Adrenergic Challenge Research Articles

Heart rate as a sympathetic marker during acute adrenergic challenge

Previous studies have shown that heart rate has a limited value in reflecting the chronic state of adrenergic overdrive characterizing several cardiovascular diseases. Whether this also applies to the ability of heart rate to reflect acute and generalized changes in sympathetic activity is unknown. In 20 healthy young subjects (age: 25.2 +/- 1.2 years, mean +/- SEM) we measured beat-to-beat blood pressure (Finapres), heart rate (HR, ECG), venous plasma norepinephrine (NE, high-performance liquid chromatography) and efferent postganglionic muscle sympathetic nerve traffic (MSNA, microneurography) at rest and during a cold pressor test and two intravenous infusions of nitroprusside at increasing doses. Both cold pressor test and nitroprusside infusions triggered marked and significant increases in HR, plasma NE and MSNA; blood pressure showing an increase with cold pressor test and a reduction with nitroprusside. The magnitude of the responses was greater with the higher than with the lower dose of nitroprusside. The HR changes induced by cold pressor test were not significantly related to the concomitant NE and MSNA changes (r = -0.08 and r = -0.18, P = NS). This was also the case for the lower and the higher dose of nitroprusside (NE: r = -0.11 and r = 0.08; MSNA: r = 0.01 and r = -0.11, P = NS for all). In contrast NE and MSNA changes induced by cold pressor test and by the lower and the higher dose of nitroprusside were significantly related to each other (r = 0.70, r = 0.89 and r = 0.79 respectively, P < 0.01 for all). In a given individual, HR responses to sympathetic challenge do not quantitatively reflect the degree of acute and generalized adrenergic activation. Qualitative information on the acute adrenergic effects of given stimuli should thus be based on the assessment of NE and MSNA rather than on HR changes.

The absence of endogenous lipid oxidation in early stage heart failure exposes limits in lipid storage and turnover

Intramyocardial lipid handling in pressure-overload-induced heart failure remains poorly understood, and the balance between endogenous and exogenous lipid utilization for mitochondrial ATP production is essentially unknown. In this study, we determined the contribution of endogenous triacylglycerols (TAG) to mitochondrial oxidation relative to that of exogenous palmitate, glucose, and endogenous glycogen in the failing, pressure-overloaded rat heart. TAG content and turnover were also assessed to determine if lipid availability and mobility were altered. Dynamic-mode 13C NMR was performed in intact hearts from aortic banded and sham operated Spraque-Dawley rats perfused with 13C-labeled palmitate or glucose to assess TAG turnover rate and palmitate oxidation rate. The fractional contributions from palmitate, glucose, glycogen, and TAG to mitochondrial ATP production were determined from NMR analysis of heart extracts. TAG oxidation was not evident in HF, whereas the contribution of TAG to oxidative ATP production was significant in shams. TAG content was 39% lower in HF compared to sham, and TAG turnover rate was 60% lower in HF. During adrenergic challenge, TAG sources were again not oxidized in the HF group. In early cardiac failure, endogenous TAG oxidation was reduced in parallel to increased carbohydrate oxidation, with no change in exogenous palmitate oxidation. This finding was consistent with reduced TAG storage and mobilization. These data further elucidate the role of intermediary and lipid metabolism in the progression of LVH to failure, and contribute to emerging evidence linking the disruption of myocardial substrate use to cardiomyopathies.

Kcnq1 contributes to an adrenergic-sensitive steady-state K + current in mouse heart

It has been suggested that Kcne1 subunits are required for adrenergic regulation of Kcnq1 potassium channels. However, in adult mouse hearts, which do not express Kcne1, loss of Kcnq1 causes a Long QT phenotype during adrenergic challenge, raising the possibility that native Kcnq1 currents exist and are adrenergically regulated even in absence of Kcne1. Here, we used immunoblotting and immunohistochemical staining to show that Kcnq1 protein is present in adult mouse hearts. Voltage-clamp experiments demonstrated that Kcnq1 contributes to a steady-state outward current ( I SS) in wild-type ( Kcnq1 +/+ ) ventricular myocytes during isoproterenol stimulation, resulting in a significant 7.1% increase in I SS density (0.43 ± 0.16 pA/pF, p < 0.05, n = 15), an effect that was absent in Kcnq1-deficient ( Kcnq1 −/− ) myocytes (−0.14 ± 0.13 pA/pF, n = 17). These results demonstrate for the first time that Kcnq1 protein is expressed in adult mouse hearts where it contributes to a β-adrenergic-induced component of I SS that does not require co-assembly with Kcne1.

Ventricular Repolarization and Heart Rate Responses During Cardiovascular Autonomic Function Testing in LQT1 Subtype of Long QT Syndrome

In the most prevalent LQT1 form of inherited long QT syndrome symptoms often occur during abrupt physical or emotional stress. Sympathetic stimulation aggravates repolarization abnormalities in experimental LQT1 models. We hypothesized that autonomic function tests might reveal the abnormal repolarization in asymptomatic LQT1 patients. We measured heart rates (HRs) and QT intervals in nine asymptomatic carriers of a C-terminal KCNQ1 mutation and 8 unaffected healthy subjects using an approach of global QT values derived from 28 simultaneous electrocardiographic leads on beat-to-beat base during Valsalva maneuver, mental stress, sustained handgrip, and light supine exercise. LQT1 patients exhibited impaired shortening of both QTpeak and QTend intervals during autonomic interventions but exaggerated lengthening of the intervals--a QT overshoot--during the recovery phases. The number of tests with a QT overshoot was 2.4 +/- 1.7 in LQT1 patients and 0.8 +/- 0.7 in unaffected subjects (P = 0.02). Valsalva strain prolonged T wave peak to T wave end interval (TPE) in LQT1 but not in unaffected patients. LQT1 patients showed diminished HR acceleration in response to adrenergic challenge whereas HR responses to vagal stimuli were similar in both groups. Standard cardiovascular autonomic provocations induce a QT interval overshoot during recovery in asymptomatic KCNQ1 mutation carriers. Valsalva maneuver causes an exaggerated fluctuation of QT and TPE intervals partly explaining the occurrence of cardiac events during abrupt bursts of autonomic activity in LQT1 patients.

Cortisol Response Mediates HIV-1-Related Cognitive Deficits Among Injecting Drug Abusers

The cortisol response is an important measure of the endocrine activity to environmental challenges and has been related to cognitive function and mood. Previous studies have shown that the cortisol response to stress is dysregulated in persons with HIV-1 infection. Since cortisol is neurotoxic and its levels have been related to cognitive dysfunction in various disorders, it is possible that neuroendocrine dysregulation may also be related to cognitive dysfunction in individuals with HIV-1 infection. The purpose of this study was to test the hypothesis that the cortisol response to an alpha adrenergic challenge, cold pressor, is related to cognitive function in HIV-infected injecting drug abusers. We used growth curve modeling to study the relationship of cold pressor challenge stimulated cortisol response to scores on the modified HIV Dementia Scale (mHDS). To test this hypothesis, we assessed the effects of HIV-1 infection on the HDS score directly and indirectly via pattern of cortisol response. The analysis showed that HIV-1 infection was directly related to mHDS performance and that it also influenced scores on the mHDS by way of individuals' pattern of cortisol response. Cortisol response to �-adrenergic challenge thus may mediate cognitive deficits in individuals with HIV-1 infection. These findings further emphasize the importance of understanding the role of stress in the cognitive problems associated with HIV-1 infection.

Experimental Model of Inappropriate Sinus Tachycardia: Initiation and Ablation

The purpose of the present study was to develop an experimental model of inappropriate sinus tachycardia (IST) by injecting a catecholamine into a fat pad containing autonomic ganglia (AG) innervating the sinus node (SN). Initial protocols in 3 groups of pentobarbital anesthetized dogs consisted of (1) slowing the heart rate (HR) by electrical stimulation of AG in the fat pad; (2) the effect of intravenous injection of epinephrine (0.1-0.3 mg) on the HR and systolic blood pressure (BP); (3) the response of SN rate to intravenously injected isoproterenol (1 microgm/kg). These studies established a reference for the response to epinephrine injection (mean dose 0.2 +/- 0.9 mg, n = 14) into the fat pad at the base of the right superior pulmonary vein (RSPV). ECG leads, right atrial and His bundle electrograms, BP and core body temperature were continuously monitored. Epinephrine, injected into the fat pad, caused a significant increase in heart rate (HR, average: 211 +/- 11/min, p < 0.05 compared to control) but little change in systolic BP, 149 +/- 10 mmHg, p = NS (Group I, N = 8). The tachycardia lasted >30 minutes. Ice mapping and P wave morphology showed the tachycardia origin in the SN in 6/8 and in the crista terminalis (CT) in 2. Injection of 0.4 cc of formaldehyde into the FP restored HR (159 +/- 16) toward baseline (154 +/- 18). In Group II (N = 6), the same regimen induced a significant increase in both HR and systolic BP (194 +/- 17/min and 230 +/- 24 mmHg, respectively) compared to control values (143 +/- 23/min, 162 +/- 24 mmHg) which lasted for > 30 minutes. Ice mapping and P wave morphology showed that the pacemaker was in the SN (1), overlying the CT (2), or atrioventricular junction (2). Formaldehyde (0.4 cc) injected into the FP restored both HR and systolic BP toward baseline values (148 +/- 29/min and 152 +/- 24 mmHg, p = NS) and prevented, slowing of the HR by electrical stimulation of the AG; moreover, the same dose of epinephrine injected intravenously increased HR and SBP but only for 2-5 minutes; Isoproterenol (1 microg/kg) injected intravenously induced essentially the same increase in sinus rate after AG ablation as in the control state (194 +/- 15/min vs 193 +/- 23/min, p = NS). Experimental IST is mainly localized in the SN or CT. Ablation of the AG terminates IST without impairing the SN response to an adrenergic challenge.

Sudden death among infants and adults: companion disorders of maladaptive sympathetic bias

Sudden infant death syndrome is the leading cause of death in infancy, but its pathophysiological mechanism has been elusive. Sudden death in adults is a common phenomenon, but the etiology in many cases remains unknown at autopsy. We hypothesize that maladaptive sympathetic bias is the explanatory mechanism that links many cases of sudden demise among adults and infants as companion syndromes. Normally, sympathetic response occurs as an adaptation to physiologic demands of the body through various autonomic reflex arcs such as chemoreceptors. Sympathetic response can become chronic and maladaptive when the normal sympathetic response fails to correct the precipitating physiologic trigger, leading to chronic activation of autonomic reflex arcs. In conditions such as infant sleep apnea or adult heart failure, a pernicious cycle of sympathetic bias may result. Chronic sympathetic bias increases susceptibility to sudden fatal arrhythmias, QT-related and otherwise, in the setting of an exaggerated adrenergic challenge. Examples of such adrenergic stressors include trauma, hypoxia, hypercapnia, acidosis, sleep arousal, illness, medical procedures, and physical activity, all of which have associations with sudden death. Our hypothesis may not only help explain the survival benefits of drugs such as beta-blockers and devices such as synchronization therapy, but also portend new application of similar therapies for many conditions of sympathetic bias.

The effect of breed, parity and body fatness on the lipolytic response of dairy cows

AbstractThe objective of this study was to examine the effect of breed, parity and body fatness on the lipolytic response of dairy cows. The lipolytic response was estimated as the plasma non-esterified fatty acid (NEFA) response to an adrenergic challenge. Four challenges per lactation were carried out on 124 Danish Holsteins, 101 Danish Red and 82 Jerseys through consecutive lactations. Within breed, there were two genetic lines. Cows were equally distributed across two feeding treatments, a normal and a low energy total mixed ration. Diet composition was constant throughout lactation. The lipolytic response was significantly affected by breed, parity and stage of lactation. Lipolytic response was greater in early lactation than other stages in lactation (P 0·001). The larger breeds had a higher lipolytic response than Jerseys (P 0·05), and showed an increase in lipolytic response between first and second parity (P 0·05), but not between second and third lactation. Lipolytic response in Jerseys was not significantly affected by parity. No line or feeding treatment effects were observed on the lipolytic response. Ultrasound measurement of the area of subcutaneous backfat was used to estimate effect of body fatness on the lipolytic response. There was an increase in lipolytic response with increasing body fatness (P 0·05) in mid lactation and the dry period. The slope of this was not affected by breed or parity. It was concluded that the lipolytic response of dairy cows, and by implication the responsiveness of the lipid reserves, varies according to breed, parity and physiological state.

Plasma non-esterified fatty acid response to a β-adrenergic challenge before or after feeding in energy underfed or overfed, dry or lactating cows

AbstractThe effects of adrenergic challenge (in order to evaluate the adipose tissue lipolytic potential) and time of challenge relative to feeding on the response curve of plasma non-esterified fatty acids (NEFA) in four underfed or overfed non-lactating non-pregnant cows were studied. Basal NEFA and NEFA response to isoproterenol (ISO; 4 nmol/kg body weight) were higher when challenged before than after feeding and higher in underfed than overfed cows. Interaction between feeding level and time of challenge was significant (P &lt; 0·001) for the rising part of NEFA response. Pooled NEFA response curves from several trials (no. = 63 challenges) were analysed in order to obtain a simplified procedure for the prediction of the NEFA response. High correlations were found between the response area or maximal NEFA response and NEFA response at 15 min (r = 0·95 and 0·98, respectively). This simplified procedure was applied on pooled data from 84 challenges in order to evaluate the effects of energy balance, physiological status, body condition score (BCS) and time of challenge relative to feeding. Energy balance had a significant effect on basal plasma NEFA and NEFA response at 15 min after ISO challenge (–7·6 and –14·2 μmol/l when the daily energy balance increased by 1 MJ, respectively). Time of ISO injection relative to feeding had a greater effect on stimulated NEFA than on basal NEFA (308 v. 239 μmol/l). There was a significant effect of BCS (41 μmol/l per unit of BCS) on the basal plasma NEFA level. The NEFA response at 15 min after ISO challenge was lower (387 μmol/l) in lactating cows than in dry cows. The NEFA response to ISO at 15 min could provide an efficient method of studying the adipose tissue lipolytic potential of cattle in vivo.

Effect of somatotropin on adipose tissue metabolism: Ontogeny of the enhanced response to adrenergic challenge in the lactating cow

Seven multiparous Holstein cows (>150 d postpartum) were used to evaluate the time course of the chronic adaptation in lipolytic response to adrenergic challenge with bovine somatotropin (bST) treatment. Cows received daily bST (sometribove; 40 mg/d) or excipient injections for 7 d (single reversal design) with a 7-d interim between periods. Epinephrine challenges (1.4 μg/kg body weight intravenously) were administered on Days −2, −1, 1, 2, 3, 5, and 7 of treatment at 10:00 a.m. (15 hr after bST or excipient injection). Frequent blood samples were collected, and concentrations of plasma glycerol (GLY) and nonesterified fatty acids (NEFA) were determined. Treatment with bST increased milk yield 23% (P < 0.05) and milk fat content 33% (P < 0.001) compared with controls. Somatotropin-treated cows entered negative energy balance by Day 3 and had higher basal plasma concentrations of GLY and NEFA than did controls by Day 2 and Day 3, respectively. Response to epinephrine, expressed as area under the response curve corrected for basal, was enhanced by bST treatment, regardless of energy balance. GLY response was greater than control by Day 1 of bST treatment (P < 0.01), and had plateaued by Day 2 (P < 0.001). The NEFA response area was higher than control and had plateaued by Day 1 of bST treatment (P < 0.001). Day 1 represented 15 hr after the first bST injection. Results illustrate that bST treatment results in enhanced in vivo lipolytic response to catecholamine challenge, and the metabolic adaptation is in place by 15 hr after the first bST injection.

Sex differences in vascular reactivity to adrenergic agents in the rat

1. 1.The study was designed to determine if there are sex-dependent differences in vascular reactivity to adrenergic agents. 2. 2.Vascular reactivity of both aortic and tail artery smooth muscle from male and female rats to various vasoactive agents was assessed. 3.li]The vascular response of aortic smooth muscle to both phenylephrine and isoproterenol were significantly greater in male rats as compared to females. 3. 4.There were apparent sex differences in responsiveness to the KCl-induced, non-receptor mediated contraction of aortic smooth muscle in that the sensitivity to KCl was enhanced in male rats. 4. 5.No sex differences were observed in tail artery preparations. 5. 6.Phentolamine reduced the maximal tension induced by KCl in the tail artery but not aortic artery preparations. This effect was not sex dependent. 6. 7.No differences in the vascular smooth muscle responsiveness to acetylcholine or sodium nitrate was observed between groups or within different vascular beds. 7. 8.The increased sensitivity of males to adrenergic challenge could explain in part some of the existing sex differences in cardiovascular disease and hypertension.

Prenatal nicotine exposure and cognitive performance in rats

In humans and animal models there is evidence that prenatal nicotine exposure causes lasting deficits in cognitive performance. The current study examined the cognitive effects of prenatal exposure of rats to 2 mg/kg/day of nicotine. This dose did not cause significant deficits in maternal weight gain, offspring litter size, or pup weight. The control offspring showed the normal ontogeny of spontaneous alternation from near chance (50%) performance to 80%–85% alternation. In contrast, the nicotine-exposed rats had the opposite progression with abnormally high alternation on days 22–30 and abnormally low alternation on days 35–52. Acquisition of choice accuracy performance on the radial-arm maze (RAM) was not altered in a major way by nicotine exposure. Minor nicotine-induced changes in choice accuracy were seen during the initial trials of acquisition. The nicotine exposed female offspring had a significantly longer response duration. Prenatal nicotine exposure did significantly alter the effects of subsequent drug challenges on choice accuracy performance. The nicotine-exposed male offspring were significantly more responsive to the amnestic effects of the nicotinic antagonist mecamylamine. In a subsequent challenge, the effects of the β-adrenergic antagonist propranolol were examined. A significant dose-related impairment in choice accuracy was seen in the control rats. In contrast, the nicotine-exposed rats did not show any significant response to propranolol. This decreased responsiveness to adrenergic challenge parallels the reduction in adrenergic response to nicotine challenge we previously found in littermates to the rats of the current study. Prenatal nicotine exposure causes subtle alterations in cognitive performance that can be magnified by challenges of nicotinic and adrenergic systems.

Functional Interrelationships Between Adrenergic and Opioid Systems in the Neuroregulation of Growth Hormone Secretion in Infant Rats

Abstract Functional interrelationships between hypothalamic adrenergic and opioid systems were studied in 10-day-old male and female rats. Either clonidine (150 mug/kg, sc), an alpha(2)-adrenoceptor agonist, or FK 33-824 (1 mg/kg, sc), a synthetic analog of met-enkephalin, increased plasma growth hormone (GH) levels, the increment being significantly higher with FK 33-824 than with clonidine. Pharmacologic blockade of opioid receptors with naloxone (5 mg/kg, sc) did not modify either basal GH levels, or the GH response to clonidine, whereas blockade of alpha(2)-adrenoceptors with yohimbine (2.5 mg/kg, sc) reduced basal GH levels and partially counteracted the FK 33-824-induced GH rise. Clonidine (150mu/kg, sc, twice daily) administered from postnatal day 5 to 9, increased basal GH levels and pituitary GH content. In these pups, acute administration of clonidine failed to further release GH, but the GH response to acute administration of FK 33-824 was significantly enhanced. A 5-day treatment with FK 33-824 (1 mg/kg, sc, twice daily), neither modified basal GH levels, nor pituitary GH content. Under these conditions, the in vivo GH response to an FK 33-824 challenge was significantly enhanced, and the response to clonidine was preserved. Pituitaries from FK 33-824-pretreated rats were hyperresponsive to GH-releasing hormone (10(-7) M). In summary, our data indicate that in rat pups: 1) two separate components i.e. one adrenergic, the other extra-adrenergic, subserve the GH-releasing effect of opioid peptides; 2) in contrast to short-term stimulation of alpha(2)-adrenoceptors, stimulation of opioid receptors does not trigger GH synthesis or induce down-regulation or tolerance; 3) short-term opioid stimulation does not affect an alpha(2)-adrenergic challenge, but sensitizes to an opioid challenge.

Alpha‐1 Adrenoceptor Involvement in the Control of Melatonin Secretion in the Golden Hamster

The nocturnal peak in pineal and serum melatonin content was reduced following administration of the selective alpha-1 adrenoceptor antagonist prazosin in a dose of 0.25 mg/kg. The effect was pronounced one hour post treatment during the late dark phase of the daily photocycle. These data confirm the reported findings that the hamster pineal sensitivity to adrenergic challenge is confined to the second part of the dark phase and indicate that postsynaptically located alpha-1 adrenoceptors are also involved in the physiological control of melatonin synthesis and/or release in that species.