Β-adrenoceptor Blockade Research Articles

Parallel effects of β-adrenoceptor blockade on cardiac function and fatty acid oxidation in the diabetic heart: Confronting the maze

Diabetic cardiomyopathy is a disease process in which diabetes produces a direct and continuous myocardial insult even in the absence of ischemic, hypertensive or valvular disease. The β-blocking agents bisoprolol, carvedilol and metoprolol have been shown in large-scale randomized controlled trials to reduce heart failure mortality. In this review, we summarize the results of our studies investigating the effects of β-blocking agents on cardiac function and metabolism in diabetic heart failure, and the complex inter-related mechanisms involved. Metoprolol inhibits fatty acid oxidation at the mitochondrial level but does not prevent lipotoxicity; its beneficial effects are more likely to be due to pro-survival effects of chronic treatment. These studies have expanded our understanding of the range of effects produced by β-adrenergic blockade and show how interconnected the signaling pathways of function and metabolism are in the heart. Although our initial hypothesis that inhibition of fatty acid oxidation would be a key mechanism of action was disproved, unexpected results led us to some intriguing regulatory mechanisms of cardiac metabolism. The first was upstream stimulatory factor-2-mediated repression of transcriptional master regulator PGC-1α, most likely occurring as a consequence of the improved function; it is unclear whether this effect is unique to β-blockers, although repression of carnitine palmitoyltransferase (CPT)-1 has not been reported with other drugs which improve function. The second was the identification of a range of covalent modifications which can regulate CPT-1 directly, mediated by a signalome at the level of the mitochondria. We also identified an important interaction between β-adrenergic signaling and caveolins, which may be a key mechanism of action of β-adrenergic blockade. Our experience with this labyrinthine signaling web illustrates that initial hypotheses and anticipated directions do not have to be right in order to open up meaningful directions or reveal new information.

Voluntary exercise does not affect stress‐induced tachycardia, but improves resistance to cardiac arrhythmias in rats

1. It is currently unknown whether long-term voluntary exercise has enduring cardioprotective effects in animal models. 2. The present study was conducted in three groups of rats: (i) sedentary controls (n = 6); (ii) 24 h runners (n = 8; unlimited access to running wheels); and (iii) 2 h runners (n = 8; access to running wheels limited to 2 h daily). After termination of the 6 week exercise protocol, all rats were implanted with the telemetric electrocardiogram transmitters and were studied 1 week later. 3. Resting heart rate (HR) values in the control rats, 24 h runners and 2 h runners were 372 ± 7, 361 ± 9 and 298 ± 5 b.p.m., respectively (P < 0.05 for 2 h runners vs controls). The high-frequency spectral power in the control rats, 24 h runners and 2 h runners was 3.9 ± 0.2, 4.3 ± 0.3 and 5.3 ± 0.3 s², respectively (P < 0.05 for 2 h runners vs controls), whereas intrinsic HR was 383 ± 3, 377 ± 2 and 346 ± 3 b.p.m., respectively (P < 0.001 for 2 h runners vs controls). Restraint stress provoked tachycardia of similar magnitude in all groups. 4. After completion of telemetric studies, haemodynamic indices and susceptibility to cardiac arrhythmias were assessed in anaesthetized animals, there were no major between-group differences in HR, arterial pressure, contractility indices or sensitivity to β-adrenoceptor stimulation (dobutamine) or blockade (atenolol). The effective refractory period in the control rats, 24 h runners and 2 h runners was 49 ± 2, 55 ± 2 and 60 ± 4 ms, respectively (P = 0.054 for 2 h runners vs controls). A significantly higher dose of aconitine was required to provoke ventricular arrhythmias in the 24 h and 2 h running groups compared with controls (489 ± 76, 505 ± 88 and 173 ± 33 μg, respectively; P < 0.05). 5. We conclude that, in rats, long-term voluntary exercise has enduring cardioprotective effects mediated at the level of both the central nervous system and the heart.

Intracoronary gastrin 17 increases cardiac perfusion and function through autonomic nervous system, CCK receptors, and nitric oxide in anesthetized pigs

The release of gastrointestinal hormones has been reported to modulate reflex cardiovascular responses caused by gastric distension, although the role played by gastrin 17 is as yet unknown. The present study was therefore planned to determine the primary in vivo effect of gastrin 17 on coronary blood flow and cardiac function and the involvement of autonomic nervous system, CCK1/2 receptors, and nitric oxide (NO). In 40 anesthetized pigs, gastrin 17 was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure. In 35 of the 40 pigs, the mechanisms of the observed hemodynamic responses were analyzed by repeating gastrin 17 infusion after autonomic nervous system and NO blockade, and after specific CCK receptors agonists/antagonists administration. Intracoronary gastrin 17 administration caused dose-related increases of both coronary blood flow and cardiac function. The intracoronary co-administration of CCK33/pentagastrin and gastrin 17 potentiated the coronary effects observed when the above agents were given alone (P <0.05). The potentiation of the cardiac response was observed only with the co-administration of pentagastrin and gastrin 17 (P <0.05). Moreover, blockade of muscarinic cholinoceptors (intravenous atropine) and of α-adrenoceptors (intravenous phentolamine) did not abolish the hemodynamic responses to gastrin 17. The cardiac and vascular effects of the hormone were prevented by blockade of β-adrenoceptors (intravenous atenolol and butoxamine), CCK1/2 receptors (intracoronary lorglumide and CAM-1028), and NO synthase (intracoronary Nω-nitro-l-arginine methyl ester). In conclusion, gastrin 17 primarily increased coronary blood flow and cardiac function through the involvement of CCK receptors, β-adrenoceptors, and NO release.

Metoprolol, but not atenolol, reduces stress induced neuropeptide Y release in pigs

Objectives. To explore if β-adrenergic receptors in the brain are involved in acute and delayed cardiovascular responses to a brief emotional stress, by comparing the effects of the β1-blockers metoprolol (lipophilic) and atenolol (hydrophilic). Design. Male dominant pigs, singleliving, freely moving, with telemetric recordings of intra-arterial pressure and ECG and assay of plasma levels of the adrenergic cotransmittor neuropeptide Y (NPY), were confronted with four alien pigs for three minutes at weekly intervals. Weeks 1 and 4 were controls, in weeks 2 and 3 randomized crossover treatment with metoprolol or atenolol were given. Results. The confrontation caused instant and transient tachycardia and more prolonged effects in terms of increased plasma NPY levels, increased arterial pressure and reduced cardiac vagal activation. The two β-blockers inhibited the tachycardia equally, but only metoprolol reduced the prolonged effects. Conclusions. Emotionally induced sympathetic activation involves peripheral release of NPY causing a prolonged increase of arterial pressure and a reduction of cardiac vagal activity. These effects are prevented by central nervous β-adrenoceptor blockade.

Effect of low sodium intake and β-blockade on renin synthesis and secretion in mice with unilateral ureteral ligation

We previously reported that sodium depletion increased renin secretion from the normal kidney in mice. We postulated that the combined procedures of sodium depletion and β-adrenoceptor blockade would affect the activity of the renin-angiotensin system. To test this hypothesis, we investigated the interaction of low sodium intake (LSI) and propranolol (PRO) on renin synthesis and secretion. To prevent the influence of tubule flow on renin secretion, mice with a left hydronephrotic kidney were used. LSI increased plasma renin concentration (PRC) 5.6-fold in the right renal vein (P<0.01). There was no net increase of PRC in the left renal vein. Tissue renin concentration (TRC) was elevated 3.6-fold and 1.3-fold in the right and left kidneys (P<0.01), respectively. After administration of PRO, PRC decreased by 34% in the right renal vein and 47% in the aorta (P<0.05); TRC was reduced by 37.5% in the right and 29.3% in the hydronephrotic kidneys (P<0.05). The combination of LSI and PRO increased PRC 3.4-fold and 1.8-fold in the right (P<0.01) and left renal veins (P<0.05), respectively. TRC increased 3.4-fold in the right (P<0.01) but only 61% in the left kidneys (P<0.05). The pattern in change of renin mRNA levels was similar to TRC but the absolute amount was smaller. There were correlations between PRC and renin mRNA, and between TRC and renin mRNA in both kidneys (P<0.001). Thus, LSI increased renin synthesis in both kidneys. However, there was no apparent renin secretion in the hydronephrotic kidney. PRO treatment suppressed renin synthesis and renin secretion, irrespective of hydronephrosis and LSI. The macula densa is critical for renin secretion under all of the circumstances studied.

β-Adrenoceptor Blockers Increase Cardiac Sympathetic Innervation by Inhibiting Autoreceptor Suppression of Axon Growth

β-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of β-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective β-blocker propranolol and the β(1)-antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, β-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the β(2)-blocker ICI 118551 did not. Norepinephrine synthesis suppression by α-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via β(1)-adrenoceptors. Immunohistochemistry revealed β(1)-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess β(1)-autoreceptors that negatively regulate axon outgrowth. Chronic β-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to β-blocker withdrawal syndrome.

Mechanisms of Modulation of Thermoregulatory Reactions during Cooling in Hypertensive Rats by the Sympathetic Nervous System

Susceptibility of thermoregulatory responses to cold to blockage of α(1)- and β-adrenoreceptors differs in health and hypertension. α(1)-Adrenoceptor blockade reduces vessel reactivity during cooling and vessel reaction to cold becomes similar to that in intact normotensive rats. Changes in the structure of metabolic response to cold in favor of non-shivering thermogenesis typical of hypertensive animals becomes even more pronounced under conditions of α(1)-adrenoceptor blockade due to inhibition of cold shivering. Blockage of β-adrenoceptors does not affect parameters of vascular response to cooling. In hypertensive rats, in contrast to normotensive animals, β-adrenoceptor blockade during cooling increased temperature thresholds for total metabolic reaction and shivering. The maximum shivering intensity also increased, which partially compensated inhibition of non-shivering thermogenesis. In the whole organism, blockade of one type of adrenoceptors during cooling leads to intensification of compensatory mechanisms realized through adrenoceptors of the other type. In hypertensive rats, compensatory capacities of thermogenic processes controlled by α(1)- and β-adrenoceptors are impaired in comparison with normotensive animals under conditions of inhibition of both shivering and non-shivering thermogenesis.

β-Adrenoceptor blockade depresses molecular and functional plasticities in the rat neocortex

β-Adrenergic receptor stimulation can significantly facilitate synaptic potentiation in the hippocampus and enhance memory processes, but its effect on neocortical plastic mechanisms is less conclusive. In the present study we determined the effect of propranolol, a β-adrenoceptor antagonist, on long-term potentiation (LTP) induced in vivo in rat occipital cortex by tetanizing stimulation of corpus callosum and observed a dose-dependent inhibition of LTP. We further administered propranolol through mini-osmotic pumps during 3 days, and observed the performance of rats in a complex operant conditioning learning paradigm and assessed the expression of brain-derived neurotrophic factor (BDNF) in the occipital cortex. Propranolol exposure depressed both the number of reinforced responses in the operant conditioning task and BDNF expression in occipital cortex. Taken together, our results suggest that propranolol impairs memory formation by inhibiting cortical LTP induction and associated BDNF expression.

Cardiac Gap Junction Channels Are Upregulated by Metoprolol: An Unexpected Effect of Beta-Blockers

Background/Aims: Since β-adrenoceptors have been shown to affect cardiac gap junction channels, we wanted to elucidate the possible effect of metoprolol on the gap junction protein connexin-43, using racemic RS-metoprolol or the isomer R-metoprolol (no β-adrenoceptor blockade) or S-metoprolol (β₁-adrenoceptor blocker). Methods: Cultured neonatal rat cardiomyocytes were exposed to either RS-metoprolol or R-metoprolol or S-metoprolol (0.1 µmol/l each) without or with additional isoprenaline (0.1 µmol/l) treatment for 24 h. Results: The β-blocker treatment did not alter the frequency of spontaneously beating cardiomyocytes, whereas sole isoprenaline administration significantly enhanced the beating frequency by about 40%. This rise could be blocked by concomitant treatment with S- or RS-metoprolol but not with R-metoprolol. Connexin-43 protein was significantly enhanced by isoprenaline and by R-, S- or RS-metoprolol treatment alone as well as with the combined administration of isoprenaline and R-, S- or RS-metoprolol. Phospho-ERK1 and connexin-43 mRNA were significantly increased by isoprenaline application alone, whereas R-, S- or RS-metoprolol alone or in combination with isoprenaline exhibited no effect. Conclusion: Both isomers of metoprolol upregulate connexin-43 in cultured cardiomyocytes by a β-adrenoceptor-independent mechanism. Since the enhanced presence of connexin-43 in cell membranes under metoprolol was not accompanied by enhanced connexin-43 mRNA, we assume that the metoprolol effect involves reduced connexin-43 degradation.

β-adrenoreceptor blocking and antihypertensive activity of PP-24, a newly synthesized aryloxypropanolamine derivative

Abstract PP-24 is a newly synthesized putative β-adrenoceptor antagonist. The objective of the study was to the evaluate β-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg−1) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 μg kg−1) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 μg kg−1). The pA2 of PP-24 to β1-, β2- and β3-adrenoceptors was 7.72 ± 0.082, 7.40 ± 0.082 and 6.39 ± 0.16, respectively. The β1/β2 selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses β-adrenoceptor blockade activity but with non-specific affinity for β1- and β2-adrenoceptor subtypes. The rank order of potency of the antagonists for β1-adrenoceptors was atenolol &amp;gt; PP-24 &amp;gt; propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of β-adrenoceptors.

Cardioprotection, attenuated systemic inflammation, and survival benefit of β1-adrenoceptor blockade in severe sepsis in rats*

To explore the hypothesis that beta-1 adrenoreceptor blockade may be protective through the attenuation of sympathetic hyperactivity and catecholaminergic inflammatory effects on cardiac and hepatic function. Prospective, randomized, controlled study. Animal laboratory in a university medical center. Male adult Wistar rats. Peripheral beta1-adrenoceptor blockade through daily intraperitoneal injection (metoprolol, 100 mg x kg(-1); atenolol, 6 mg x kg(-1)) or central nervous system beta1-adrenoceptor blockade (intracerebroventricular metoprolol, 25 microg) to achieve approximately 20% heart rate reduction in rats for 2 days before or after the induction of lethal endotoxemia, cecal ligation and puncture, or fecal peritonitis. Peripheral beta1-adrenoceptor blockade established for 2 days before lethal endotoxemia markedly improved survival in both metoprolol-treated (n = 16; log rank test, p = .002) and atenolol-treated (n = 15; p = .03) rats. Overall mortality in cecal ligation and puncture was similar between metoprolol (40%; n = 10) and saline (50%; n = 10) pretreatment (p = .56), but the median time to death was increased by 33 hrs in metoprolol-treated rats (p = .03). Metoprolol pretreatment reduced hepatic expression of proinflammatory cytokines and lowered plasma interleukin-6 (both p < .05). Myocardial protein expression of interleukin-18 and monocyte chemoattractant protein-1, key mediators of cardiac dysfunction in sepsis, were also reduced (p < .05). Peripheral beta1-adrenoceptor blockade commenced 6 hrs after lethal endotoxemia or fecal peritonitis did not improve survival. However, arterial blood pressure was preserved and left ventricular contractility restored similar to that found in nonseptic controls. Central nervous system beta1-adrenoceptor blockade (metoprolol) did not reduce plasma cytokines or mortality, despite enhancing parasympathetic tone. Peripheral beta1-adrenoceptor blockade offers anti-inflammatory and cardioprotective effects, with mortality reduction if commenced before a septic insult. Its role in sepsis should be explored further.

β-adrenergic blockade attenuates cardiac dysfunction and myofibrillar remodelling in congestive heart failure

Although β-adrenoceptor (β-AR) blockade is an important mode of therapy for congestive heart failure (CHF), subcellular mechanisms associated with its beneficial effects are not clear. Three weeks after inducing myocardial infarction (MI), rats were treated daily with or without 20 and 75 mg/kg atenolol, a selective β1-AR antagonist, or propranolol, a non-selective β-AR antagonist, for 5 weeks. Sham operated rats served as controls. All animals were assessed haemodynamically and echocardiographically and the left ventricle (LV) was processed for the determination of myofibrillar ATPase activity, α- and β-myosin heavy chain (MHC) isoforms and gene expression as well as cardiac troponin I (cTnI) phosphorylation. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated cardiac hypertrophy and lung congestion in addition to increasing LV ejection fraction and LV systolic pressure as well as decreasing heart rate, LV end-diastolic pressure and LV diameters in the infarcted animals. Treatment of infarcted animals with these agents also attenuated the MI-induced depression in myofibrillar Ca2+-stimulated ATPase activity and phosphorylated cTnI protein content. The MI-induced decrease in α-MHC and increase in β-MHC protein content were attenuated by both atenolol and propranolol at low and high doses; however, only high dose of propranolol was effective in mitigating changes in the gene expression for α-MHC and β-MHC. Our results suggest that improvement of cardiac function by β-AR blockade in CHF may be associated with attenuation of myofibrillar remodelling.

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.

Both β1- and β2-adrenoceptors contribute to feedforward coronary resistance vessel dilation during exercise

During exercise, beta-feedforward coronary vasodilation has been shown to contribute to the matching of myocardial oxygen supply with the demand of the myocardium. Since both beta(1)- and beta(2)-adrenoceptors are present in the coronary microvasculature, we investigated the relative contribution of these subtypes to beta-feedforward coronary vasodilation during exercise as well as to infusion of the beta(1)-agonist norepinephrine and the beta(1)- and beta(2)-agonist isoproterenol. Chronically instrumented swine were studied at rest and during graded treadmill exercise (1-5 km/h) under control conditions and after beta(1)-blockade with metoprolol (0.5 mg/kg iv) and beta(1)/beta(2)-blockade with propranolol (0.5 mg/kg iv). The selectivity and degree of beta-blockade of metoprolol and propranolol were confirmed using isoproterenol infusion (0.05-0.4 microg. kg(-1).min(-1)) under resting conditions. Isoproterenol-induced coronary vasodilation was mediated through the beta(2)-adrenoceptor, whereas norepinephrine-induced coronary vasodilation was principally mediated through the beta(1)-adrenoceptor. Exercise resulted in a significant increase in left ventricular norepinephrine release and epinephrine uptake. beta(1)-Adrenoceptor blockade with metoprolol had very little effect under resting conditions. However, during exercise, metoprolol attenuated the increase in myocardial oxygen supply in excess of the reduction in myocardial oxygen demand, as evidenced by a progressive decrease in coronary venous Po(2). Consequently, metoprolol caused a clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po(2). Additional beta(2)-adrenoceptor blockade with propranolol further inhibited myocardial oxygen supply during exercise, resulting in a further clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po(2). In conclusion, both beta(1)- and beta(2)-adrenoceptors contribute to the beta-feedforward coronary resistance vessel dilation during exercise.

Amelioration of Cardiac Remodeling in Congestive Heart Failure by β-Adrenoceptor Blockade is Associated with Depression in Sympathetic Activity

This study investigated whether improvement in cardiac function and attenuation of cardiac remodeling by some beta-adrenoceptor (beta-AR) antagonists were associated with a depression in sympathetic activity in congestive heart failure (CHF) due to myocardial infarction (MI). Although cardiac dysfunction, hypertrophy and dilatation as well as increased plasma level of catecholamines are known to occur in CHF, the relationship between these parameters is poorly understood. Three weeks after occlusion of the coronary artery, rats were treated daily with 20 and 75 mg/kg of either atenolol or propranolol for 5 weeks. Sham-operated rats served as controls. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated the MI-induced cardiac hypertrophy, increases in left ventricular (LV) end-diastolic pressure, LV end-systolic volume and LV end-diastolic volume as well as depressions in LV systolic pressure, LV fractional shortening and cardiac output. PR interval was decreased and QT( c ) interval was increased in CHF; these alterations were ameliorated by both atenolol and propranolol. The increased level of plasma epinephrine in CHF was also depressed by both low and high doses of atenolol and propranolol whereas the increased level of plasma norepinephrine was reduced by high but not low doses of these drugs. The results indicate that the beneficial effects of beta-AR antagonists on cardiac remodeling and heart dysfunction in CHF may be due to the blockade of beta-ARs in the myocardium and a depression in the sympathetic activity.

Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of memory for emotionally arousing events through interactions with the noradrenergic system of the basolateral complex of the amygdala (BLA). We previously reported that intra-BLA administration of a β-adrenoceptor agonist immediately after inhibitory avoidance training enhanced memory consolidation and increased hippocampal expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc). In the present experiments corticosterone (3 mg/kg, i.p.) was administered to male Sprague-Dawley rats immediately after inhibitory avoidance training to examine effects on long-term memory, amygdala norepinephrine levels, and hippocampal Arc expression. Corticosterone increased amygdala norepinephrine levels 15 min after inhibitory avoidance training, as assessed by in vivo microdialysis, and enhanced memory tested at 48 h. Corticosterone treatment also increased expression of Arc protein in hippocampal synaptic tissue. The elevation in BLA norepinephrine appears to participate in corticosterone-influenced modulation of hippocampal Arc expression as intra-BLA blockade of β-adrenoceptors with propranolol (0.5 μg/0.2 μL) attenuated the corticosterone-induced synaptic Arc expression in the hippocampus. These findings indicate that noradrenergic activity at BLA β-adrenoceptors is involved in corticosterone-induced enhancement of memory consolidation and expression of the synaptic-plasticity-related protein Arc in the hippocampus.

Active metabolites formed during hepatic first-pass: simulations featuring their contribution to the overall effect in altered liver clearance and drug-drug interactions

Background Phase I and occasionally also phase II metabolites may contribute to the overall effect of a drug. This is not always apparent or revealed, since total concentrations of metabolites may be low in relation to parent drug concentrations. In the case of carvedilol, using a comparison of HPLC and β1-specific radioligand receptor binding assay (RRA), it was possible to demonstrate that regarding βadrenoceptor blockade the effect appears directly linked to the serum compartment, which indicates instantaneous equilibrium between the blood compartment and the biophase, and that oxidative metabolites significantly contribute to the effect, particularly after oral administration. This drug serves as model compound in different approaches for evaluating the role of formation of active metabolites during first-pass when hepatic clearance varies.

Propranolol improves cutaneous wound healing in streptozotocin-induced diabetic rats

Sympathetic nerve failure has been proposed as a contributing factor in impaired cutaneous wound healing in diabetes mellitus. Nevertheless, no studies have shown whether β-adrenoceptor blockade through β-blocker (e.g., propranolol) administration may alter healing of diabetic cutaneous lesions. This study evaluated macro- and microscopically the effects of propranolol administration on cutaneous wound healing in streptozotocin-induced diabetic rats. Acute diabetes was induced by a single intraperitoneal injection of streptozotocin 14 days before wounding. Animals were treated with propranolol (50 mg/kg) dissolved in drinking water; controls received water only. Administration of β-receptor antagonist began 1 day before wounding and was continued daily until euthanasia. A full-thickness excisional lesion (1 cm 2) was created. The wound area was measured weekly and the animals were killed 14 days after wounding. Lesions and adjacent skin were formalin-fixed and paraffin-embedded. Sections were stained with hematoxylin-eosin, Sirius red, and toluidine blue, and immunostained for CD-68, alpha-smooth muscle actin and proliferating cell nuclear antigen. The wound area was significantly smaller in the propranolol-treated group than in the control group 7 and 14 days after wounding. Inflammatory cell numbers and metalloproteinase-9 levels were reduced in the propranolol-treated group compared to the control group 14 days after wounding. Cell proliferation, mast cell number, collagen deposition, blood vessel density, and nitric oxide levels were increased in the propranolol-treated group compared to the control group 14 days after wounding. Propranolol administration improves cutaneous wound healing of hyperglycemic diabetic rats by reducing the local inflammatory response and improving subsequent phases of the repair process.

Normotensive sodium loading in normal man: regulation of renin secretion during β-receptor blockade

Saline administration may change renin-angiotensin-aldosterone system (RAAS) activity and sodium excretion at constant mean arterial pressure (MAP). We hypothesized that such responses are elicited mainly by renal sympathetic nerve activity by beta1-receptors (beta1-RSNA), and tested the hypothesis by studying RAAS and renal excretion during slow saline loading at constant plasma sodium concentration (Na+ loading; 12 micromol Na+.kg(-1).min(-1) for 4 h). Normal subjects were studied on low-sodium intake with and without beta1-adrenergic blockade by metoprolol. Metoprolol per se reduced RAAS activity as expected. Na+ loading decreased plasma renin concentration (PRC) by one-third, plasma ANG II by one-half, and plasma aldosterone by two-thirds (all P < 0.05); surprisingly, these changes were found without, as well as during, acute metoprolol administration. Concomitantly, sodium excretion increased indistinguishably with and without metoprolol (16 +/- 2 to 71 +/- 14 micromol/min; 13 +/- 2 to 55 +/- 13 micromol/min, respectively). Na+ loading did not increase plasma atrial natriuretic peptide, glomerular filtration rate (GFR by 51Cr-EDTA), MAP, or cardiac output (CO by impedance cardiography), but increased central venous pressure (CVP) by approximately 2.0 mmHg (P < 0.05). During Na+ loading, sodium excretion increased with CVP at an average slope of 7 micromol.min(-1).mmHg(-1). Concomitantly, plasma vasopressin decreased by 30-40% (P < 0.05). In conclusion, beta1-adrenoceptor blockade affects neither the acute saline-mediated deactivation of RAAS nor the associated natriuretic response, and the RAAS response to modest saline loading seems independent of changes in MAP, CO, GFR, beta1-mediated effects of norepinephrine, and ANP. Unexpectedly, the results do not allow assessment of the relative importance of RAAS-dependent and -independent regulation of renal sodium excretion. The results are compatible with the notion that at constant arterial pressure, a volume receptor elicited reduction in RSNA via receptors other than beta1-adrenoceptors, decreases renal tubular sodium reabsorption proximal to the macula densa leading to increased NaCl concentration at the macula densa, and subsequent inhibition of renin secretion.

Beneficial Effect of the Central Nervous System β-Adrenoceptor Blockade on the Failing Heart

Heart failure patients are routinely given beta-adrenoceptor antagonists (beta-blockers), although the mechanism(s) underlying their beneficial effects is not fully resolved. It is not entirely clear how long-term application of negative inotropic compounds improves cardiac performance, slows remodeling processes, and decreases mortality. All beta-blockers, which produce a beneficial effect in heart failure, have in common a high degree of lipophilicity and, therefore, have the ability to cross the blood-brain barrier. Here, we show that blockade of beta-adrenoceptors directly in the brain (chronic intracerebroventricular administration of metoprolol) attenuates the progression of left ventricular remodeling in a rat model of myocardial infarction-induced heart failure. These results provide the first direct evidence that the action of certain beta-blockers in the brain could contribute to their beneficial effect on the failing heart.