the groups were observed. Insulin-like growth factor I messenger RNA (mRNA) was quantified using a solution hybridization assay. After 4 days of renal hypertension, there was a significant increase in left ventricular insulin-like growth factor I mRNA (2.0 x 10(-18) +/- 0.48 x 10(-18) versus 0.4 x 10(-18) +/- 0.07 x 10(-18) mol.microgram DNA-1), which was no longer detectable 7 days after clipping.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilators inhibit acute alpha 1-adrenergic receptor-induced trophic responses in the vasculature.

Cardiovascular hypertrophy plays an important role in the development and maintenance of hypertension. Hyperactivity of the sympathetic nervous system may be one of the initiating factors responsible for the stimulation of growth processes involved in these structural alterations. We have used a well-established early biochemical marker of cellular growth processes, induction of ornithine decarboxylase (ODC), to determine whether alpha 1-adrenergic receptor-induced vascular trophic responses are dependent on arterial pressure elevation. Hydralazine or felodipine were coadministered to control the alpha 1-adrenergic receptor agonist-induced rise in mean arterial pressure (MAP). Methoxamine (2, 5, or 10 mg/kg s.c.) increased the average MAP (up to 20 mm Hg) and vascular ODC activity (up to ninefold) above control rats over 4 hours. Concomitant administration of hydralazine (0.5, 1.25, or 5 mg/kg s.c.) or felodipine (100 or 250 micrograms/kg s.c.) with methoxamine (10 mg/kg) attenuated the alpha 1-adrenergic receptor-induced activation of ODC in the aorta and mesenteric resistance vasculature, as well as the MAP increases. Vasodilators alone did not lower basal vascular ODC activity. The major findings include: 1) alpha 1-adrenergic receptor activation dose-dependently induces vascular ODC activity concomitantly with MAP elevation, 2) vasodilators inhibited both the alpha 1-adrenergic receptor-induced MAP increases and the activation of mesenteric vascular and aortic ODC, and 3) the stimulus-response correlation between MAP elevation and mesenteric (r = 0.78) and aortic (r = 0.92) ODC activation was characterized by a logistic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased expression of growth hormone receptor mRNA and insulin-like growth factor-I mRNA in volume-overloaded hearts.

Recent results suggest that insulin-like growth factor-I (IGF-I) may be involved in the transition of a hemodynamic load into cardiac hypertrophy and that the expression of IGF-I seems to be coupled to increased wall stress. The present study investigated the role of growth hormone (GH) and IGF-I in myocardial hypertrophy induced by volume overload. An aortocaval fistula (ACF) was created in male Wistar rats, and experiments were performed 2, 4, and 7 days after the onset of volume overload. Right and left ventricular (RV and LV, respectively) myocardial expression of GH receptor mRNA and IGF-I mRNA were quantitated by a solution hybridization RNase protection assay. RV GH receptor mRNA content was elevated on the fourth and seventh days after the induction of the shunt, with peak levels (0.63 +/- 0.16 versus 0.14 +/- 0.03 amol/microgram DNA for the sham-operated animals; P < .01) after 4 days. Similarly, IGF-I mRNA was significantly increased in the RV of shunted animals (1.26 +/- 0.13 versus 0.56 +/- 0.05 amol/micrograms DNA; P < .01) 7 days after surgery. In the left ventricle, where systolic pressure was reduced in ACF rats, no differences could be detected in GH receptor and IGF-I mRNA content between ACF and sham-operated rats on any of the experimental days. There was no difference in the ratio of RV to LV weight during the experimental period. We have shown that the thin-walled right ventricle responds to volume overload with an increase of GH receptor mRNA content followed by elevated expression of IGF-I mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal angiotensin-converting enzyme inhibition in the rat induces persistent abnormalities in renal function and histology.

Recently, we reported that neonatal blockade of the renin-angiotensin system in the rat produces irreversible abnormalities in renal histology associated with increased diuresis. In the present study, we assessed the long-term consequences of neonatal angiotensin-converting enzyme inhibition on renal function. Rats were injected with 10 mg.kg-1.d-1 enalapril or vehicle from day 3 to day 24 after birth. Urine concentrating ability, renal function, and renal histology were assessed in 16-week-old rats. There was a twofold increase in diuresis and water intake in enalapril-treated rats throughout the study course. Urine osmolality after 24 hours of water deprivation was 1008 +/- 108 and 2549 +/- 48 mOsm.kg-1 (P < .05) in enalapril- and vehicle-treated rats, respectively. Glomerular filtration rate (0.54 +/- 0.03 versus 0.75 +/- 0.06 mL.min-1x100 g body wt-1, P < .05) and effective renal plasma flow (1.76 +/- 0.09 versus 2.19 +/- 0.14 mL.min-1x100 g body wt-1, P < .05) were reduced in neonatally enalapril-treated versus control rats. Absolute and fractional urinary sodium excretion values were elevated (P < .05) in enalapril-treated rats. Semiquantitative assessment of renal histology demonstrated statistically significant degrees of papillary atrophy, interstitial fibrosis and inflammation, tubular atrophy and dilatation, and focal glomerulosclerosis in neonatally enalapril-treated rats. In conclusion, neonatal angiotensin-converting enzyme inhibition in the rat produces irreversible alterations in renal function and morphology, demonstrating the importance of an intact renin-angiotensin system neonatally for normal renal development.

Blunted cardiovascular growth induction during prolonged nitric oxide synthase blockade.

The goal of the present study was to characterize the activation profile of the growth-related enzyme ornithine decarboxylase (ODC) in cardiovascular tissue during hypertension induced by chronic NO synthase blockade in relation to the development of structurally based changes in the heart and blood vessels. In previously instrumented conscious rats, mean arterial pressure and ODC activation were measured in cardiovascular tissue of rats treated with N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg per day P.O.) for 4 hours and 1, 6, and 12 days. After 12 days of L-NAME treatment alone or in combination with 3% L-ornithine, structurally based hindlimb resistance properties were assessed. A marginal activation of ODC in the left ventricle and aorta was seen at 4 hours but returned to control levels at 1, 6, and 12 days of L-NAME treatment. A slightly prolonged yet transient activation of ODC occurred in the mesenteric vascular bed. Structurally based hindlimb vascular resistance was enhanced by 15% at maximum vasoconstrictor tone, and no change in cardiac mass occurred with L-NAME treatment. L-NAME+3% L-ornithine treatment resulted in a similar level of structural upregulation compared with L-NAME treatment alone. In summary, 12 days of L-NAME treatment resulted in only a modest change in vascular resistance, and only at maximum constriction, and no cardiac hypertrophy despite the presence of marked hypertension. The results of the present study indicate that either (1) pressure alone is not a sufficient stimulus to induce cardiovascular growth processes or (2) L-NAME may be "nonspecifically" inhibiting cardiovascular growth processes.

Left ventricular blood flow during aortic pressure reduction in hypertensive dogs.

We measured left ventricular blood flow with radioactive microspheres during aortic pressure reduction in 10 open-chest, anesthetized dogs with left ventricular hypertrophy due to chronic hypertension and in 10 matched normotensive dogs. Heart rate and left atrial pressure were held constant, and autonomic reflexes were abolished with ganglionic blockade. Aortic diastolic pressure was lowered from baseline to 90, 75, and 60 mm Hg with an arteriovenous fistula. During aortic pressure reduction, a stepwise decline in the endocardial-to-epicardial flow ratio in hypertrophied hearts from 1.23 +/- 0.04 at baseline to 0.96 +/- 0.09 at a diastolic pressure of 75 mm Hg parallelled that in normal hearts and was not associated with any deterioration in left ventricular performance. However, a further fall in the endocardial-to-epicardial flow ratio to 0.76 +/- 0.10 at a diastolic pressure of 60 mm Hg in hypertrophied hearts exceeded that in normal hearts (0.92 +/- 0.05, p less than 0.05) and was accompanied by evidence of left ventricular isovolumic and end-systolic dysfunction. We conclude that in hearts with pressure-overload left ventricular hypertrophy, aortic pressure reduction causes a transmural blood flow redistribution from subendocardial to subepicardial muscle layers. At moderately low aortic pressures, this redistribution is more pronounced than in normal hearts and is associated with functional evidence of myocardial ischemia.

Cardiac insulin-like growth factor I and growth hormone receptor expression in renal hypertension.

The aim of the present study was to investigate the role of insulin-like growth factor I in the development of cardiac hypertrophy in two-kidney, one clip hypertension by relating growth hormone receptor and insulin-like growth factor I receptor mRNA levels to insulin-like growth factor I gene transcription using a solution hybridization/RNase protection assay. Two-kidney, one clip hypertension was induced in male Wistar rats, and experiments were performed 2, 4, 7, and 12 days after surgery. Systolic blood pressure was elevated 2, 7, and 12 days after clipping (P < .001). Left ventricular weights were increased 2, 4, 7, and 12 days after surgery (P < .01). Associated with the rise in blood pressure, left ventricular insulin-like growth factor I mRNA was increased 2, 7, and 12 days after surgery (P < .01). Furthermore, growth hormone receptor and insulin-like growth factor I receptor gene expression increased specifically in the left ventricle of renal hypertensive rats (P < .05 and P < .001, respectively). Left ventricular growth hormone receptor mRNA peaked 7 days after induction of renal artery stenosis. These results show that insulin-like growth factor I, growth hormone receptor, and insulin-like growth factor I receptor mRNA increase in the pressure-overloaded left ventricle of two-kidney, one clip rats, suggesting a role for insulin-like growth factor I and the growth hormone/insulin-like growth factor I axis in the development of cardiac hypertrophy.

Evidence for increased renal norepinephrine overflow during sodium restriction in humans.

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organ's fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.

Induction of growth hormone receptor and insulin-like growth factor-I mRNA in aorta and caval vein during hemodynamic challenge.

Induction of two-kidney, one clip hypertension (renal hypertension) is characterized by a slow increase in left ventricular tension and aortic wall stress, as opposed to aortocaval fistula or shunt volume overload, which induces a marked and rapid onset of wall stress in the caval vein and right ventricle. In the present study, we applied hemodynamic challenge to study the growth response involving gene expression of insulin-like growth factor-I (IGF-I) and growth hormone receptor (GH-R) mRNA in aorta and caval vein. Volume overload and pressure overload were induced in Wistar rats by means of shunt and renal hypertension, respectively. Systolic pressure was measured before excision of the great vessels, which was performed between 2 and 12 days postoperatively. Aortic and caval vein IGF-I and GH-R mRNA expressions were measured by means of a solution hybridization assay, and the caval vein was analyzed for IGF-I protein by immunohistochemistry. In the volume-distended but not pressurized caval vein in shunt rats, verified by telemetry recordings, there was an eightfold increase in IGF-I and 3.5-fold increase in GH-R mRNA at day 4 versus control. The IGF-I protein appeared to be localized in smooth muscle cells. In the aorta of the renal hypertension group, changes were of a slower onset. At day 7, there was a fourfold increase in IGF-I and five-fold increase of GH-R mRNA expressions versus sham-operated rats. Both the shunt caval vein and renal hypertension aorta showed evidence of a structural adaptation of the growth response. The present study suggests that acute elevation in vascular wall stress is an important triggering factor for overexpression of IGF-I and GH-R mRNA in great vessels. The growth hormone/insulin-like growth factor axis may be an important link in mediating structurally adaptive growth responses in the blood vessel wall.

Substantial production of dopamine in the human gastrointestinal tract.

Considerable urinary excretion of dopamine metabolites indicates that large amounts of dopamine are produced in unknown locations of the body. This study assessed the contribution of mesenteric organs (gastrointestinal tract, spleen, and pancreas) to the total body production of dopamine in humans and examined the presence of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase, in gastrointestinal tissues. Blood sampled from an artery and portal and hepatic veins in eight subjects and from arterial and renal venous sites in other subjects was analyzed for plasma concentrations of dopamine and its metabolites. The activity and distribution of tyrosine hydroxylase was also examined in tissue samples from the stomach and duodenum. Higher concentrations of dopamine and its metabolites in portal venous than arterial plasma indicated substantial production of dopamine by mesenteric organs (12.0 nmol/min) amounting to 42-46% of the renal removal of circulating dopamine metabolites. Tissue samples showed immunoreactive tyrosine hydroxylase in nonneuronal cell bodies and detectable levels of tyrosine hydroxylase in nonneuronal cell bodies and detectable levels of tyrosine hydroxylase enzyme activity. The results show that mesenteric organs produce close to half of the dopamine formed in the body, most of which is unlikely to be derived from sympathetic nerves but may reflect production in a novel nonneuronal dopaminergic system.