Α-adrenergic Blockade Research Articles

Sympathetic nerve-dependent regulation of mucosal vascular tone modifies airway smooth muscle reactivity

The airways contain a dense subepithelial microvascular plexus that is involved in the supply and clearance of substances to and from the airway wall. We set out to test the hypothesis that airway smooth muscle reactivity to bronchoconstricting agents may be dependent on airway mucosal blood flow. Immunohistochemical staining identified vasoconstrictor and vasodilator nerve fibers associated with subepithelial blood vessels in the guinea pig airways. Intravital microscopy of the tracheal mucosal microvasculature in anesthetized guinea pigs revealed that blockade of α-adrenergic receptors increased baseline arteriole diameter by ~40%, whereas the α-adrenergic receptor agonist phenylephrine produced a modest (5%) vasoconstriction in excess of the baseline tone. In subsequent in vivo experiments, tracheal contractions evoked by topically applied histamine were significantly reduced (P < 0.05) and enhanced by α-adrenergic receptor blockade and activation, respectively. α-Adrenergic ligands produced similar significant (P < 0.05) effects on airway smooth muscle contractions evoked by topically administered capsaicin, intravenously administered neurokinin A, inhaled histamine, and topically administered antigen in sensitized animals. These responses were independent of any direct effect of α-adrenergic ligands on the airway smooth muscle tone. The data suggest that changes in blood flow in the vessels supplying the airways regulate the reactivity of the underlying airway smooth muscle to locally released and exogenously administered agents by regulating their clearance. We speculate that changes in mucosal vascular function or changes in neuronal regulation of the airway vasculature may contribute to airways responsiveness in disease.

The muscle metaboreflex: reining in the heart?

the muscle metaboreflex, also known as the muscle chemoreflex, is one of the principal mediators of the cardiovascular exercise response. This reflex is thought to be triggered by metabolic by-products of ischemia that stimulate afferent nerve endings in skeletal muscle and leads to an increase in

Muscle metaboreflex-induced coronary vasoconstriction functionally limits increases in ventricular contractility

Muscle metaboreflex activation during dynamic exercise induces a substantial increase in cardiac work and oxygen demand via a significant increase in heart rate, ventricular contractility, and afterload. This increase in cardiac work should cause coronary metabolic vasodilation. However, little if any coronary vasodilation is observed due to concomitant sympathetically induced coronary vasoconstriction. The purpose of the present study is to determine whether the restraint of coronary vasodilation functionally limits increases in left ventricular contractility. Using chronically instrumented, conscious dogs (n = 9), we measured mean arterial pressure, cardiac output, and circumflex blood flow and calculated coronary vascular conductance, maximal derivative of ventricular pressure (dp/dt(max)), and preload recruitable stroke work (PRSW) at rest and during mild exercise (2 mph) before and during activation of the muscle metaboreflex. Experiments were repeated after systemic alpha(1)-adrenergic blockade ( approximately 50 microg/kg prazosin). During prazosin administration, we observed significantly greater increases in coronary vascular conductance (0.64 + or - 0.06 vs. 0.46 + or - 0.03 ml x min(-1) x mmHg(-1); P < 0.05), circumflex blood flow (77.9 + or - 6.6 vs. 63.0 + or - 4.5 ml/min; P < 0.05), cardiac output (7.38 + or - 0.52 vs. 6.02 + or - 0.42 l/min; P < 0.05), dP/dt(max) (5,449 + or - 339 vs. 3,888 + or - 243 mmHg/s; P < 0.05), and PRSW (160.1 + or - 10.3 vs. 183.8 + or - 9.2 erg.10(3)/ml; P < 0.05) with metaboreflex activation vs. those seen in control experiments. We conclude that the sympathetic restraint of coronary vasodilation functionally limits further reflex increases in left ventricular contractility.

Is there a delay in the activation of non‐noradrenergic vasoconstriction during cold exposure in human skin?

This study tested the hypothesis that cutaneous vasoconstriction during brief cold exposure occurs entirely through noradrenergic mechanisms. In 6 subjects, 2 microdialysis (MD) fibers were placed in the forearm skin. A control fiber received lactated ringers and the other received 5mM yohimbine (α‐adrenergic blockade). Skin blood flow was assessed at each site (laser‐Doppler flowmetry) and cutaneous vascular conductance (CVC) was calculated (red blood cell flux/mean arterial pressure). Subjects were exposed to 10 min of cold stress (water‐perfused suit). CVC was reduced by 64 ± 9 % in the control site (P&lt;0.05 vs. baseline) but unchanged in the yohimbine site during cold stress. In a follow‐up protocol (n=3) we added a third MD site with yohimbine + 1mM propranolol and extended the cold stress to 30 min. CVC was reduced in the control site throughout cold stress, but showed vasoconstriction during only the second half of the cold stress in both yohimbine and yohimbine + propranolol sites. Thus, short duration cold exposure can elicit cutaneous vasoconstriction mediated solely through noradrenergic mechanisms, whereas more prolonged cold stress also activates non‐noradrenergic vasoconstriction. Supported by the Evonuk and ACSM Foundations

Diversified cardiovascular actions of six homologous natriuretic peptides (ANP, BNP, VNP, CNP1, CNP3, and CNP4) in conscious eels

The natriuretic peptide (NP) family consists of seven paralogs [atrial NP (ANP), brain NP (BNP), ventricular NP (VNP), and C-type NP 1-4 (CNP1-4)] in teleosts, but relative biological activity of the seven NPs has not been comprehensively examined using homologous peptides. In this study, we newly identified CNP3 and CNP4 in eels to use homologous peptides, but the CNP2 gene may have been silenced in this species. The CNP4 gene was expressed exclusively in the brain as CNP1, but the CNP3 gene, from which cardiac ANP, BNP, and VNP were generated by tandem duplication, was most abundantly expressed in the pituitary, suggesting its local action. All NPs induced hypotension dose dependently after intra-arterial injection with a potency order of ANP > VNP > BNP > CNP4 > CNP1 = CNP3. The degree of hypotension was similar at the ventral and dorsal aorta, indicating similar actions on the branchial and systemic circulation. The hypotension induced by cardiac NPs was longer lasting than CNPs, probably because of the difference in preferential receptors. Among cardiac NPs, the hypotensive effect of VNP lasted much longer than those of ANP and BNP, even though VNP disappeared from the blood more quickly than ANP. To analyze the unique effect of VNP, we examined possible involvement of the autonomic nervous system using ANP, VNP, and CNP3. Beta-adrenergic blockade diminished hypotensive effects of all three NPs, but alpha-adrenergic and cholinergic blockade enhanced only the effect of VNP, suggesting a specific mechanism for the VNP action. The NP-induced tachycardia was diminished by all blockers examined. Furthermore, the cardiovascular action of VNP was not impaired by a blocker of NP receptor, HS-142-1. Taken together, the homologous NPs exhibit diverse cardiovascular actions in eels partially through the autonomic nervous system, and the unique VNP action may be mediated by a novel receptor that has not been identified in teleosts.

The Day-Night Difference of Blood Pressure Is Increased in AT1A-Receptor Knockout Mice on a High-Sodium Diet

Abnormal circadian variation of blood pressure (BP) increases cardiovascular risk. In this study, we examined the influence of angiotensin AT(1A) receptors on circadian BP variation, and specifically on its behavioral activity-related and -unrelated components. BP and locomotor activity were recorded by radiotelemetry in AT(1A)-receptor knockout mice (AT(1A)(-/-)) and their wild-type controls (AT(1A)(+/+)) placed on a normal-salt diet (NSD) or high-salt diet (HSD, 3.1% Na). The 24-h BP was lower in AT(1A)(-/-) than AT(1A)(+/+) mice on a NSD (92 +/- 2 and 118 +/- 2 mm Hg, respectively), whereas the day-night BP difference (DeltaDNBP) was similar between groups (11 +/- 2 and 12 +/- 1 mm Hg, respectively). HSD increased BP by 20 +/- 2 mm Hg and DeltaDNBP by 7 +/- 1 mm Hg in AT(1A)(-/-) mice, without affecting these parameters much in AT(1A)(+/+) mice. The DeltaDNBP increase in AT(1A)(-/-) mice was caused by nondipping BP during the inactive late-dark period. Conversely, BP rise associated with circadian behavioral activation during the early dark period was not altered by HSD in AT(1A)(-/-) mice. The BP change associated with spontaneous ultradian activity-inactivity bouts was also similar between strains on HSD as was the BP rise associated with induced (cage-switch) behavioral activity. Ganglionic or alpha(1)-adrenergic blockade decreased BP in both strains; HSD did not affect this response in AT(1A)(-/-), but abolished it in AT(1A)(+/+) mice. AT(1A)-receptor deficiency, when combined with HSD, can increase circadian BP difference in mice. This increase is mediated principally by activity-unrelated factors, such as the nonsuppressibility of basal resting sympathetic tone by HSD, thus suggesting a form of salt-/volume-dependent hypertension.

Doxazosin treatment alters stromal cell behavior and increases elastic system fibers deposition in rat prostate

Doxazosin (DOX), an α-adrenoceptor antagonist, induces the relaxation of smooth muscle cell tonus and reduces the clinical symptoms of benign prostatic hyperplasia (BPH). However, the effects of DOX in the prostate stromal microenvironment are not fully known. In a previous study, we showed that DOX treatment for 30 days increased deposition of collagen fibers in the three rat prostatic lobes. Herein, we investigated the effects of DOX on stromal cell ultrastructure and elastic fiber deposition. Adult Wistar rats were treated with DOX (25 mg/kg/day); and the ventral, dorsal, and anterior prostates were excised at 30 days of treatment. The prostatic lobes were submitted to histochemical and stereological-morphometric analyze and transmission electron microscopy (TEM). Histochemical staining plus stereological analysis of the elastic fiber system showed that DOX-treated prostatic lobes presented more elaunin and elastic fibers than controls, mainly in the ventral lobe. Ultrastructural analysis showed that fibroblasts and smooth muscle cells from DOX-treated prostates presented active synthetic phenotypes, evidenced by enlarged rough endoplasmic reticulum and Golgi apparatus cisterns, and confirmed the observation of thickened elaunin fibers. Our findings suggest that, under α-adrenergic blockade by DOX, the fibroblasts become more active and smooth muscle cells shift from a predominantly contractile to a more synthetic phenotype. The deposition of collagen and elastic system fibers in the prostatic stroma may counterbalance the absence of smooth muscle tone during α-blockers treatment.

Comparing the Effects of Carvedilol Enantiomers on Regression of Established Cardiac Hypertrophy Induced by Pressure Overload

Pressure overload diseases such as valvular stenosis and systemic hypertension morphologically manifest in patients as cardiac concentric hypertrophy. Preventing cardiac remodeling due to increased pressure overload is important to reduce the morbidity and mortality. A recent clinical study has shown that carvedilol has beneficial effects on the survival rate of patients with heart failure. This may be due to the actions of carvedilol such as β-adrenoceptor blockade and the α1-adrenergic receptor blockade effects. Therefore, we investigated whether carvedilol can reverse preexisting cardiac hypertrophy and we compared the effects of racemic carvedilol and the carvedilol enantiomers. Cardiac hypertrophy was induced in rats by suprarenal transverse abdominal aortic constriction (AC). Fifteen weeks after AC surgery, concentric hypertrophy was identified in the AC group by performing echocardiography. Low dose S- and SR-carvedilol (2 ㎎/㎏/day), which were orally administered for three weeks, caused significant regression of the cardiac hypertrophy, and this most significantly occurred in the rats that received S-carvedilol. However, R-carvedilol did not reduce cardiac hypertrophy. Regression of cardiac hypertrophy by carvedilol was confirmed on the echocardiograms and electrocardiograms. These results suggest that carvedilol could reverse the development of leftventricular concentric hypertrophy that is induced by pressure overload. S-carvedilol is proposed to be superior to SR-and R-carvedilol as a beneficial treatment for cardiac hypertrophy.

Sympathetic Control of the Cerebral Vasculature in Humans

The role of the sympathetic nervous system in cerebral autoregulation remains poorly characterized. We examined cerebral blood flow responses to augmented arterial pressure oscillations with and without sympathetic blockade and compared them with responses in the forearm circulation. An oscillatory lower body negative pressure of 40 mm Hg was used at 6 frequencies from 0.03 to 0.08 Hz in 11 healthy subjects with and without alpha-adrenergic blockade by phentolamine. Sympathetic blockade resulted in unchanged mean pressure and cerebral flow. The transfer function relationship to arterial pressure at frequencies >0.05 Hz was significantly increased in both the cerebral and brachial circulations, but the coherence of the relation remained weak at the lowest frequencies in the cerebral circulation. Our data demonstrate a strong, frequency-dependent role for sympathetic regulation of blood flow in both cerebral and brachial circulations. However, marked differences in the response to blockade suggest the control of the cerebral circulation at longer time scales is characterized by important nonlinearities and relies on regulatory mechanisms other than the sympathetic system.

Sympathetic restraint of muscle blood flow during hypoxic exercise

Control of exercising muscle blood flow is a balance between local vasodilatory factors and the increase in global sympathetic vasoconstrictor outflow. Hypoxia has been shown to potentiate the muscle sympathetic nerve response to exercise, potentially limiting the increase in muscle blood flow. Accordingly, we investigated sympathetic restraint to exercising muscle during whole body exercise in hypoxia. Six dogs chronically instrumented with ascending aortic and hindlimb flow probes and a terminal aortic catheter were studied at rest and mild [2.5 miles/h (mph), 5% grade] and moderate (4.0 mph, 10% grade) exercise while breathing room air or hypoxia (Pa(O(2)) approximately 45 mmHg) in the intact control condition and following systemic alpha-adrenergic blockade (phentolamine). Hypoxia caused an increase in cardiac output (CO), hindlimb flow (Flow(L)), and blood pressure (BP), while total (Cond(T)) and hindlimb conductance (Cond(L)) were unchanged at rest and mild exercise but increased with moderate exercise. During both mild and moderate exercise, alpha-blockade in normoxia resulted in significant vasodilation as evidenced by increases in CO (10%), Flow(L) (17%), Cond(T) (33%), Cond(L) (43%), and a decrease in BP (-18%), with the increase in Cond(L) greater than the increase in Cond(T) during mild exercise. Compared with the normoxic response, alpha-blockade in hypoxia during exercise resulted in a significantly greater increase in Cond(T) (59%) and Cond(L) (74%) and a correspondingly greater decrease in BP (-34%) from baseline. These findings indicate that there is considerable hypoxia-induced sympathetic restraint of muscle blood flow during both mild and moderate exercise, which helps to maintain arterial blood pressure in hypoxia.

Effect of Tamsulosin on Systemic Blood Pressure and Nonneurogenic Dysfunctional Voiding in Children

A number of therapies for dysfunctional voiding in children have been proposed after conservative measures have failed. Prior studies have shown significant improvement in lower urinary tract symptoms with alpha1-adrenergic antagonists. Nonselective alpha1-adrenergic antagonists can result in systemic vasodilatation and hypotension. We examined the effects of tamsulosin, a uroselective alpha1A-adrenergic antagonist, on blood pressure, as well as its safety and efficacy in the treatment of dysfunctional voiding in a pediatric population. A total of 23 children without anatomical or neurogenic abnormalities presented with lower urinary tract symptoms refractory to conservative measures. All children had increased post-void residual urine or abnormal uroflowmetry in the absence of pelvic floor activity suggestive of bladder neck dysfunction. All patients were administered tamsulosin daily. Voiding diaries, blood pressure, uroflowmetry studies and patterns along with assessment of post-void residual urine were obtained before and after beginning tamsulosin in all children. Median duration of tamsulosin therapy was 7 months, and patient followup was 20 months. The number of voiding and incontinent episodes significantly decreased during treatment compared to baseline (p <0.05). Mean blood pressures before and during tamsulosin treatment were 98/55 mm Hg and 110/61 mm Hg, respectively. Significant increases in average and maximum urinary flow rates along with reduction in post-void residual urine were observed during tamsulosin therapy compared to baseline values (p <0.01). A 50% reduction in the number of abnormal uroflow patterns was observed with tamsulosin therapy. Tamsulosin demonstrated no clinically significant effect on blood pressure, while proving to be a safe and effective treatment option for lower urinary tract symptoms in a select pediatric population.

Mechanisms of Inhaled Fine Particulate Air Pollution–Induced Arterial Blood Pressure Changes

BackgroundEpidemiologic studies suggest a positive association between fine particulate matter and arterial blood pressure, but the results have been inconsistent.ObjectivesWe investigated the effect of ambient particles on systemic hemodynamics during a 5-hr exposure to concentrated ambient air particles (CAPs) or filtered air (FA) in conscious canines.MethodsThirteen dogs were repeatedly exposed via permanent tracheostomy to CAPs (358.1 ± 306.7 μg/m3, mean ± SD) or FA in a crossover protocol (55 CAPs days, 63 FA days). Femoral artery blood pressure was monitored continuously via implanted telemetry devices. We measured baroreceptor reflex sensitivity before and after exposure in a subset of these experiments (n = 10 dogs, 19 CAPs days, 20 FA days). In additional experiments, we administered α-adrenergic blockade before exposure (n = 8 dogs, 16 CAPs days, 15 FA days). Blood pressure, heart rate, rate–pressure product, and baroreceptor reflex sensitivity responses were compared using linear mixed-effects models.ResultsCAPs exposure increased systolic blood pressure (2.7 ± 1.0 mmHg, p = 0.006), diastolic blood pressure (4.1 ± 0.8 mmHg; p < 0.001), mean arterial pressure (3.7 ± 0.8 mmHg; p < 0.001), heart rate (1.6 ± 0.5 bpm; p < 0.001), and rate–pressure product (539 ± 110 bpm × mmHg; p < 0.001), and decreased pulse pressure (−1.7 ± 0.7 mmHg, p = 0.02). These changes were accompanied by a 20 ± 6 msec/mmHg (p = 0.005) increase in baroreceptor reflex sensitivity after CAPs versus FA. After α-adrenergic blockade, responses to CAPs and FA no longer differed significantly.ConclusionsControlled exposure to ambient particles elevates arterial blood pressure. Increased peripheral vascular resistance may mediate these changes, whereas increased baroreceptor reflex sensitivity may compensate for particle-induced alterations in blood pressure.

Response to Letter by Prakash

Response: In his/her letter regarding our article in Stroke ,1 Dr Prakash suggests that our report of impaired cerebral autoregulation (CA) during hypotension was a result of the perfusion pressure falling below the lower limits of CA, rather than our experimental strategy of using an α-adrenergic blockade of cerebral vessels with Prazosin. However, based on previous literature, the idea of a perfusion pressure–related impairment of CA is untenable for the following reasons:

α-Adrenoceptor blockade modifies neurally induced atrial arrhythmias

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Dissociation Between Sympathetic Nerve Traffic and Sympathetically Mediated Vascular Tone in Normotensive Human Obesity

Obesity increases the risk of hypertension and its cardiovascular complications. This has been partly attributed to increased sympathetic nerve activity, as assessed by microneurography and catecholamine assays. However, increased vasoconstriction in response to obesity-induced sympathoactivation has not been unequivocally demonstrated in obese subjects without hypertension. We evaluated sympathetic alpha-adrenergic vascular tone in the forearm by brachial arterial infusion of the alpha-adrenoreceptor antagonist phentolamine (120 microg/min) in normotensive obese (daytime ambulatory arterial pressure: 123+/-1/77+/-1 mm Hg; body mass index: 35+/-1 kg/m(2)) and lean (daytime ambulatory arterial pressure: 123+/-2/77+/-2 mm Hg; body mass index: 22+/-1 kg/m(2)) subjects (n=25 per group) matched by blood pressure, age, and gender. Microneurographic sympathetic nerve activity to skeletal muscle was significantly higher in obese subjects (30+/-3 versus 22+/-1 bursts per minute; P=0.02). Surprisingly, complete alpha-adrenergic receptor blockade by phentolamine (at concentrations sufficient to completely inhibit norepinephrine and phenylephrine-induced vasoconstriction) caused equivalent vasodilatation in obese (-57+/-2%) and lean subjects (-57+/-3%; P=0.9). In conclusion, sympathetic vascular tone in the forearm circulation is not increased in obese normotensive subjects despite increased sympathetic outflow. Vasodilator factors or mechanisms occurring in obese normotensive subjects could oppose the vasoconstrictor actions of increased sympathoactivation. Our findings may help to explain why some obese subjects are protected from the development of hypertension.

The role of botulinum toxin a in the management of lower urinary tract symptoms

Lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) is the most common disease affecting men older than age 40. Although rarely life threatening, BPH may significantly affect quality of life. The mainstay nonsurgical therapy for BPH includes α-adrenergic blockade and/or 5-α-reductase inhibitors. However, current regimens require the daily administration of medication for an indefinite time. Botulinum toxin type A (BTX-A) is an injectable neurotoxin indicated to treat blepharospasm, strabismus, axillary hyperhydrosis, cervical dystonia, and glabellar lines. When injected intraprostatically, BTX-A may treat BPH-related symptoms. This article reviews evidence of BTX-A safety and efficacy in the treatment of LUTS related to BPH. Results are also presented from our first phase 1, dose-escalating study to evaluate the dose-related toxicity of BTX-A to treat LUTS due to BPH. Ultimately, the LUTS-related improvements seen in our study were consistent with earlier published trials using BTX-A to treat LUTS.

Cardiovascular responses to peripheral chemoreflex activation and comparison of different methods to evaluate baroreflex gain in conscious mice using telemetry

Peripheral chemoreceptors located in the carotid bodies are the primary sensors of systemic hypoxia. Although the pattern of responses elicited by peripheral chemoreceptor activation is well established in rats, lambs, and rabbits, the cardiovascular responses to peripheral chemoreflex activation in conscious mice have not been delineated. Here we report that stimulation of peripheral chemoreceptors by potassium cyanide (KCN) in conscious mice elicits a unique biphasic response in blood pressure that is characterized by an initial and robust rise followed by a decrease in blood pressure, which is accompanied by a marked reduction in heart rate. The depressor and bradycardic responses to KCN were abolished by muscarinic receptor blockade with atropine, and the pressor response was abolished by alpha-adrenergic receptor blockade with prazosin, suggesting that vagal and sympathetic drive to the heart and sympathetic drive to the vasculature mediate these cardiovascular responses. These studies characterized the chemoreflex in conscious mice and established the reliability of using them for studying hypoxia-related diseases such as obstructive sleep apnea. In another series of experiments, two methods for analyzing baroreflex sensitivity were compared: the classical pharmacological approach using phenylephrine and sodium nitroprusside (i.e., the Oxford technique) or the sequence method for analyzing spontaneous baroreflex activity. Our findings indicate that both methods are reliable, and the sequence method certainly has its benefits as a predictive tool in the context of long-term noninvasive studies using telemetry. However, for absolute determination of baroreflex function, analysis of spontaneous baroreflex activity should be complemented by the classical pharmacological method.

Reduction in α-adrenergic receptor-mediated vascular tone contributes to improved arterial compliance with endurance training

Background Regular aerobic exercise improves large artery compliance in middle-aged and older humans. However, the underlying mechanisms are unknown. We tested the hypothesis that the improved central arterial compliance with endurance training is mediated by decreased α-adrenergic tone and/or increased endothelial function. Methods Seven sedentary healthy adults (60 ± 3 years) underwent systemic α-adrenergic blockade (phentolamine) and nitric oxide synthase (NOS) inhibition using N G-monomethyl- l-arginine in sequence before and after a 3-month moderate endurance training (walk/jog, 4–5 days/week). Phentolamine was given first to isolate the contribution of nitric oxide to arterial compliance by minimizing reflex suppression of sympathetic tone resulting from systemic NOS inhibition as well as to assess the α-adrenergic receptor-mediated modulation of arterial compliance. Results Baseline arterial compliance (via simultaneous ultrasound and applanation tonometry on the carotid artery) increased 34 ± 12% after exercise training ( P < 0.01). When α-adrenergic blockade was performed, arterial compliance increased 37 ± 6% ( P < 0.01) before the exercise training but did not change significantly after the training. Decreases in arterial compliance from the α-adrenergic blockade to the subsequent additional NOS blockade were not different before and after exercise training. Conclusion Our results suggest that the reduction in α-adrenergic receptor-mediated vascular tone contributes to the improved central arterial compliance with endurance training.

Role of Peptide YY in Intestinal and Gallbladder Motility in Dogs

The purpose of this study was to characterize the action of exogenous PYY, an ileocolonic peptide released by fatty meal, and that released by Heal perfusion with oleate on intestinal and gallbladder motility patterns and the posssible role of the adrenergic pathway in this action. Dogs were equipped with chronic duodenal electrodes for recording myoelectric activity and with a cannula in the gallbladder fundus for measuring the gallbladders intraluminal pressure and volume and calculating its motility index (MI) and emptying rate. After intravenous infusion of PYY, there was a dose-dependent prolongation of the migrating motor complex (MMC) interval and almost complete abolition of the contractions and emptying of gallbladder during the duodenal activity front. After meat feeding or during intravenous infusion of cerulein, 50 pmol/(kg · h), the MMC was interrupted and replaced by irregular spike activity, accompanied by a marked increase in the gallbladder MI and about 80% to 90% reduction of its volume. PYY, 200 pmol/(kg · h), reduced significantly the meal- or cerulein-induced duodenal spike activity but failed to affect the MI and volume of the gallbladder. Similar changes in fasted and fed patterns of motility were observed after Heal oleate (16 mM/h), producing plasma PYY levels in a range similar to that observed after infusion of exogenous PYY. The inhibitory effects of PYY or Heal fat on intestinal myoelectric activity were reversed in part by α-adrenergic blockade (phentolamine). We conclude that exogenous PYY or endogenous hormone released by Heal oleate inhibits the interdigestive and postprandial motility pattern of the small bowel but does not affect gallbladder motility, and that the inhibition of intestinal motility involves, at least in part, the adrenergic pathway.

Comparison of pharmacodynamics between carvedilol and metoprolol in rats with isoproterenol-induced cardiac hypertrophy: Effects of carvedilol enantiomers

A recent clinical study has shown that carvedilol has a significantly more favorable effect than metoprolol on survival rate in patients with heart failure. This may be due to actions of carvedilol such as β2-adrenoceptor blockade, α-adrenergic receptor blockade and other properties such as anti-oxidant effects that are not yet fully understood. We compared the effects of racemic carvedilol, metoprolol and carvedilol enantiomers on cardiac hypertrophy at similar heart rate in rats with isoproterenol-induced cardiac hypertrophy. Continuous administration of isoproterenol for 2 weeks produced heart failure, which is characterized by an increased heart rate, cardiac hypertrophy and downregulation of β-adrenoceptors. The doses of racemic carvedilol and metoprolol were adjusted to obtain a similar heart rate in rats with isoproterenol-induced cardiac hypertrophy. The reduction of left ventricular weight and improvement of cAMP production induced by carvedilol were superior to those induced by metoprolol. Although heart rate, blood pressure and cAMP production were not affected by R-carvedilol, left ventricular weight was significantly reduced as a result of α-adrenoceptor blockade. The improvement of cAMP production by S-carvedilol was significantly higher than that induced by coadministration of R-carvedilol and metoprolol, suggesting that β2-adrenoceptor blockade partly contributed to the improvement of signal transduction in rats with isoproterenol-induced cardiac hypertrophy. This study has demonstrated that the effects of carvedilol on cAMP production and cardiac hypertrophy in rats with isoproterenol-induced cardiac hypertrophy are superior to those induced by metoprolol at a similar heart rate.