Biomedical subjects
Publications and source records attributed to Jens Jordan.
We report on a patient with long-standing severe autonomic failure that affected his sympathetic and parasympathetic nervous systems. Antibodies against the ganglionic acetylcholine receptors were detected in the serum. Removal of the antibodies by means of plasma exchange resulted in a dramatic clinical improvement.
ANG II applied to the interstitial space influences carbohydrate and lipid metabolism in a tissue-specific fashion. Thus endogenous ANG II may have a tonic effect on tissue metabolism that could be reversed with ANG II type 1 (AT1) receptor blockade, particularly during adrenergic stimulation. We studied 14 obese men. They were treated for 10 days with the AT1 receptor blocker irbesartan or with placebo in a double-blind and crossover fashion. At the end of each treatment period, we assessed skeletal muscle and adipose tissue metabolism using the microdialysis technique. The ethanol dilution technique was applied to follow changes in tissue blood flow. Measurements were obtained at baseline and during application of incremental isoproterenol concentrations through the microdialysis catheter. Blood pressure decreased from 133 +/- 3/84 +/- 3 to 128 +/- 3/79 +/- 2 mmHg for systolic and diastolic blood, respectively (P = 0.02 and 0.006, respectively) with AT1 receptor blockade. Isoproterenol perfusion caused a dose-dependent increase in dialysate glycerol in adipose tissue and in skeletal muscle. Irbesartan slightly reduced the isoproterenol-induced glycerol response in adipose tissue (P < 0.05 by ANOVA). Ethanol ratio, interstitial glucose supply, and lactate production in adipose tissue and skeletal muscle were similar with placebo and irbesartan. We conclude that AT1 receptor blockade in obese men does not reveal a major tonic ANG II effect on interstitial glucose supply, lipolysis, or glycolysis in skeletal muscle, either at rest or during beta-adrenergic stimulation. Endogeneous ANG II may slightly increase adipose tissue lipolysis. The mechanism may promote the redistribution of triglycerides from adipose tissue toward other organs.
OBJECTIVES: The contribution of endothelial function to tissue oxygenation is not well understood. Muscle blood oxygen level-dependent MRI (BOLD MRI) provides data largely dependent on hemoglobin (Hb) oxygenation. We used BOLD MRI to assess endothelium-dependent signal intensity (SI) changes. METHODS AND RESULTS: We investigated mean BOLD SI changes in the forearm musculature using a gradient-echo technique at 1.5 T in 9 healthy subjects who underwent a protocol of repeated acetylcholine infusions at 2 different doses (16 and 64 microg/min) and N(G)-monomethyl-L-arginine (L-NMMA; 5 mg/min) into the brachial artery. Sodium nitroprusside was used as a control substance. For additional correlation with standard methods, the same protocol was repeated, and forearm blood flow was measured by strain gauge plethysmography. We obtained a significant increase in BOLD SI during acetylcholine infusion (64 microg/min) and a significant decrease for L-NMMA infusion (P<0.005 for both). BOLD SI showed a different kinetic signal than did blood flow, particularly after intermittent ischemia and at high flow rates. CONCLUSIONS: In standard endothelial function tests, BOLD MRI detects a dissociation of tissue Hb oxygenation from blood flow. BOLD MRI may be a useful adjunct in assessing endothelial function.
Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood pressure buffering. We tested the hypothesis that gender influences baroreflex regulation of heart rate and sympathetic vasomotor tone. We recruited 32 normal-weight healthy subjects (17 men and 15 women). ECGs for heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity (MSNA) were measured. Baroreflex heart rate and MSNA regulation were assessed using incremental phenylephrine and nitroprusside infusions. Baseline blood pressure was similar in men and women. MSNA was 21+/-2.5 bursts/min in women and 19+/-2.8 bursts/min in men (NS). The gain of the baroreflex MSNA curves was similar in women and men (-1.9+/-0.2 bursts/min per mm Hg in men and -2.0+/-0.3 bursts/min per mm Hg in women). Baroreflex gain for heart rate regulation was 17+/-3.2 ms/mm Hg in women and 19+/-1.9 ms/mm Hg in men (NS). We conclude that baroreflex gains for heart rate and sympathetic MSNA regulation are similar in women and men. However, the probability for congruence between men and women in terms of the MSNA baroreflex curves was 0.06% for burst rate, 0.4% for burst incidence, and 0.01% for burst area. In women, the MSNA baroreflex curve may be shifted to slightly lower blood pressure such that at a given blood pressure MSNA tends to be lower.
The baroreflex receives less attention nowadays because most students of hypertension are convinced that faulty volume regulation by the kidneys is responsible for long-term blood pressure increases. However, unusual patients with bilateral destruction of the normal blood pressure-sensing mechanisms can develop profound chronic hypertension. We present 2 patients with baroreflex failure. Both had volatile hypertension with systolic readings up to 300 mm Hg documented over years. Both had muscle sympathetic nerve activity that was increased even while resting. Treating these patients was a stochastic challenge. The therapy is frequently based on medicines that are no longer commonly prescribed.
CONTEXT: Atrial natriuretic peptide (ANP) in pharmacological concentrations stimulates lipid mobilization in humans. OBJECTIVE: The objective was to determine the hemodynamic and metabolic response to physiologically relevant ANP concentrations. DESIGN: The design was a human physiological study, conducted in 2004. SETTING: The study was conducted at an academic research institute. PARTICIPANTS: Fourteen healthy normal-weight men (30 +/- 1.2 yr) participated in the study. INTERVENTION: Intravenous infusion of human ANP (h-ANP) was administered at rates of 6.25, 12.5, and 25 ng/kg.min. MAIN OUTCOME MEASURES: We studied local changes in blood flow and glucose and lipid metabolism of abdominal sc adipose tissue and femoral skeletal muscle by microdialysis. Overall changes in energy expenditure and substrate oxidation rates were monitored by indirect calorimetry. RESULTS: The increase in serum nonesterified fatty acids and glycerol concentrations were correlated with ANP plasma concentrations (r(2) = 0.86 and r(2) = 0.76, respectively). In adipose tissue, glycerol increased from 53 +/- 6 micromol/liter to 87+/-13 micromol/liter (P < 0.001). In femoral skeletal muscle, glycerol concentrations did not change, whereas lactate-to-pyruvate ratio decreased from 91 +/- 23 to 32 +/- 4 (P < 0.001). Indirect calorimetry indicated an increase in lipid oxidation (P < 0.05) concomitantly with a decrease in carbohydrate oxidation (P < 0.01), without changes in overall energy expenditure. CONCLUSIONS: ANP briskly stimulates lipid mobilization and oxidation at plasma concentrations that are encountered in conditions such as heart failure. Natriuretic-peptide induced lipid mobilization might contribute to cardiac cachexia. Drugs that interfere with the natriuretic peptide system should be evaluated for potential metabolic side effects.
BACKGROUND: Short-term and tonic regulation of arterial blood pressure (BP) differ in premenopausal women and men of similar age. The autonomic nervous system (ANS) plays a critical role in BP regulation. METHODS AND RESULTS: To test the hypothesis that women have lower tonic ANS support of BP (reduction in intra-arterial BP during acute ganglionic blockade [GB] with intravenous trimethaphan) and less effective baroreflex buffering (BRB) of BP (potentiation of the systolic BP [SBP] response to bolus phenylephrine during versus before GB) than men, 51 healthy adults, 22 premenopausal women (aged 28+/-1 years, mean+/-SE) and 29 men (aged 27+/-1 years), were studied. Women had lower baseline SBP and plasma catecholamine concentrations than men (P<0.05). Tonic ANS support of BP was approximately 50% to 65% lower in the women (P<0.001). The reductions in BP during GB were related to baseline plasma catecholamine concentrations (r=-0.31 to -0.41, P<0.05). Acute BRB of BP was 47% smaller in the women (3.3+/-0.5 versus 6.3+/-0.9, P=0.006) and was related to the SBP responses to phenylephrine before GB (R2=0.71, P<0.0001). Systemic alpha1-adrenergic vascular responsiveness (SBP response to bolus phenylephrine during GB) was not different (women 21.5+/-2 mm Hg versus men 18.6+/-2 mm Hg, P=0.3). CONCLUSIONS: Premenopausal women have lower tonic sympathoadrenal activity-related ANS support of BP and less effective BRB of BP than men of similar age. The lower tonic ANS support of BP could contribute to the lower chronic BP levels of premenopausal women, whereas attenuated BRB of BP may help explain less effective BP regulation in women in response to vasoactive drugs and acute stress.
Regulator of G protein signaling (RGS2) deletion in mice prolongs signaling by G protein-coupled vasoconstrictor receptors and increases blood pressure. However, the exact mechanism of the increase in blood pressure is unknown. To address this question we tested autonomic nervous system function and blood pressure regulation in RGS2-deficient mice (RGS2-/-). We measured arterial blood pressure and heart rate (HR) with telemetry, computed time and frequency-domain measures for blood pressure and HR variability (HRV) as well as baroreflex sensitivity [BRS-low frequency (LF)], and assessed environmental stress sensitivity. Mean arterial blood pressure (MAP) was approximately 10 mmHg higher in RGS2-/-compared with RGS2+/+mice, while HR was not different between the groups, indicating a resetting of the baroreceptor reflex. Atropine increased MAP more in RGS2-/-than in RGS2+/+mice while HR responses were not different. Urinary norepinephrine excretion was higher in RGS2-/-than in RGS2+/+mice. The blood pressure decrease following prazosin was more pronounced in RGS2-/-mice than in RGS2+/+mice. The LF and high-frequency (HF) power of HRV were reduced in RGS2-/-compared with controls while BRS-LF and SBP-LF were not different. Atropine and atropine+metoprolol markedly reduced the HRV parameters in the time (RMSSD) and frequency domain (LF, HF, LF/HF) in both strains. Environmental stress sensitivity was increased in RGS2-/-mice compared with controls. We conclude that the increase in blood pressure in RGS2-/-mice is not solely explained by peripheral vascular mechanisms. A central nervous system mechanism might be implicated by an increased sympathetic tone. This state of affairs could lead to a baroreceptor-HR reflex resetting, while BRS remains unimpaired.
BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is a common adjunctive obesity treatment. Acute studies in healthy subjects suggested that an inhibitory central nervous mechanism might attenuate the peripheral stimulatory effect on the sympathetic nervous system. This notion has not been tested in overweight and obese patients. METHODS: We conducted a randomized, controlled clinical study in hypertensive patients with BMI > or = 27 to < 40 kg/m(2). After 4 week placebo run-in period patients were randomized to four different antihypertensive treatments or placebo. After 4 weeks of antihypertensive therapy, patients were additionally treated with sibutramine 15 mg o. d. for 3 months. Patients underwent cardiovascular autonomic reflex testing and a graded head-up tilt test at the end of each phase. RESULTS: Mean body weight decreased from 98.5+/-4 to 94.7+/-4 kg (p<0.05) between end of placebo run-in and end of sibutramine treatment. Supine blood pressure was 154+/-3/80+/-2, 145+/-3/76+/-2 and 150+/-3/79+/-2mmHg at the end of placebo run-in, after antihypertensive titration (ns) and end of sibutramine treatment (ns), respectively. Blood pressure was affected similarly during head up tilt testing. The systolic blood pressure response to cold pressor testing was diminished with sibutramine (p<0.01). Sibutramine decreased low frequency systolic blood pressure oscillations in the supine position (p<0.01). CONCLUSIONS: Resting blood pressure tends to increase with sibutramine, whereas blood pressure during sympathetic stimulation and low frequency blood pressure oscillations are decreased. These paradoxical changes are consistent with previous studies in healthy subjects and suggest a combination of peripheral and central nervous system mechanisms.
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Recent studies suggest that water drinking elicits acute changes in human physiology. Water drinking profoundly increases blood pressure in patients with autonomic failure. Water drinking also increases blood pressure in quadriplegic patients, cardiac transplant recipients, and older healthy subjects, but to a lesser extent. Blood pressure does not change in healthy young subjects. More recently, water drinking was shown to increase energy expenditure. The acute changes in cardiovascular regulation and in energy expenditure with water drinking appear to be mediated through activation of the sympathetic nervous system. The sympathetic activation may involve a spinal reflex-like mechanism. The stimulus that causes the sympathetic activation is not known. The acute water pressor response can be exploited in the treatment of patients with impaired orthostatic tolerance caused by autonomic failure, postural tachycardia syndrome, or, perhaps, neurocardiogenic (vasovagal) syncope. The increase in energy expenditure with water drinking should be recognized as an important confounding variable in metabolic studies and may hold some promise as an adjunctive measure in the prevention or treatment of obesity.
OBJECTIVE: None of the current hypertension guidelines provides specific guidance regarding pharmacological management of obese hypertensive patients. Treatment recommendations for lean hypertensives may not be simply extrapolated to obese hypertensive persons. DESIGN: Randomized, double-blind, parallel-group study with a 13-week treatment period. SETTING: Multicenter study in Germany. PATIENTS: Obese patients with mild to moderate uncomplicated essential hypertension. INTERVENTION: Patients were treated with valsartan at a maximal dose of 160 mg/day or with atenolol at a maximal dose of 100 mg/day. Hydrochlorothiazide at doses of 12.5-25 mg was added in patients with blood pressure > 140/90 mmHg on monotherapy. MAIN OUTCOME MEASURES: Blood pressure, lipid and glucose metabolism, and highly sensitive C-reactive protein (hsCRP) were monitored. RESULTS: Sixty-seven patients were randomized to valsartan and 65 patients to atenolol. With valsartan, systolic blood pressure (SBP) decreased from 160.8 +/- 8.9 to 140.5 +/- 13.3 mmHg and diastolic blood pressure (DBP) from 96.1 +/- 7.0 to 85.1 +/- 8.1 mmHg by the end of the study. With atenolol, SBP decreased from 159.3 +/- 6.8 to 139.8 +/- 14.5 mmHg and DBP from 95.0 +/- 6.8 to 83.5 +/- 7.5 mmHg (P = 0.91 for SBP and P = 0.34 for DBP between interventions). Body weight did not change with either treatment. We did not see a significant difference in the response of lipid levels or hsCRP between interventions. To assess the cumulative effect of each intervention on glucose metabolism over the trial duration, we calculated individual areas under the curve for homeostasis model assessment for insulin resistance (HOMA-IR) over time. The resulting area under the curve was significantly smaller with valsartan compared with atenolol (P = 0.02). CONCLUSIONS: Beta-adrenoreceptor blockers and AT1-receptor blockers, particularly in combination with low-dose diuretics, effectively lower blood pressure in obese hypertensives. However, metabolic responses differ between both treatment strategies, with beneficial effects of AT1-receptor blockers. AT1-receptor blockers are a good choice in obese hypertensives, given the profoundly increased diabetes risk in this population.
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At a given degree of adiposity, metabolic and cardiovascular risk varies markedly between individuals. Animal studies suggest that differentially expressed systemic activation of monocytes contributes to the obesity-associated risk variability. We tested the hypothesis that systemic monocyte activation is associated with changes in adipose tissue and skeletal muscle metabolism. In 17 obese hypertensive patients, we assessed CD11b expression on circulating monocytes, gene expression in adipose tissue biopsies, and obtained blood samples and adipose tissue and skeletal muscle microdialysis samples in the fasted state and during a glucose load. Patients were stratified into groups with higher and lower CD11b expression on monocytes. Expression of the macrophage marker CD68 was increased markedly in adipose tissue of subjects with higher CD11b expression. Although no differences in systemic insulin sensitivity were found between both groups, patients with higher peripheral CD11b expression showed a markedly augmented increase in dialysate glucose in adipose tissue during oral glucose tolerance testing and increased adipose tissue lipolysis as well. Our data demonstrate that human monocyte activation is associated with tissue-specific changes in glucose and lipid metabolism. These findings may be explained in part by monocyte/macrophage infiltration of adipose tissue, which appears to interfere with insulin responsiveness.
Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by -34% for CB-1 and -59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.
Free and receptor-bound leptin may be regulated by different mechanisms. Genes that influence the concentration of these fractions may have an important functional bearing. We determined circulating leptin receptor concentrations, bound as well as free leptin concentrations, and body composition in 24 monozygotic (MZ) and in 22 dizygotic (DZ) twin pairs. Bound leptin and leptin receptor concentrations were inversely correlated with body fat content. Free leptin concentrations were directly correlated with body fat content. The correlations in age- and sex-adjusted free leptin, bound leptin, and leptin receptor concentrations were higher between MZ twins than between DZ twins. Adjusted heritability (h2) estimates were 0.28 for free leptin, 0.73 for bound leptin, and 0.55 for leptin receptor. The genetic correlation with body fat was -0.58 for the leptin receptor, -0.20 for bound leptin, and 0.93 for free leptin. Our data are consistent with a strong genetic influence on leptin receptor and bound leptin and a weaker genetic influence on free leptin concentrations. The same genes that lower bound leptin and leptin receptor concentrations may increase fat mass or vice versa.
BACKGROUND: The use of ephedra alkaloids in over-the-counter preparations has been associated with potentially serious cerebrovascular events. Because of its potential association with hemorrhagic strokes, phenylpropanolamine has been largely substituted for by pseudoephedrine, but it is not clear whether this is indeed a safer alternative. It would be important to understand the cardiovascular effects of ephedra alkaloids, but these are normally masked by baroreflex buffering mechanisms. We therefore investigated the effects of ephedra alkaloids in patients with autonomic impairment and explored their potential interaction with water ingestion. METHODS AND RESULTS: The cardiovascular effects of phenylpropanolamine or pseudoephedrine, alone and in combination with water, were determined in 13 subjects with impairment of baroreflex function due to autonomic failure. Phenylpropanolamine, 12.5 to 25 mg PO, increased systolic blood pressure (SBP) by 21+/-14 mm Hg after 90 minutes. However, when ingested with 16 oz of room temperature tap water, phenylpropanolamine increased SBP by 82+/-2 mm Hg. Pseudoephedrine, 30 mg PO, increased SBP on average 52+/-9 mm Hg when taken with 16 oz of water and by as much as 88 mm Hg. CONCLUSIONS: Ephedra alkaloids increase blood pressure significantly in individuals with impaired baroreflex function. Concomitant ingestion of ephedra alkaloids and water produced a greater increase in blood pressure. If used cautiously, this interaction can be beneficial in the treatment of orthostatic hypotension. On the other hand, it could contribute to the cardiovascular complications associated with the use of ephedra alkaloids, given that baroreflex function varies widely in normal individuals and is impaired in several medical conditions.
Alpha-2 adrenoceptors are important in baroreflex regulation. We tested the impact of alpha-2 adrenoceptors on heart rate variability (HRV) and spontaneous baroreflex sensitivity (BRS) in conscious mice with telemetry (TA11PA-C20). Baseline beat-to-beat measurements (2 hours between 8:00 am to 12:00 pm) were compared with measurements after intraperitoneal alpha-2 adrenoceptor blockade (yohimbine 2 mg/kg) and alpha-2 adrenoceptor stimulation (clonidine 1, 10, and 50 mg/kg). Blood pressure (BP) was 128+/-6/87+/-6 mm Hg and heart rate (HR) was 548+/-18 bpm at baseline. BRS, calculated with the cross-spectral method, was 1.2+/-0.1 ms/mm Hg at baseline. BP increased 20+/-2/13+/-2 mm Hg with yohimbine. HR increased by 158+/-23 bpm. BRS did not change. BP decreased 16+/-7/5+/-4 mm Hg with 1 mg/kg of clonidine and did not change with a higher dose. HR decreased with clonidine (176+/-28, 351+/-21, 310+/-29 bpm during 1, 10, and 50 mg/kg of clonidine, P<0.01). HRV (total power=4629+/-465, 7002+/-440, and 6452+/-341 ms2 during 1, 10, and 50 mg/kg of clonidine, P<0.01) and BRS were profoundly increased with clonidine (14+/-1, 13+/-1, and 10+/-1 ms/mm Hg, P<0.01). The effects of clonidine were abolished with atropine (2 mg/kg plus 50 mg/kg of clonidine) but not with metoprolol (4 mg/kg plus 50 mg/kg of clonidine). These data suggest that alpha-2 adrenoceptors exert a regulatory influence on autonomic cardiovascular control and baroreflex function. The effect of clonidine on baroreflex HR regulation is mediated by the parasympathetic nervous system. These murine data fit well with recent human observations regarding parasympathetic activation via alpha-2 adrenoceptors.