Down-regulation Of Β-adrenoceptors Research Articles

Sepsis-induced cardiac dysfunction: a review of pathophysiology.

It is well known that cardiac dysfunction in sepsis is associated with significantly increased mortality. The pathophysiology of sepsis-induced cardiac dysfunction can be summarized as involving impaired myocardial circulation, direct myocardial depression, and mitochondrial dysfunction. Impaired blood flow to the myocardium is associated with microvascular dysfunction, impaired endothelium, and ventriculo-arterial uncoupling. The mechanisms behind direct myocardial depression consist of downregulation of β-adrenoceptors and several myocardial suppressants (such as cytokine and nitric oxide). Recent research has highlighted that mitochondrial dysfunction, which results in energy depletion, is a major factor in sepsis-induced cardiac dysfunction. Therefore, the authors summarize the pathophysiological process of cardiac dysfunction in sepsis based on the results of recent studies.

P5992Why aortic valve disease may persist after surgery? A joint basic science - Clinical effort

Abstract Background Diseases of the aortic valve are a common reason for heart surgery. Aortic stenosis (AS) is associated with pressure and aortic regurgitation (AR) with a volume overload of the left ventricle (LV). Over time both pathologies lead to systolic and diastolic heart failure, while progressive downregulation of β-adrenoceptors occurs. While LV re-remodeling occurs in the majority of patients after aortic valve surgery, LV dysfunction persists in one fourth of such patients and leads to a terminal heart failure. We aimed to investigate whether differential remodeling in the protein kinase A (PKA) dependent inotropic response in myocytes and myocardial tissue obtained from patients undergoing aortic valve surgery is associated with the LV re-remodeling after surgery. Methods Preoperatively, pro BNP levels were measured and left ventricular strain analysis via echocardiography was performed. Interventricular septal biopsy was obtained intraoperatively in 10 patients who underwent aortic valve surgery. In-vitro contractility was analyzed in myocardial tissue paced with 4 Hz at 37 °C. Freshly isolated cells were transduced with an adenovirus expressing a cytosolic Förster resonance energy transfer (FRET) based cAMP biosensor (Epac1-camps). After 48 hours of culture, Föster-resonance energy transfer (FRET) was used for the first time to measure cAMP in 60 isolated human ventricular myocytes. Isoprenaline (10 nM – 10 μM) was used for β-adrenoceptor activation and forskolin (10 μmol) to activate adenylyl cyclase directly. Results We found a significantly downregulated β-adrenergic sensitivity in cardiomyocytes of patients with aortic valve disease, although contractile response to forskolin was maintained. Furthermore, we found a clear association between reduced sensitivity to isoprenaline (i.e., high EC50 values) and low maximum effect size to isoprenaline in myocardial tissue of patients with aortic valve disease, pointing out relevant β-adrenoceptor dysfunction. There were no significant differences in basal myocardial force between tissue samples of patients with AR and AS. Conclusion Collectively, our data show a profound remodelling in the cAMP/PKA pathway in patients with aortic valve disease. These disturbances may have an impact on the postoperative ventricular function and possibly on the long-term LV re-remodelling after aortic valve surgery.

Downregulation of β-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR.

β-adrenergic receptors (β-ARs) play an important role in cardiac remodeling, which is the key pathological process in various heart diseases and leads to heart failure. However, the regulation of β-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of β1- and β2-AR expression in cardiac remodeling. The rat model of cardiac remodeling was established by subcutaneous injection of isoproterenol(ISO) at the dose of 0.25 mg·kg−1·d−1 for 7days. We found that the expression of β1- and β2-ARs decreased in the remodeling heart. The mechanisms may include the inhibition of DNA transcription and the increase of mRNA degradation. cAMP-response element binding protein(CREB) is a well-known transcription factor of β-AR. However, the expression and activation of CREB was not changed in the remodeling heart. Further, human Antigen-R (HuR), a RNA binding protein, which binds to the 3'-untranslated region of the β-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of β-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of β-AR expression in ISO induced cardiac remodeling.

Biological Pacemaker Engineered by Nonviral Gene Transfer in a Mouse Model of Complete Atrioventricular Block

We hypothesized that a nonviral gene delivery of the hyperpolarization-activated HCN2 channel combined with the beta(2)-adrenergic receptor (ADRB2) would generate a functional pacemaker in a mouse model of complete atrioventricular block (CAVB) induced by radiofrequency ablation of the His bundle. Plasmids encoding HCN2 and ADRB2 mixed with tetronic 304, a poloxamine block copolymer, were injected in the left ventricular free wall (HCN2-ADRB2 mice). Sham mice received a noncoding plasmid. CAVB was induced 5 days later. Ventricular escape rhythms in HCN2-ADRB2 mice were significantly faster than in sham mice at day 15 after ablation and later. In HCN2-ADRB2 mice, QRS complexes were larger than in sham mice and characterized by abnormal axes. Immunostaining of GFP-HCN2 fusion protein showed an expression of HCN2 channel in left ventricular myocardium for at least 45 days after injection. In the mouse, CAVB induces progressive hypertrophy and heart failure leading to 50% mortality after 110 days. HCN2-ADRB2 mice survived 3 weeks longer than sham mice. Finally, beta-adrenergic input increased ventricular escape rhythms significantly more in HCN2-ADRB2 mice than in sham mice. In conclusion, nonviral gene transfer can produce a functional cardiac biological pacemaker regulated by sympathetic input, which improves life expectancy in a mouse model of CAVB.

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.

Vitamin E Reduces Antidepressant-Related β-Adrenoceptor Down-Regulation in Cultured Cells. Comparable Effects on St. John’s Wort and Tricyclic Antidepressant Treatment

The mode of action of antidepressants is still a matter of debate. Acute inhibition of neurotransmitter reuptake in central neuronal synapses, followed by a down-regulation of central postsynaptic beta-adrenoceptor (beta-AR) numbers were consistently observed in vivo, while a reduction in surface beta-AR density was found in cell cultures. Effects of the tricyclic antidepressant desipramine (DMI) were abolished by vitamin E (alpha-TOC) in vitro as well as in vivo. Alpha-TOC interfered with antidepressant-induced changes of cellular plasma membrane properties and with recycling of beta-AR. St. John's wort (SJW) extract reduced beta-AR numbers in cultured cells to a similar extent as DMI or the selective serotonin re-uptake inhibitor fluoxetine. We chronically co-exposed cell cultures to SJW extract and to alpha-TOC. Receptor down-regulation following exposure to the plant extract was inhibited in the presence of alpha-TOC suggesting a mode of action of SJW extract comparable to that of synthetic antidepressants. Inhibition of cell proliferation by the plant extract was also significantly reduced by alpha-TOC.

Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure

BackgroundSince only little is known on stem cell therapy in non-ischemic heart failure we wanted to know whether a long-term improvement of cardiac function in non-ischemic heart failure can be achieved by stem cell transplantation.MethodsWhite male New Zealand rabbits were treated with doxorubicine (3 mg/kg/week; 6 weeks) to induce dilative non-ischemic cardiomyopathy. Thereafter, we obtained autologous bone marrow stem cells (BMSC) and injected 1.5–2.0 Mio cells in 1 ml medium by infiltrating the myocardium via a left anterolateral thoracotomy in comparison to sham-operated rabbits. 4 weeks later intracardiac contractility was determined in-vivo using a Millar catheter. Thereafter, the heart was excised and processed for radioligand binding assays to detect β1- and β2-adrenoceptor density. In addition, catecholamine plasma levels were determined via HPLC. In a subgroup we investigated cardiac electrophysiology by use of 256 channel mapping.ResultsIn doxorubicine-treated animals β-adrenoceptor density was significantly down-regulated in left ventricle and septum, but not in right ventricle, thereby indicating a typical left ventricular heart failure. Sham-operated rabbits exhibited the same down-regulation. In contrast, BMSC transplantation led to significantly less β-adrenoceptor down-regulation in septum and left ventricle. Cardiac contractility was significantly decreased in heart failure and sham-operated rabbits, but was significantly higher in BMSC-transplanted hearts. Norepinephrine and epinephrine plasma levels were enhanced in heart failure and sham-operated animals, while these were not different from normal in BMSC-transplanted animals. Electrophysiological mapping revealed unaltered electrophysiology and did not show signs of arrhythmogeneity.ConclusionBMSC transplantation improves sympathoadrenal dysregualtion in non-ischemic heart failure.

Nicotine produces antidepressant-like actions: Behavioral and neurochemical evidence

Converging lines of evidence indicate the involvement of nicotinic acetylcholine receptors in depressive illness and antidepressant drug action. We investigated the effects of sub-chronic and chronic treatment with imipramine, nicotine and their combination on: (a) the ability of a dopamine-mimetic challenge to produce locomotor stimulation and (b) cortical density of β-adrenoceptors. One week of treatment with imipramine (10 mg/kg, twice daily) did not result in an altered response to the apomorphine (0.15 mg/kg) challenge, but after 2 weeks, the imipramine-treated rats demonstrated hyperactivity. Conversely, such increased locomotor response was observed in rats treated with nicotine (0.4 mg/kg, twice daily) for 1 but not for 2 weeks. Groups treated with nicotine+imipramine for 1 and 2 weeks demonstrated equally high hyperactivity in response to the apomorphine challenge. This effect was not different from the effects of 1-week treatment with nicotine or 2-week treatment with imipramine. The density of β-adrenoceptors was equally decreased by 2 (but not 1) weeks of the treatment with imipramine, nicotine and their combination. The present behavioral and neurochemical data suggest the antidepressant-like effect of the chronic treatment with nicotine. It appears that the potentiation of the dopamine-mimetic-induced hyperactivity cannot be explained by β-adrenoceptor down-regulation.

Cellular Mechanisms of Depressed Atrial Contractility in Patients With Chronic Atrial Fibrillation

After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood. Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (>/=3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. ss-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca(2+), isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca(2+) was maintained, and the postrest potentiation was preserved. Beta-adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients. After prolonged AF, atrial contractility was reduced by 75%. The impairment of beta-adrenergic modulation of contractile force cannot be explained by downregulation of ss-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca(2+) channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca(2+) shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.

Changes of beta-adrenergic signaling in compensated human cardiac hypertrophy depend on the underlying disease.

In human heart failure, desensitization of the beta-adrenergic signal transduction has been reported to be one of the main pathophysiological alterations. However, data on the beta-adrenergic system in human compensated cardiac hypertrophy are very limited. Therefore, we studied the myocardial beta-adrenergic signaling in patients suffering from hypertrophic obstructive cardiomyopathy (HOCM, n = 9) or from aortic valve stenosis (AoSt, n = 8). beta-Adrenoceptor density determined by [(125)I]iodocyanopindolol binding was reduced in HOCM and AoSt compared with nonhypertrophied, nonfailing myocardium (NF) of seven organ donors. In HOCM the protein expression of stimulatory G protein alpha-subunit (G(s)alpha) measured by immunoblotting was unchanged, whereas the inhibitory G protein alpha-subunit (Galpha(i-2)) was increased. In contrast, in AoSt, Galpha(i-2) protein was unchanged, but G(s)alpha protein was increased. Adenylyl cyclase stimulation by isoproterenol was reduced in HOCM but not in AoSt. Plasma catecholamine levels were normal in all patients. In conclusion, both forms of hypertrophy are associated with beta-adrenoceptor downregulation but with different changes at the G protein level that occur before symptomatic heart failure due to progressive dilatation of the left ventricle develops and are not due to elevated plasma catecholamine levels.

Effect of norepinephrine release on adrenoceptors in severe seizure genetically epilepsy-prone rats

The genetically epilepsy-prone rat (GEPR) seizure model is characterized by extensive abnormalities in brain noradrenergic function. Earlier studies had suggested that GEPRs might not regulate adrenoceptors in a normal fashion. The purpose of the present study was to determine if GEPR-9s are capable of up and down regulation of α 1- and β-adrenoceptors in response to increments or decrements in extracellular norepinephrine. Seizure induction has been shown to increase extracellular norepinephrine. Chronic sound or electroshock-induced seizures caused down regulation of β-adrenoceptors in frontal cortex and in hippocampus from GEPR-9s. Similarly, chronic daily treatment with the norepinephrine reuptake inhibitor desmethylimipramine produced down regulation of β-adrenoceptors in frontal cortex and in hippocampus from GEPR-9s. As is the case in neurologically normal animals, chronic electroshock-induced seizure did not cause down regulation of β-adrenoceptors in 6-hydroxydopamine pretreated GEPR-9s. Chronic electroshock treatment also caused up-regulation of α 1-adrenoceptors in frontal cortex but not in hippocampus. In 6-hydroxydopamine pretreated GEPR-9s, chronic electroshock treatment caused a further up-regulation of α 1-adrenoceptors in frontal cortex but not in hippocampus. Taken together, these results indicate that GEPR-9s are capable of up and down regulation of α 1- and β-adrenoceptors in a manner that is qualitatively similar to the regulation of these receptors in normal animals. Whether the regulation of brain adrenoceptors is quantitatively different in GEPRs from normal animals remains to be established.

Myocardial β-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity

Chronic administration of norepinephrine for 8 weeks has been shown to reduce neuronal norepinephrine uptake activity and increase interstitial norepinephrine concentration in the heart. To determine whether the changes could lead to myocardial β-adrenoceptor down-regulation or β-adrenergic subsensitivity, we measured left ventricular contractile responses to dobutamine, myocardial β-adrenoceptor density, β subtype distribution, competitive inhibition agonist binding, and adenylyl cyclase activity activation by isoproterenol, 5′-guanylylimidodiphosphate, and forskolin in dogs after a norepinephrine or saline infusion for 8 weeks. We found that norepinephrine infusion reduced myocardial β-adrenoceptor density, β 1-adrenoceptor subtype density, and high-affinity site for isoproterenol. Left ventricular contractile responses to dobutamine were reduced in the norepinephrine-infused animals. In addition, norepinephrine infusion decreased the basal adenylyl cyclase activity and the adenylyl cyclase responses to isoproterenol, 5′-guanylylimidodiphosphate, and forskolin. The findings indicate that a decrease in cardiac norepinephrine uptake predisposes the heart to norepinephrine-induced myocardial β-adrenoceptor down-regulation, and that norepinephrine, when present in a sufficient amount over a long period as it is in chronic heart failure, can reduce myocardial β-adrenergic responsiveness by both homologous and heterologous desensitization.

Deprenyl prevents the cardiac sympathetic nerve terminal abnormalities and β-adrenoceptor downregulation in pacing-induced heart failure

Deprenyl prevents the cardiac sympathetic nerve terminal abnormalities and β-adrenoceptor downregulation in pacing-induced heart failure

Time Course of Alterations in Phospholipid Fatty Acids and Number ofβ-Adrenoceptors in the Rat Heart During Adrenergic Stimulationin vivo

The purpose of this study was to test the hypothesis that catecholamine induced down-regulation ofβ-adrenoceptors in cardiac muscle is facilitated by modifications of the lipid milieu in cellular membranes. The time course of down-regulation ofβ-adrenoceptors and changes in the fatty acid composition of phospholipids was examined in the rat heart during adaptation to repeated epinephrine administration. By this we studied a possible relationship between modulation of the membrane phospholipids and the properties ofβ-adrenoceptors during 7 days of epinephrine administration. The fatty acid composition of cardiac membrane phosphatidylcholine (PC) and phosphatidylethanolamine (PE) and BmaxandKdof [3H]dihydroalprenolol binding toβ-adrenoceptors were measured in rats after 1, 2, 3, 5 and 7 days of epinephrine administration. Thein vivoadrenergic stimulation led to a significant response of phospholipid fatty acyl chains. In both PC and PE the linoleic acid (18:2n-6) level decreased markedly. The docosahexanoic acid (22:6n-3) level increased in PE and the arachidonic acid (20:4n-6) level increased in PC. These fatty acid changes were all significant after 3–5 days of epinephrine administration. During the 7 day epinephrine administration, the polyunsaturated fatty acid levels in the phospholipids of purified cardiac sarcolemma changed in the same way as in the phospholipids of whole ventricular muscle. The number of binding sites ofβ-adrenoceptors (Bmax) decreased as expected. The decrease in Bmaxoccurred later than the changes in their lipid environment and was only significant after 7 days of epinephrine administration. The conclusion is that during adaptation to epinephrine administration, the down-regulation ofβ-adrenoceptors is preceded by alterations in the polyunsaturated fatty acid composition of phospholipids in heart muscle. This supports the concept of a regulatory role of membrane lipids in the response ofβ-adrenoceptors to prolonged stimulation.

Effect of alterations in extracellular norepinephrine on adrenoceptors: a microdialysis study in freely moving rats

Chronic electroshock treatment (once daily for 12 days) increases extracellular norepinephrine in the frontal cortex and hippocampus as measured by microdialysis. This chronic treatment produced an elevation of basal norepinephrine overflow into extracellular space while both the first and the twelfth treatments produced a transient increase in norepinephrine overflow of about 40 min. Acutely, desmethylimipramine (10 mg/kg) treatment significantly increased extracellular norepinephrine. While chronic desmethylimipramine (once daily for 10 days) increased basal overflow of norepinephrine in the frontal cortex and hippocampus, the tenth daily administration of desmethylimipramine did not produce a statistically significant increase in extracellular norepinephrine. Both daily electroshock and daily desmethylimipramine produced down regulation of β-adrenoceptors in the hippocampus and the frontal cortex. Chronic electroshock caused up regulation of α-adrenoceptors in the frontal cortex but not in the hippocampus while chronic desmethylimipramine administration did not alter α-adrenoceptors in either structure. Depletion of norepinephrine with reserpine or with 6-hydroxydopamine prevented the down regulation of β-adrenoceptors while depletion of this neurotransmitter did not prevent the electroshock-induced up regulation of α-adrenoceptors in the frontal cortex. These data suggest that down regulation of β-adrenoceptors is mediated through increases in extracellular norepinephrine. In contrast, up regulation of α-adrenoceptors appears to be independent of norepinephrine release and does not require the presence of noradrenergic neurons in order to be induced by electroshock.

SSRI normalizes β-adrenoceptor down-regulation in rat brain under chronic unpredictable stress : T. Matsushita, M. Asakura, Y. Sasuga, N. Bodaiji, K. Osada, S. Miyamoto, J. Imafuku, H. Hasegawa, A. Aoba. Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216 Japan

SSRI normalizes β-adrenoceptor down-regulation in rat brain under chronic unpredictable stress : T. Matsushita, M. Asakura, Y. Sasuga, N. Bodaiji, K. Osada, S. Miyamoto, J. Imafuku, H. Hasegawa, A. Aoba. Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216 Japan

Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?

Wistar-Kyoto rats are reported to be very passive in the forced swimming test. In addition, they did not respond to acute administration of either desipramine or 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT). In the present experiment, it was studied whether or not they respond to acute and chronic administration of imipramine and the possible relationship to down-regulation of β-adrenoceptors and 5-HT 1 and 5-HT 2 receptors. Sprague-Dawley and Brown–Norway rats were included in the study as it has been previously demonstrated that the two strains respond to acute desipramine and 8-OH-DPAT administration. Whereas acute administration of imipramine (15 mg/kg, three times in a 24 h period) significantly increased struggling and reduced immobility in Sprague-Dawley and Brown Norway rats, Wistar-Kyoto rats failed to respond to the drug. After chronic treatment with imipramine (13 days plus the acute imipramine treatment at the end of the treatment period), the three strains showed a positive response that was always significantly greater than the response to acute administration, but which was much lower in Wistar-Kyoto than in the other two strains. Down-regulation of both β-adrenoceptors and 5-HT 2 receptors was observed 24 h after the forced swimming test in acutely and chronically imipramine-treated rats of the three strains, except that in Sprague-Dawley rats β-adrenoceptors did not change after acute imipramine. No significant decrease in 5-HT 1 binding sites was observed in any strain. Acute imipramine administration caused a similar anorexia in Wistar-Kyoto as in the other strains and at least the same level of down-regulation of β-adrenoceptors and 5-HT 2 receptors. In addition, serum imipramine levels on the day after the last drug administration were higher in Wistar-Kyoto than in the other two strains. All these data suggest that the subsensitivity to imipramine observed in Wistar-Kyoto rats: (i) can not be primarily explained by pharmacokinetic differences, and (ii) does not appear to be related to the monoaminergic systems. Wistar-Kyoto rats might be therefore not only a good animal model of depressive-like (passive) behavior, but also a model of resistance to antidepressants which could be used to investigate the neurobiological basis of such resistance, which is also observed in some depressed patients.

The cardiac beta-adrenoceptor-mediated signaling pathway and its alterations in hypertensive heart disease.

Hypertension-induced cardiac hypertrophy is a predictor of the development of cardiac failure. It is unknown which cellular markers contribute to the progression from compensated hypertrophy to failure. In heart failure, several signal transduction defects leading to adenylate cyclase desensitization have been demonstrated, such as beta-adrenoceptor downregulation, increase of inhibitory G protein expression, and uncoupling of beta-adrenergic receptors, presumably by an increase of receptor kinase activity. In hypertensive heart disease, most studies have been performed in rat models of hypertension. As in heart failure, heterologous adenylyl cyclase desensitization occurs. The mechanisms are often different between the heterogeneous models for acquired and genetic hypertension, but Gi protein alterations and beta-adrenoceptor downregulation have been observed frequently. The underlying mechanism for desensitization is most likely a sympathetic activation in established hypertension rather than genetic alterations of signal transduction proteins. The data available suggest that beta-adrenergic desensitization could represent a mechanism that contributes to the progression from hypertrophy to failure. The key question remains whether those hypertensive patients who develop heart failure are more prone to beta-adrenergic desensitization or whether early intervention to reduce sympathetic activity is more effective in preventing or delaying the transition from compensated hypertrophy to overt failure.

Relationship between Desensitization and Downregulation of β-Adrenoceptors in Cardiac Tissues after Prolonged In Vivo Infusion of T-0509, a β1-Adrenoceptor Agonist

To examine the contribution of β-adrenoceptor (βAR) downregulation to desensitization of βARs by chronic administration of a βAR agonist, we compared the adenylyl cyclase (AC) activities in two kinds of cardiac ventricular membranes with decreased available βARs: one was derived from rats infused with a selective β1AR agonist, T-0509 [( — )-(R)-1-(3,4-dihydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)-amino]ethanol hydrochloride], in vivo (40 μg/kg/hr, s.C. for 6 days); and the other was obtained from treatment of control membranes with an irreversible βAR antagonist, bromoacetyl alprenolol methane (BAAM). T-0509 infusion decreased the densities of βARs and β2ARs by 26% and 32%, respectively, and reduced the maximal isoproterenol-stimulated AC activity by 53%. The amount of GSα and Giα proteins in the membranes was not significantly changed by T-0509 infusion. To make preparations that mimic the T-0509-induced downregulation, we treated the control membranes with 100 nM BAAM in vitro. The BAAM treatment decreased the Bmax value of [125I]iodocyanopindolol for βARs and β2ARs by 29% and 36%, respectively, whereas it reduced the maximal effect of isoproterenol on AC activity only by 37%. These results suggest that downregulation of βARs cannot fully account for the desensitization by chronic treatment of T-0509 and that other mechanism(s) can play a significant role in the loss of responsiveness.

Beta-blockade prevents ventricular failure following aortic regurgitation in rabbits.

This study investigated the effects of chronic beta-blockade on the pathophysiology of heart failure following induction of aortic regurgitation (AR). Nine rabbits with AR were administered propranolol continuously for 7 days (AR+P), 8 rabbits with AR received vehicle for the same period (AR+C), and 7 rabbits underwent sham operation. Cardiac output was lower and the left-ventricular end-diastolic pressure was higher in AR+C than in sham-operated rabbits, but there was no difference in the right-ventricular end-diastolic pressure between the two groups. Down-regulation of beta-adrenoceptors was observed in the left ventricle, but not in the right ventricle. All of these variables were reversed in AR+P. In left-ventricular failure produced by AR, (1) the augmentation of adrenergic drive occurred selectively in the left ventricle, and (2) propranolol blunted adrenergic drive and played a protective role against myocardial damage.