Biomedical subjects

André Diedrich

Publications and source records attributed to André Diedrich.

At least 19 recordsLinked to original sources

PubMed2006

Human cerebral autoregulation before, during and after spaceflight.

Exposure to microgravity alters the distribution of body fluids and the degree of distension of cranial blood vessels, and these changes in turn may provoke structural remodelling and altered cerebral autoregulation. Impaired cerebral autoregulation has been documented following weightlessness simulated by head-down bed rest in humans, and is proposed as a mechanism responsible for postspaceflight orthostatic intolerance. In this study, we tested the hypothesis that spaceflight impairs cerebral autoregulation. We studied six astronauts approximately 72 and 23 days before, after 1 and 2 weeks in space (n = 4), on landing day, and 1 day after the 16 day Neurolab space shuttle mission. Beat-by-beat changes of photoplethysmographic mean arterial pressure and transcranial Doppler middle cerebral artery blood flow velocity were measured during 5 min of spontaneous breathing, 30 mmHg lower body suction to simulate standing in space, and 10 min of 60 deg passive upright tilt on Earth. Dynamic cerebral autoregulation was quantified by analysis of the transfer function between spontaneous changes of mean arterial pressure and cerebral artery blood flow velocity, in the very low- (0.02-0.07 Hz), low- (0.07-0.20 Hz) and high-frequency (0.20-0.35 Hz) ranges. Resting middle cerebral artery blood flow velocity did not change significantly from preflight values during or after spaceflight. Reductions of cerebral blood flow velocity during lower body suction were significant before spaceflight (P < 0.05, repeated measures ANOVA), but not during or after spaceflight. Absolute and percentage reductions of mean (+/- s.e.m.) cerebral blood flow velocity after 10 min upright tilt were smaller after than before spaceflight (absolute, -4 +/- 3 cm s(-1) after versus -14 +/- 3 cm s(-1) before, P = 0.001; and percentage, -8.0 +/- 4.8% after versus -24.8 +/- 4.4% before, P < 0.05), consistent with improved rather than impaired cerebral blood flow regulation. Low-frequency gain decreased significantly (P < 0.05) by 26, 23 and 27% after 1 and 2 weeks in space and on landing day, respectively, compared with preflight values, which is also consistent with improved autoregulation. We conclude that human cerebral autoregulation is preserved, and possibly even improved, by short-duration spaceflight.

Adaptation, Physiological↗

PubMed2006

Contribution of endothelial nitric oxide to blood pressure in humans.

Impaired endothelial-derived NO (eNO) is invoked in the development of many pathological conditions. Systemic inhibition of NO synthesis, used to assess the importance of NO to blood pressure (BP) regulation, increases BP by approximately 15 mm Hg. This approach underestimates the importance of eNO, because BP is restrained by baroreflex mechanisms and does not account for a role of neurally derived NO. To overcome these limitations, we induced complete autonomic blockade with trimethaphan in 17 normotensive healthy control subjects to eliminate baroreflex mechanisms and contribution of neurally derived NO. Under these conditions, the increase in BP reflects mostly blockade of tonic eNO. N(G)-Monomethyl-l-arginine (250 microg/kg per minute IV) increased mean BP by 6+/-3.7 mm Hg (from 77 to 82 mm Hg) in intact subjects and by 21+/-8.4 mm Hg (from 75 to 96 mm Hg) during autonomic blockade. We did not find a significant contribution of neurally derived NO to BP regulation after accounting for baroreflex buffering. To further validate this approach, we compared the effect of NOS inhibition during autonomic blockade in 10 normotensive individuals with that of 6 normotensive smokers known to have endothelial dysfunction but who were otherwise normal. As expected, normotensive smokers showed a significantly lower increase in systolic BP during selective eNO blockade (11+/-4.5 versus 30+/-2.3 mm Hg in normotensive individuals; P<0.005). Thus, we report a novel approach to preferentially evaluate the role of eNO on BP control in normal and disease states. Our results suggest that eNO is one of the most potent metabolic determinants of BP in humans, tonically restraining it by approximately 30 mm Hg.

Adult↗

PubMed2006

Spike detection in human muscle sympathetic nerve activity using the kurtosis of stationary wavelet transform coefficients.

The accurate assessment of autonomic sympathetic function is important in the diagnosis and study of various autonomic and cardiovascular disorders. Sympathetic function in humans can be assessed by recording the muscle sympathetic nerve activity, which is characterized by synchronous neuronal discharges separated by periods of neural silence dominated by colored Gaussian noise. The raw nerve activity is generally rectified, integrated, and quantified using the integrated burst rate or area. We propose an alternative quantification involving spike detection using a two-stage stationary wavelet transform (SWT) de-noising method. The SWT coefficients are first separated into noise-related and burst-related coefficients on the basis of their local kurtosis. The noise-related coefficients are then used to establish a threshold to identify spikes within the bursts. This method demonstrated better detection performance than an unsupervised amplitude discriminator and similar wavelet-based methods when confronted with simulated data of varying burst rate and signal to noise ratio. Additional validation on data acquired during a graded head-up tilt protocol revealed a strong correlation between the mean spike rate and the mean integrate burst rate (r=0.85) and burst area rate (r=0.91). In conclusion, the kurtosis-based wavelet de-noising technique is a potentially useful method of studying sympathetic nerve activity in humans.

Action Potentials↗

PubMed2006

A simplified two-component model of blood pressure fluctuation.

We propose a simple moving-average (MA) model that uses the low-frequency (LF) component of the peroneal muscle sympathetic nerve spike rate (LF(spike rate)) and the high-frequency (HF) component of respiration (HF(Resp)) to describe the LF neurovascular fluctuations and the HF mechanical oscillations in systolic blood pressure (SBP), respectively. This method was validated by data from eight healthy subjects (23-47 yr old, 6 male, 2 female) during a graded tilt (15 degrees increments every 5 min to a 60 degrees angle). The LF component of SBP (LF(SBP)) had a strong baroreflex-mediated feedback correlation with LF(spike rate) (r = -0.69 +/- 0.05) and also a strong feedforward relation to LF(spike rate) [r = 0.58 +/- 0.03 with LF(SBP) delay (tau) = 5.625 +/- 0.15 s]. The HF components of spike rate (HF(spike rate)) and SBP (HF(SBP)) were not significantly correlated. Conversely, HF(Resp) and HF(SBP) were highly correlated (r = -0.79 +/- 0.04), whereas LF(Resp) and LF(SBP) were significantly less correlated (r = 0.45 +/- 0.08). The mean correlation coefficients between the measured and model-predicted LF(SBP) (r = 0.74 +/- 0.03) in the supine position did not change significantly during tilt. The mean correlation between the measured and model-predicted HF(SBP) was 0.89 +/- 0.02 in the supine position. R(2) values for the regression analysis of the model-predicted and measured LF and HF powers indicate that 78 and 91% of the variability in power can be explained by the linear relation of LF(spike rate) to LF(SBP) and HF(Resp) to HF(SBP). We report a simple two-component model using neural sympathetic and mechanical respiratory inputs that can explain the majority of blood pressure fluctuation at rest and during orthostatic stress in healthy subjects.

Adult↗

PubMed2006

Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and metabolic regulation.

CONTEXT: Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipid and carbohydrate metabolism in humans. OBJECTIVE: The objective of the study was to determine the metabolic and cardiovascular interaction of beta-adrenergic receptors and ANP. DESIGN: This was a crossover study, conducted 2004-2005. SETTING: The study was conducted at an academic clinical research center. PATIENTS: PATIENTS included 10 healthy young male subjects (body mass index 24 +/- 1 kg/m2). INTERVENTION: We infused iv incremental ANP doses (6.25, 12.5, and 25 ng/kg.min) with and without propranolol (0.20 mg/kg in divided doses followed by 0.033 mg/kg.h infusion). Metabolism was monitored through venous blood sampling, im, and sc microdialysis and indirect calorimetry. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings. MAIN OUTCOME MEASURES: Venous nonesterified fatty acid, glycerol, glucose, and insulin; and microdialysate glucose, glycerol, lactate, and pyruvate were measured. RESULTS: ANP increased heart rate dose dependently. beta-Adrenergic receptor blockade abolished the response. ANP elicited a dose-dependent increase in serum nonesterified fatty acid and glycerol concentrations. The response was not suppressed with propranolol. Venous glucose and insulin concentrations increased with ANP, both without or with propranolol. ANP induced lipid mobilization in sc adipose tissue. In skeletal muscle, microdialysate lactate increased, whereas the lactate to pyruvate ratio decreased, both with and without propranolol. Higher ANP doses increased lipid oxidation, whereas energy expenditure remained unchanged. Propranolol tended to attenuate the increase in lipid oxidation. CONCLUSIONS: Selected cardiovascular ANP effects are at least partly mediated by beta-adrenergic receptor stimulation. ANP-induced changes in lipid mobilization and glycolysis are mediated by another mechanism, presumably stimulation of natriuretic peptide receptors, whereas substrate oxidation might be modulated through adrenergic mechanisms.

Adipose Tissue↗

PubMed2006

Influences of norepinephrine transporter function on the distribution of sympathetic activity in humans.

Previous studies suggest that neuronal norepinephrine transporter function may regulate the distribution of sympathetic activity among blood vessels, heart, and kidney; we tested the functional relevance in humans. Sixteen healthy men (26+/-1 years) ingested 8 mg of the selective norepinephrine reuptake transporter inhibitor reboxetine or a matching placebo on 2 separate days in a double-blind, randomized, crossover fashion. We monitored heart rate, thoracic bioimpedance, blood pressure, glomerular filtration rate, and renal blood flow. Ninety minutes after ingestion of the test medication, subjects were tilted to a 45 degrees head-up position, where they remained for an additional 30 minutes. Reboxetine increased supine systolic blood pressure through an increase in cardiac output whereas systemic vascular resistance decreased. Furthermore, reboxetine increased heart rate, particularly with a head-up tilt. Supine plasma renin activity was 0.71+/-0.15 ng angiotensin (Ang)/L per mL/h with placebo and 0.36+/-0.07 ngAng/L per mL/h with reboxetine (P<0.01). Supine plasma Ang II concentrations were also decreased with reboxetine. Both plasma renin activity and Ang II concentrations remained suppressed during head-up tilt. On placebo, renal vascular resistance increased with head-up tilt. The response was abolished with norepinephrine reuptake inhibition. We conclude that norepinephrine reuptake function profoundly influences the distribution of sympathetic activity between the heart, vasculature, and kidney in humans. All of these changes are physiologically relevant because they lead to corresponding changes in organ function.

Adrenergic Uptake Inhibitors↗

PubMed2006

Management of hypertension in the setting of autonomic dysfunction.

Supine hypertension is a common finding in patients with autonomic failure; it is associated with end-organ damage and produces nighttime pressure diuresis with worsening of orthostatic hypotension. During the daytime, it is best treated by avoiding the supine posture. At night, simple measures such as raising the head of the bed by 6 to 9 inches can be effective, but most patients require pharmacologic treatment. Transdermal nitroglycerin (0.1 to 0.2 mg/h) or nifedipine (30 mg, orally) has proved to be effective. Hydralazine and minoxidil are usually less effective but may be useful in a given patient. One key therapeutic concept is the hypersensitivity of these patients to depressor agents, requiring a careful titration of the doses on an individual basis. For those patients with proven residual sympathetic tone, as in multiple system atrophy, central sympatholytics such as clonidine may provide an alternative.

Journal Article↗

PubMed2005

Electrical activation of the human vestibulo-sympathetic reflex.

Muscle sympathetic nerve activity (MSNA) is modulated on a beat-to-beat basis by the baroreflex. Vestibular input from the otolith organs also modulates MSNA, but characteristics of the vestibulo-sympathetic reflex (VSR) are largely unknown. The purpose of this study was to elicit the VSR with electrical stimulation to estimate its latency in generating MSNA. The vestibular nerves of seven subjects were stimulated across the mastoids with short trains of high frequency, constant current pulses. Pulse trains were delivered every fourth heartbeat at delays of 300-700 ms after the R wave of the electrocardiogram. Vestibular nerve stimulation given 500 ms after the R wave significantly increased baroreflex-driven MSNA, as well as the diastolic blood pressure threshold at which bursts of MSNA occurred. These changes were specific to beats in which vestibular stimulation was applied. Electrical stimulation across the shoulders provided a control condition. When trans-shoulder trials were subtracted from trials with vestibular nerve stimulation, eliminating the background baroreflex-driven sympathetic activity, there was a sharp increase in MSNA beginning 660 ms after the vestibular nerve stimulus and lasting for about 60 ms. The increase in the MSNA produced by vestibular nerve stimulation, and the associated increase in the diastolic blood pressure threshold at which the baroreflex-driven bursts occurred, provide evidence for the presence of a short-latency VSR in humans that is likely to be important for the maintenance of blood pressure during rapid changes in head and body position with respect to gravity.

Adult↗

PubMed2005

Tyramine-induced vasodilation mediated by dopamine contamination: a paradox resolved.

We reported previously that intravenous administration of tyramine induced a paradoxical forearm vasodilation and an increase in plasma dopamine, raising the possibility that dopamine is released by or converted from tyramine in vivo. Alternatively, tyramine can be nonenzymatically oxidized into dopamine in vitro, and this contamination may be responsible for the increase in plasma dopamine and forearm vasodilation. To distinguish between these possibilities, we measured the hemodynamic and neurohumoral effects of an intravenous infusion of a specially prepared dopamine-free tyramine solution in 8 normal volunteers at a dose that increased systolic blood pressure by approximately 25 mm Hg (from 107+/-5 to 133+/-5 mm Hg; P <0.001) and compared it with an equivalent dose of norepinephrine. Tyramine increased plasma norepinephrine (139+/-18 to 226+/-30 pg/mL; P <0.02), its intraneuronal metabolite dihydroxyphenylglycol (980+/-73 to 2245+/-206 pg/mL; P <0.001), and systemic vascular resistance, but not plasma dopamine or its intraneuronal metabolite dihydroxyphenylacetic acid. Tyramine and norepinephrine produced nonsignificant increases in forearm vascular resistance. We conclude that tyramine-induced forearm vasodilation reported in previous studies is explained by the presence of dopamine contamination in tyramine preparations. Intravenous administration of dopamine-free tyramine and norepinephrine produced equivalent systemic vasoconstriction. The forearm vasculature was not useful in monitoring the vasoconstrictive effects of either agent. The possibility of dopamine contamination needs to be considered when interpreting previously published studies using tyramine as a pharmacological tool to assess sympathetic function, and it must be avoided in future studies.

Adult↗

PubMed2005

Management of hypertension in the setting of autonomic failure: a pathophysiological approach.

We discuss 2 cases presenting clinically with disabling orthostatic hypotension and severe supine hypertension. This is a common presentation of autonomic failure, and one that challenges conventional treatment. Clinical findings of isolated autonomic failure were the most prominent manifestation in case 1, whereas a movement disorder was the key finding in case 2. The differential diagnosis and treatment of orthostatic hypotension is discussed from a pathophysiological approach. Understanding of the underlying mechanisms of disorders of the autonomic nervous system is fundamental for an effective management of these patients and provides insight into more common disorders such as essential hypertension.

Aged↗

PubMed2005

Endurance exercise training in orthostatic intolerance: a randomized, controlled trial.

Orthostatic intolerance is a syndrome characterized by chronic orthostatic symptoms of light-headedness, fatigue, nausea, orthostatic tachycardia, and aggravated norepinephrine levels while standing. The aim of this study was to assess the protective effect of exercise endurance training on orthostatic symptoms and to examine its usefulness in the treatment of orthostatic intolerance. 2768 military recruits were screened for orthostatic intolerance by questionnaire. Tilt-table testing identified 36 cases of orthostatic intolerance out of the 2768 soldiers. Subsequently, 31 of these subjects with orthostatic intolerance entered a randomized, controlled trial. The patients were allocated randomly to either a "training" (3 months jogging) or a "control" group. The influence of exercise training on orthostatic intolerance was assessed by determination of questionnaire scores and tilt-table testing before and after intervention. After training, only 6 individuals of 16 still had orthostatic intolerance compared with 10 of 11 in the control group. The Fisher exact test showed a highly significant difference in diagnosis between the 2 groups (P=0.008) at the end of the study. Analysis of the questionnaire-score showed significant interaction between time and group (P=0.001). The trained subjects showed an improvement in the average symptom score from 1.79+/-0.4 to 1.04+/-0.4, whereas the control subjects showed no significant change in average symptom score (2.09+/-0.6 and 2.14+/-0.5, respectively). Our data demonstrate that endurance exercise training leads to an improvement of symptoms in the majority of patients with orthostatic intolerance. Therefore, we suggest that endurance training should be considered in the treatment of orthostatic intolerance patients.

Adult↗

PubMed2005

Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men.

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.

Adaptation, Physiological↗

PubMed2005

Can we diagnose, treat or even understand neurally mediated syncope?

There are significant gaps in our understanding of the pathophysiology, diagnosis and treatment of NMS (neurally mediated syncope). Contributions in this area will be welcomed by patients and physicians taking care of them alike. In this issue of Clinical Science, Simek and co-workers report a novel non-invasive physiological measurement that does not require head-up tilt to diagnose NMS. However, validation studies applied to an unselected patient population are needed before we can judge how useful this test will be in the diagnosis of NMS.

Adult↗

PubMed2005

Influence of an insertion variant in the 5'UTR of the endothelin-1 gene on orthostatic intolerance.

BACKGROUND: Orthostatic intolerance is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has shown that orthostatic intolerance is influenced by endothelial nitric oxide synthase gene polymorphisms. Since endothelin-1 (ET-1) is one of the most important vasoconstrictor peptides, a frequent adenine insertion polymorphism within the 5'-untranslated region (5'UTR), which is of functional importance for ET-1 expression, could influence orthostatic intolerance. The aim of this study was therefore to ascertain whether this frequent variant of the endothelin-1 gene influences the risk for orthostatic intolerance. METHODS: We studied 257 white patients (120 cases with orthostatic intolerance and 137 controls) for genotyping of the 5'UTR I variant. From this cohort, 111 patients and 99 control subjects underwent a tilt-table test or an upright posture study, including monitoring of blood pressure, heart rate, and plasma catecholamines, in the supine position and during 30 minutes of standing. Genotyping was performed in all participants. Chi tests of independence were used to test for associations between orthostatic intolerance and genotype. In addition, an association of the insertion polymorphism with hemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way analysis of variance. RESULTS: The 5'UTR I variant was significantly less common in patients with orthostatic intolerance (allele frequency 0.36 and 0.28, in controls and cases, respectively). Additionally, we found a significant decrease in the risk of orthostatic intolerance among people who were homozygous for the 5'UTR variant (I/I) compared with the wild-type variant (D/D) (odds ratio, 0.41; 95% confidence interval, 0.17 to 0.97; P = 0.04). No association between the 5'UTR variant and heart rate or blood pressure regardless of diagnosis was found. CONCLUSIONS: Our current results suggest that the hereditary adenine insertion variant in the 5'-UTR of the endothelin-1 gene is protective for orthostatic intolerance. The increased ET-1 protein expression that has been linked with the I variant might be associated with a more efficient hemodynamic response to standing. This is likely one of several common genetic loci that may represent modifiers of orthostatic intolerance phenotypes.

5' Untranslated Regions↗

PubMed2004

Norepinephrine transporter-deficient mice exhibit excessive tachycardia and elevated blood pressure with wakefulness and activity.

BACKGROUND: Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the norepinephrine transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance. METHODS AND RESULTS: We telemetrically monitored NET-deficient (NET(-/-)) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET(-/-) mice compared with NET(+/+) controls (103+/-0.6 versus 99+/-0.4 mm Hg; P<0.01), and corresponding pressures increased to 122+/-0.3 and 116+/-0.3 mm Hg (P<0.0001) with activity. Heart rate was also greater in resting NET(-/-) mice (565+/-5 versus 551+/-3 bpm; P<0.05), and genotypic differences were highly significant during the active phase (640+/-5 versus 607+/-3 bpm; P<0.0001). Conversely, the respiratory rate of resting NET(-/-) mice was dramatically reduced, whereas increases after the day/night shift surpassed those of controls. Plasma catecholamines in NET(-/-) and NET(+/+) mice were as follows: NE, 69+/-8 and 32+/-7; dihydroxyphenylglycol, 2+0.4 and 17+/-3; epinephrine, 15+/-3 and 4+/-0.6; and dopamine, 13+/-4 and 4+/-1 pmol/mL. Catechols in urine, brain, and heart also were determined. CONCLUSIONS: Resting mean arterial pressure and heart rate are maintained at nearly normal levels in NET-deficient mice, most likely as a result of increased central sympathoinhibition. However, sympathetic activation with wakefulness and activity apparently overwhelms central modulation, amplifying peripheral catecholaminergic signaling, particularly in the heart.

Animals↗

PubMed2004

Water potentiates the pressor effect of ephedra alkaloids.

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.

Aged↗

PubMed2004

Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation.

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.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2003

Blockade of nucleoside transport is required for delivery of intraarterial adenosine into the interstitium: relevance to therapeutic preconditioning in humans.

BACKGROUND: Adenosine, a known mediator of preconditioning, has been infused into the coronary circulation to induce therapeutic preconditioning, eg, in preparation for angioplasty. However, results have been disappointing. We tested the hypothesis that endothelial nucleoside transporter acts as a barrier impeding the delivery of intravascular adenosine into the underlying myocardium and that this can be overcome with dipyridamole, a nucleoside transporter blocker. METHODS AND RESULTS: We infused saline or adenosine (0.125 and 0.5 mg/min) into the brachial artery while monitoring forearm blood flow (FBF) and interstitial adenosine levels with microdialysis probes implanted in the flexor digitorum superficialis of the forearm in 7 healthy volunteers during intravenous administration of saline or dipyridamole (loading dose, 0.142 mg/kg per min for 5 minutes followed by 0.004 mg/kg per min). Adenosine produced near maximal forearm vasodilation, increasing FBF from 4.0+/-0.7 to 10.4+/-1.9 and 13.1+/-1.6 mL/100 mL per min for the low and high doses, respectively, but did not increase muscle dialysate adenosine concentration (from 88+/-21 to 65+/-23 and 85+/-26 nmol/L). Intravenous dipyridamole enhanced resting muscle dialysate adenosine (from 77+/-25 to 147+/-50 nmol/L), adenosine-induced increase in FBF (from 4.1+/-0.8 to 12.6+/-3 and 15.1+/-3 mL/100 mL per min for the low and high dose, respectively), and the delivery of adenosine into the interstitium (to 290+/-80 and 299+/-143 nmol/L for the low and high dose, respectively, P=0.04). CONCLUSIONS: Intravascular adenosine is likely ineffective in inducing myocardial preconditioning because of poor interstitial delivery. This can be overcome by blocking the nucleoside transporter with dipyridamole.

Adenosine↗