Stimulation Of Β1 Research Articles

Compartmentation of β2 -adrenoceptor stimulated cAMP responses by phosphodiesterase types 2 and 3 in cardiac ventricular myocytes.

In cardiac myocytes, cyclic AMP (cAMP) produced by both β1 - and β2 -adrenoceptors increases L-type Ca2+ channel activity and myocyte contraction. However, only cAMP produced by β1 -adrenoceptors enhances myocyte relaxation through phospholamban-dependent regulation of the sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2). Here we have tested the hypothesis that stimulation of β2 -adrenoceptors produces a cAMP signal that is unable to reach SERCA2 and determine what role, if any, phosphodiesterase (PDE) activity plays in this compartmentation. The cAMP responses produced by β1 -and β2 -adrenoceptor stimulation were studied in adult rat ventricular myocytes using two different fluorescence resonance energy transfer (FRET)-based biosensors, the Epac2-camps, which is expressed uniformly throughout the cytoplasm of the entire cell and the Epac2-αKAP, which is targeted to the SERCA2 signalling complex. Selective activation of β1 - or β2 -adrenoceptors produced cAMP responses detected by Epac2-camps. However, only stimulation of β1 -adrenoceptors produced a cAMP response detected by Epac2-αKAP. Yet, stimulation of β2 -adrenoceptors was able to produce a cAMP signal detected by Epac2-αKAP in the presence of selective inhibitors of PDE2 or PDE3, but not PDE4. These results support the conclusion that cAMP produced by β2 -adrenoceptor stimulation was not able to reach subcellular locations where the SERCA2 pump is located. Furthermore, this compartmentalized response is due at least in part to PDE2 and PDE3 activity. This discovery could lead to novel PDE-based therapeutic treatments aimed at correcting cardiac relaxation defects associated with certain forms of heart failure.

\u03b21 integrin, ILK and mTOR regulate collagen synthesis in mechanically loaded tendon cells

Tendons are specialized tissues composed primarily of load-responsive fibroblasts (tenocytes) embedded in a collagen-rich extracellular matrix. Habitual mechanical loading or targeted exercise causes tendon cells to increase the stiffness of the extracellular matrix; this adaptation may occur in part through collagen synthesis or remodeling. Integrins are likely to play an important role in transmitting mechanical stimuli from the extracellular matrix to tendon cells, thereby triggering cell signaling pathways which lead to adaptive regulation of mRNA translation and protein synthesis. In this study, we discovered that mechanical stimulation of integrin β1 leads to the phosphorylation of AKT, an event which required the presence of integrin-linked kinase (ILK). Repetitive stretching of tendon cells activates the AKT and mTOR pathways, which in turn regulates mRNA translation and collagen expression. These results support a model in which integrins are an upstream component of the mechanosensory cellular apparatus, regulating fundamental tendon cell functions relevant to exercise-induced adaptation and mechanotherapy.

Elucidating the Molecular Determinants of Pro-arrhythmic Proclivities of Beta-blocking Drugs

Sympathetic stimulation of cardiac β1 and β2 adrenergic receptors (β1AR and β2AR) is essential for controlling heart rhythm and vascular tone. While endogenous neurotransmitters like norepinephrine activate these receptors in normal physiological conditions, a variety of their antagonists, called beta-blockers, are utilized to downregulate their activity and thus reduce heart rate, lower blood pressure, and prevent arrhythmias. However, these drugs are capable of binding to cardiac ion channels, eliciting deleterious side-effects that remain poorly understood.

An Exploratory Study in Healthy Male Subjects of the Mechanism of Mirabegron-Induced Cardiovascular Effects.

To explore the role of β1 -adrenoceptors (ARs) in the heart rate response to the selective β3 -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective β1/2 -AR antagonist propranolol (160 mg), the selective β1 -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected. Mirabegron increased heart rate and systolic blood pressure and reduced stroke volume, whereas cardiac output and diastolic blood pressure were unaffected. Mirabegron-induced changes were attenuated by propranolol and bisoprolol. The data indicate that mirabegron has a positive chronotropic effect at supratherapeutic concentrations, which is at least partly mediated by stimulation of β1 -AR.

Stimulation of β1- and β2-adrenoceptors dilates retinal blood vessels in rats

Our previous studies have demonstrated that adrenaline dilates rat retinal arterioles by stimulating propranolol-sensitive β-adrenoceptors and β3-adrenoceptors, and selective stimulation of β2- or β3-adrenoceptors causes retinal vasodilator responses. In the present study, we compared the effects of β1- and β2-adrenoceptor stimulation on rat retinal arterioles in vivo. Rat ocular fundus images were captured using an original high-resolution digital fundus camera. Diameters of retinal arterioles contained in the images were measured. Systemic blood pressure and heart rate were recorded continuously. Denopamine, a β1-adrenoceptor agonist, increased the diameter of retinal arterioles and heart rate, and produced a small but statistically insignificant decrease in mean arterial pressure. CGP20712A, a β1-adrenoceptor antagonist, but not ICI118551, a β2-adrenoceptor antagonist, significantly prevented denopamine-induced retinal vasodilator and heart rate responses. Salbutamol, a β2-adrenoceptor agonist, increased the diameter of retinal arterioles and decreased mean arterial pressure without significantly changing heart rate. The effects of salbutamol were significantly prevented by ICI118551, but not by CGP20712A. These results suggest that stimulation of β1- and β2-adrenoceptors dilates retinal blood vessels and indicate that all three β-adrenoceptor subtypes (β1, β2, and β3) may be involved in the retinal vasodilator response to adrenaline in rats.

Ractopamine, a livestock feed additive, is a full agonist at trace amine-associated receptor 1.

Ractopamine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC's physiological actions begin with its stimulation of β1- and β2-adrenergic receptor-mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC's psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for intracellular cAMP, we found that RAC and p-tyramine (TYR) produced concentration-dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse trace amine-associated receptor 1 (mTAAR1), which was completely reversed by the trace amine-associated receptor 1 (TAAR1)-selective antagonist EPPTB [N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human β2-adrenergic receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human β2-adrenergic receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug.

Synergistic, but not separate, stimulation of accumbal β1- and β2-adrenoceptors alters the accumbal dopamine efflux in freely moving rats

The effects of intra-accumbal infusion of selective agonists for the β-adrenoceptor subtypes on the noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats were investigated, using in vivo microdialysis. Neither β1-(dobutamine: 0.06 and 0.12pmol) nor β2-adrenoceptor agonist (salbutamol: 0.36 and 3.6pmol) altered the basal noradrenaline and dopamine efflux in the nucleus accumbens. Co-administration of 0.06pmol of dobutamine with salbutamol (3.6pmol) did not affect the noradrenaline levels, but it increased the dopamine efflux to approximately 120%. Co-administration of 0.12pmol of dobutamine with salbutamol (0.36 or 3.6pmol) also increased DA efflux to approximately 120% without affecting noradrenaline levels. The non-selective β-adrenoceptor antagonist l-propranolol (1200pmol) that did not alter the basal noradrenaline and dopamine levels, suppressed the dopamine efflux, induced by co-administration of dobutamine (0.12pmol) and salbutamol (3.6pmol). The doses mentioned are the total amount of drug over the 60-min infusion period. The present results support our previously reported conclusion that stimulation of accumbal β-adrenoceptors which are suggested to be postsynaptically located on accumbal dopaminergic terminals, can enhance the dopamine efflux in the nucleus accumbens. The present study also provides in vivo neurochemical evidence that concomitant, but not separate, activation of accumbal β1- and β2-adrenoceptors synergistically increases the accumbal dopamine efflux.

Age-related up-regulation of β3-adrenergic receptor in heart-failure rats

Stimulation of β1- and β2-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the β3-AR is also expressed in the heart and that its stimulation leads to negative inotropic effects. The aim of this study was to investigate the expression of β3-AR in age-related heart-failure rats and its relevance to left ventricular dysfunction. Aging male Wistar rats were divided into young and aging groups according to age, and each group included sham-operation and heart-failure subgroups. Left ventricular end-diastolic pressure (LVEDP) and the ratio of left ventricular weight to body weight (LV/BW) were significantly higher for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). However, the left ventricular end-systolic pressure (LVESP) and the maximal rate of rise or fall of left ventricular pressure were all significantly lower for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). β3-AR protein levels increased significantly when heart failure worsened in aging rats. These results suggest that β3-AR expression in age-related heart-failure rats and left ventricular function were highly correlated.

β-Arrestin–dependent activation of Ca2+/calmodulin kinase II after β1–adrenergic receptor stimulation

Ca2+/calmodulin kinase II (CaMKII) plays an important role in cardiac contractility and the development of heart failure. Although stimulation of β1–adrenergic receptors (ARs) leads to an increase in CaMKII activity, the molecular mechanism by which β1-ARs activate CaMKII is not completely understood. In this study, we show the requirement for the β1-AR regulatory protein β-arrestin as a scaffold for both CaMKII and Epac (exchange protein directly activated by cAMP). Stimulation of β1-ARs induces the formation of a β-arrestin–CaMKII–Epac1 complex, allowing its recruitment to the plasma membrane, whereby interaction with cAMP leads to CaMKII activation. β-Arrestin binding to the carboxyl-terminal tail of β1-ARs promotes a conformational change within β-arrestin that allows CaMKII and Epac to remain in a stable complex with the receptor. The essential role for β-arrestin and identification of the molecular mechanism by which only β1-ARs and not β2-ARs activate CaMKII significantly advances our understanding of this important cellular pathway.

NO production and eNOS phosphorylation induced by epinephrine through the activation of β-adrenoceptors

Epinephrine plays a key role in the control of vasomotor tone; however, the participation of the NO/cGMP pathway in response to beta-adrenoceptor activation remains controversial. To evaluate the involvement of the endothelium in the vascular response to epinephrine, we assessed NO production, endothelial NO synthase phosphorylation, and tissue accumulation of cGMP in the perfused arterial mesenteric bed of rat. Epinephrine elicited a concentration-dependent increase in NO (EC(50) of 45.7 pM), which was coupled to cGMP tissue accumulation. Both NO and cGMP production were blocked by either endothelium removal (saponin) or NO synthase inhibition (N(omega)-nitro-L-arginine). Blockade of beta(1)- and beta(2)-adrenoceptors with 1 microM propranolol or beta(3)-adrenoceptor with 10 nM SR 59230A displaced rightward the concentration-NO production curve evoked by epinephrine. Selective stimulation of beta(1)-, beta(2)-, or beta(3)-adrenoceptors also resulted in NO and cGMP production. Propranolol (1 microM) inhibited the rise in NO induced by isoproterenol or the beta(2)-adrenoceptor agonists salbutamol, terbutaline, or fenoterol. Likewise, 10 nM SR 59230A reduced the effects of the beta(3)-adrenoceptor agonists BRL 37344, CGP 12177, SR 595611A, or pindolol. The NO production induced by epinephrine and BRL 37344 was associated with the activation of the phosphatidylinositol 3-kinase/Akt pathway and phosphorylation of eNOS in serine 1177. In addition, in anaesthetized rats, bolus administration of isoproterenol, salbutamol, or BRL 37344 produced NO-dependent reductions in systolic blood pressure. These findings indicate that beta(1)-, beta(2)-, and beta(3)-adrenoceptors are coupled to the NO/cGMP pathway, highlighting the role of the endothelium in the vasomotor action elicited by epinephrine and related beta-adrenoceptor agonists.

Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix

Background/Aims: The hepatitis B virus HBx protein is associated with the development of hepatocellular carcinoma (HCC). However, its possible contribution to tumor spreading has not been explored. The migration of tumor cells through the extracellular matrix (ECM) represents a crucial step in tumor metastasis. Our aim was to study the effect of HBx on the integrin-mediated cell–ECM interaction, and its possible consequences for cell migration.Methods: Cell–ECM interaction was evaluated by static adhesion experiments, using blocking and stimulating anti-β1 integrin mAbs. ECM receptor expression was analyzed by flow cytometry. The cellular distribution of the activated β1 integrin subunit was determined by immunofluorescence analysis, and cell motility was determined by wound-healing assays.Results: HBx-bearing cells showed decreased adhesion to fibronectin, which correlated with a decreased expression of the α5 integrin subunit. The activated β1 subunit was redistributed to the tips of pseudopodial protrusions of HBx-bearing cells, whereas it was evenly localized in the control cells. HBx-induced cell migration was abrogated by irreversible stimulation of β1 integrins.Conclusions: These results suggest that HBx might play a role in tumor spreading by modulating the adhesion–deadhesion balance of the cells in the primary tumor site and favoring integrin-mediated cell migration.

Both beta(2)- and beta(1)-adrenergic receptors mediate hastened relaxation and phosphorylation of phospholamban and troponin I in ventricular myocardium of Fallot infants, consistent with selective coupling of beta(2)-adrenergic receptors to G(s)-protein.

In adult human heart, both beta(1)- and beta(2)-adrenergic receptors mediate hastening of relaxation; however, it is unknown whether this also occurs in infant heart. We compared the effects of stimulation of beta(1)- and beta(2)-adrenergic receptors on relaxation and phosphorylation of phospholamban and troponin I in ventricle obtained from infants with tetralogy of Fallot. Myocardium dissected from the right ventricular outflow tract of 27 infants (age range 21/2 to 35 months) with tetralogy of Fallot was set up to contract 60 times per minute. Selective stimulation of beta(1)-adrenergic receptors with (-)-norepinephrine (NE) and beta(2)-adrenergic receptors with (-)-epinephrine (EPI) evoked phosphorylation of phospholamban (at serine-16 and threonine-17) and troponin I and caused concentration-dependent increases in contractile force (-log EC(50) [mol/L] NE 5.5+/-0.1, n=12; EPI 5.6+/-0.1, n=13 patients), hastening of the time to reach peak force (-log EC(50) [mol/L] NE 5.8+/-0.2; EPI 5.8+/-0.2) and 50% relaxation (-log EC(50) [mol/L] NE 5.7+/-0.2; EPI 5.8+/-0.1). Ventricular membranes from Fallot infants, labeled with (-)-[(125)I]-cyanopindolol, revealed a greater percentage of beta(1)- (71%) than beta(2)-adrenergic receptors (29%). Binding of (-)-epinephrine to beta(2)-receptors underwent greater GTP shifts than binding of (-)-norepinephrine to beta(1)-receptors. Despite their low density, beta(2)-adrenergic receptors are nearly as effective as beta(1)-adrenergic receptors of infant Fallot ventricle in enhancing contraction, relaxation, and phosphorylation of phospholamban and troponin I, consistent with selective coupling to G(s)-protein.

Central effects of different β-blocking agents in spontaneously hypertensive rats

In the normal heart the ratio of β1/β2-receptors in both atria and ventricles is about 75:25; in the failing heart the ratio is about 60:40. Stimulation of either β1- or β2-receptors results in a positive chronotropic and inotropic response. In the periphery, with the exception of lipolysis, renin release, control of intraocular pressure and intestinal relaxation, β2-related activity predominates. The nature of the β2-receptor is being unravelled and it has now been cloned. The gb-receptor antagonist is ‘anchored’ via disulfide bonding. Subsequent events involve the regulatory protein guanine nucleotide which couples the receptor to adenylate cyclase. β-receptor density may by up- or down-regulated. β-stimulation down-regulates (uncouples and internalizes or sequestrates) and β-antagonism up-regulates β-receptor numbers, but the functional implications of such changes are not always clear. A partial agonist occupies a receptor site and competitively inhibits the full agonist (e.g. noradrenaline). A partial agonist differs from a full agonist in that maximal response of a tissue is less. When background sympathetic activity is absent or very low a partial agonist will act as an agonist, e.g. increase heart rate, but when background tone is high the partial agonist will behave functionally as an antagonist, e.g. decrease heart rate. In animals partial agonist activity (PAA) can be assessed in many ways. In the catecholamine-depleted (reserpine or syrosingopine), vagotomized or pithed, intact animal β-activity can be assessed via changes in heart rate, cardiac contractility and atrioventricular conduction. Isolated organs can also be used such as atria, papillary muscle, tracheal, mesenteric artery and uterine preparations. The choice of animals is important as marked species differences in response can occur. In man assessing PAA is difficult due to the presence of an intact sympathetic system: the problem can be overcome by autonomic blockade of constrictor and vagal reflexes with prazosin, clonidine and atropine but leaving the β-receptor mediated responses unimpaired. β1 and β2-selective PAA can also be gauged via an increased sleeping heart rate (basal sympathetic tone) in the presence and absence of a β1 and β2-selective antagonist. β1-selective PAA can also cause an increase in resting systolic blood pressure. β2-selective PAA may be further assessed by a fall in DBP, increased blood flow, fall in peripheral resistance or increased finger tremor. Isolated human tissue such as lymphocytes (β2) or myocardial biopsy material, (β1 and β2) can be used to assess down-regulation of β-receptor density as a measure of PAA. Expression of PAA depends upon receptor affinity and tissue response (β-receptors are coupled to the effector enzyme via a guanine nucleotide regulatory protein) and the efficiency of coupling determines whether or not the drug acts as an antagonist (zero coupling), partial agonist or full agonist. For any one agent this may vary from tissue to tissue and from species to species. In man, β1-selective PAA, depending on its degree, will diminish or abolish antihypertensive efficacyat rest; in contrast, β2-selective PAA is associated with a fall in resting blood pressure due to peripheral vasodilation. The cardiovascular pharmacodynamic and clinical implications of PAA are discussed, as exemplified by a nonselective agent with nonselective PAA (pindolol); a nonselective agent with primarily β2-selective PAA (dilevalol); a β1-selective agent with low/moderate PAA (epanolol); and a β1-selective agent with moderate/high PAA (xamoterol). Also discussed are the effects of the above four types of PAA on various adverse reactions, i.e. fatigue, cold peripheries, heart failure, hypotension, bronchoconstriction, CNS side effects, tremor, rebound phenomena and plasma lipid changes.

Oxytocics, Tocolytics, and Prostaglandins

Summary Tocolytic and oxytocic therapies are widely used in contemporary obstetric practice. The anesthesiologist is often called upon to participate in the care of patients who are receiving uterotonic medications. In addition to their effects on the myometrium, each of these drugs has direct and indirect effects on a variety of organ systems. Oxytocin stimulates the uterus to contract via changes in intracellular calcium. Its direct vasodilating and antidiuretic properties lead to the possibility of hypotension or water overload. Ergotamines used for postpartum uterine atony carry the risk of generalized vasoconstriction and hypertension that may be life threatening. Prostaglandins of both the E and F classes stimulate uterine contractions. Side effects include nausea, vomiting, diarrhea, and hyperpyrexia. The two classes differ in their hemodynamic effects: prostaglandin E leads to a decrease in SVR and blood pressure with no change or a decrease in pulmonary vascular resistance; PGF2α generates an increase in blood pressure, heart rate, cardiac output, and pulmonary vascular resistance. Prostaglandin F2α also stimulates bronchoconstriction. The most common tocolytics are β-sympathomimetics and magnesium sulfate. The side effects of β-adrenergic therapy arise from stimulation of both β1 and β2 receptors. Inotropic and chronotropic effects on the myocardium may be sufficient to cause ischemia. Pulmonary edema is associated with β-mimetic therapy. Glucose and electrolyte balance should be monitored during treatment. Magnesium sulfate decreases uterine tone probably by antagonizing calcium at the cellular level. As plasma levels increase, progressive depression of the respiratory, CNS, and cardiac systems follows. Toxic levels are more likely in the patient with renal function impairment. Calcium serves to reverse magnesium toxicity. Because of its effects at the neuromuscular junction, magnesium potentiates both depolarizing and nondepolarizing muscle relaxants. Familiarity with the range of effects of these drugs should assist the anesthesiologist in providing safe passage for the pregnant patient and her fetus from the antepartum to postpartum period.

The Role of Cardiac β1- and β2-Adrenoceptor Stimulation in Heart Failure

Substantial evidence has accumulated that in the human heart both β1- and β2-adrenoceptors coexist. As a rule. the amount of β2-adrenoceptors is higher in the atria (about 30% of the total β-adrenoceptor population) than in the ventricular myocardium (about 20%). Both β1- and β2-adrenoceptors couple to adenylate cyclase and mediate positive inotropic effects of isoproterenol and epinephrine on isolated. electrically driven cardiac preparations. In the atria. stimulation of both β1- and β2-adrenoceptors causes maximal increases in contractile force: in the ventricular myocardium. however. only β1-adrenoceptor stimulation maximally increases contractile force. whereas β2-adrenoceptor stimulation evokes only submaximal increases. On the other hand. norepinephrine induces its positive inotropic effect on atrial and ventricular preparations solely via β1-adrenoceptor stimulation. Because norepinephrine is the main transmitter of the human sympathetic nervous system. this indicates that under normal physiological conditions. the heart rate and contractility are under the control of cardiac β1-adrenoceptors. whereas cardiac β2-adrenoceptors play only a minor role. if at all. However, in situations of stress, when large amounts of epinephrine (acting at both β1- and β2-adrenoceptors with the same affinity) are released from the adrenal medulla. activation of cardiac β2-adrenoceptors may contribute to an additional increase in heart rate and/or contractility. In chronic heart failure. cardiac β-adrenoceptor function decreases (presumably due to endogenous “downregulation” by the elevated catechol-amines). and this decrease is related to the severity of the disease (judged clinically by NYHA functional class). However, cardiac β1- and β2-adrenoceptors seem to be differentially affected in different kinds of heart failure: in end-stage dilated cardiomyopathy. β1-adrenoceptors selectively decrease. whereas β2-adrenoceptors are nearly normal. Under these (pathological) conditions. β2-adrenoceptors may substitute for the loss in β1-adrenoceptors. thereby maintaining contractility. at least partially. On the other hand, in endstage ischemic cardiomyopathy. tetralogy of Fallot, and mitral valve disease. both β1- and β2-adrenoceptors concomitantly decrease. The reason for this differential regulation of cardiac β1- and β2-adrenoceptors in different forms of heart failure remains to be elucidated.

SOME NEW POSITIVE INOTROPIC AGENTS

In the search for new effective positive inotropic agents for the treatment of congestive heart failure (CHF), interest has focused mainly on two groups of agents namely adrenoceptor agonists and drugs inhibiting phosphodiesterase. Common for drugs belonging to both groups is that their positive inotropic effects seem to involve an increase in the intracellular concentration of cyclic AMP. Drugs acting by stimulation of beta 1- and/or beta 2-adrenoceptors (e.g. dopamine, dobutamine, prenalterol, pirbuterol, salbutamol, terbutaline, fenoterol) have initial beneficial effects, but seem to be ineffective for long-term treatment. This has been suggested to be due to desensitization of the beta-adrenoceptors, and means, if this effect can be definitely established, that beta-adrenoceptor stimulation should be restricted to the acute treatment of CHF. Among drugs inhibiting phosphodiesterase, sulmazole, amrinone, milrinone, and fenoximone all have been shown to improve cardiac performance in patients with CHF during short-term treatment. However, results of long-term treatment with most of these drugs seem less encouraging. It has been suggested that these drugs may not be an effective approach to treatment of patients with CHF, since even if it is possible to achieve short-term gains, the long-term effects on the myocardium may be detrimental. Their ultimate place in the treatment of CHF remains to be established.