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Biomedical subjects

J D Port

Publications and source records attributed to J D Port.

At least 37 records · Page 2Linked to original sources

Neuropoiesis: proposal for a connectionistic neurobiology.

Given current assumptions about the biology of neural organization, some connectionists believe that it may not be possible to accurately model the brain's neural architecture. We have identified five restrictive neurobiological dogmas that we believe have limited the exploration of more fundamental correlations between computational and biological neural networks. We postulate that: 1) the dendritic tree serves as a synapse storage device rather than a simple summation device; 2) connection strength between neurons depends on the number and location of synapses of similar weight, not on synapses of variable weights; 3) axonal sprouting occurs regularly in adult organisms; 4) the postsynaptic genome directly controls the presynaptic cell via mRNA, rather than indirectly by the expression of NCAMs, reverse neurotransmitters, etc.; 5) dendritic spines serve a trophic function by controlling development of new sprouts via a process we term retroduction. We entertain an alternative formulation of a computational neural element that is fully consistent with modern neuroscience research. We then show how our model neuron can learn under Hebbian conditions, and extend the model to explain non-Hebbian, one-trial learning. This work is significant because by stretching the theoretical boundaries of modern neuroscience, we show how connectionists can potentially create new, more biologically-based neural elements which, when, interconnected into networks, exhibit not only properties of existing backpropagation networks, but other physiological properties as well.

Adult↗

Age-related changes in beta-adrenergic neuroeffector systems in the human heart.

BACKGROUND: Aging decreases cardiac beta-adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the beta-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts. METHODS AND RESULTS: Twenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of beta-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total beta-receptor density assessed by maximum [125I]ICYP binding (beta max) was reduced in older hearts by 37% in left ventricles and 31% in right ventricles (both P < .05), and the downregulation was confined to the beta 1 subtype (r = .78 left ventricle beta 1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P < .05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (beta 2-agonist), and by the G protein-sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P < .05) with cholera toxin (Gs) but no difference with pertussis toxin (Gi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts. CONCLUSIONS: There is a profound decrease in cardiac beta-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of beta 1-receptors, uncoupling of beta 2-receptors, and abnormal G protein-mediated signal transduction.

Adenylyl Cyclases↗

Up-regulation of beta 2-adrenergic receptors in previously transplanted, denervated nonfailing human hearts.

OBJECTIVES: The purpose of this study was to examine beta-adrenergic receptor signal transduction in denervated, previously transplanted human ventricular myocardium. BACKGROUND: In model systems, surgical denervation typically results in both presynaptic and postsynaptic supersensitivity in beta-adrenergic receptor pathways and alteration in G protein-mediated signal transduction. METHODS: We examined beta-adrenergic receptor signal transduction in the left and right ventricles removed from nine subjects with a previous transplant and surgical denervation 25 +/- 4 months after their first transplantation. Twenty-six hearts removed from organ donors served as control hearts. RESULTS: Total beta-adrenergic receptor density and stimulation of muscle contraction in isolated right ventricular trabeculae by the nonselective agonist isoproterenol were similar in the transplant and donor groups. Beta 1-receptor density was not different in the left ventricles of the two groups but tended to be reduced (by 29%, p = 0.09) in transplant right ventricles. By contrast, beta 2-receptor density was higher in transplant left and right ventricles relative to the respective values in donor ventricles by 33% in left ventricles and 97% in right ventricles (both p < 0.05). Isoproterenol, which in particulate fractions of human heart stimulates adenylyl cyclase primarily via beta 2-receptors, produced a greater increase in cyclic adenosine monophosphate generation in membranes prepared from transplant left ventricles and right ventricles compared with donors. In contrast, guanosine 5'-[beta,gamma-imido]triphosphate, sodium fluoride and forskolin, which stimulate adenylyl cyclase through nonreceptor/G protein-sensitive mechanisms, yielded similar degrees of adenylyl cyclase stimulation in the two groups, and both pertussis toxin- and cholera toxin-catalyzed adenosine diphosphate ribosylation were not altered in transplanted left ventricles. CONCLUSIONS: These data indicate that the transplanted human heart exhibits an up-regulation of functional beta 2-adrenergic receptors.

Adenylyl Cyclases↗

Reduced beta 1 receptor messenger RNA abundance in the failing human heart.

Heart failure in humans is characterized by alterations in myocardial adrenergic signal transduction, the most prominent of which is down-regulation of beta 1-adrenergic receptors. We tested the hypothesis that down-regulation of beta 1-adrenergic receptors in the failing human heart is related to decreased steady-state levels of beta 1 receptor mRNA. Due to the extremely low abundance of beta 1 receptor mRNA, measurements were possible only by quantitative polymerase chain reaction (QPCR) or by RNase protection methods. Because the beta 1 receptor gene is intronless and beta 1 receptor mRNA abundance is low, QPCR yielded genomic amplification in total RNA, and mRNA measurements had to be performed in poly (A)(+)-enriched RNA. By QPCR the concentration of beta 1 receptor mRNA varied from 0.34 to 7.8 x 10(7) molecules/microgram poly(A)(+)-enriched RNA, and the assay was sensitive to 16.7 zeptomol. Using 100-mg aliquots of left ventricular myocardium obtained from organ donors (nonfailing ventricles, n = 12) or heart transplant recipients (failing ventricles, n = 13), the respective beta 1 mRNA levels measured by QPCR were 4.2 +/- 0.7 x 10(7)/micrograms vs. 2.10 +/- 0.3 x 10(7)/micrograms (P = 0.006). In these same nonfailing and failing left ventricles the respective beta 1-adrenergic receptor densities were 67.9 +/- 6.9 fmol/mg vs. 29.6 +/- 3.5 fmol/mg (P = 0.0001). Decreased mRNA abundance in the failing ventricles was confirmed by RNase protection assays in total RNA, which also demonstrated a 50% reduction in beta 1 message abundance. We conclude that down-regulation of beta 1 receptor mRNA contributes to down-regulation of beta 1 adrenergic receptors in the failing human heart.

Antisense Elements (Genetics)↗

Cross-talk between tyrosine kinase and G-protein-linked receptors. Phosphorylation of beta 2-adrenergic receptors in response to insulin.

Protein kinases play a pivotal role in the propagation and modulation of transmembrane signaling pathways. Two major classes of receptors, G-protein-linked and tyrosine kinase receptors not only propagate signals but also are substrates for phosphorylation in response to stimulation by agonist ligands. Insulin (operating via tyrosine kinase receptors) and catecholamines (operating by G-protein-linked receptors) are counterregulatory with respect to lipid and carbohydrate metabolism. How, on a cellular level, these two distinct classes of receptors may cross-regulate each other remains controversial. In the present work we identify a novel cross-talk between members of two distinct classes of receptors, tyrosine kinase (insulin) and G-protein-linked (beta-adrenergic) receptors. Treatment of DDT1 MF-2 hamster vas deferens smooth muscle cells with insulin promoted a marked attenuation (desensitization) of beta-adrenergic receptor-mediated activation of adenylylcyclase. Measured by immune precipitation of beta 2-adrenergic receptors from cells metabolically labeled with [32P]orthophosphate, the basal state of receptor phosphorylation was increased 2-fold by insulin. Phosphoamino acid analysis revealed that for insulin-stimulated cells, the beta 2-adrenergic receptors showed increased phosphorylation on tyrosyl and decreased phosphorylation on threonyl residues. Phosphorylation of the beta-adrenergic receptor was rapid and peaked at 30 min following stimulation of cells by insulin. beta-Adrenergic receptor phosphorylation and attenuation of catecholamine-sensitive adenylylcyclase provide a biochemical basis for the counterregulatory effects of insulin upon catecholamine action.

Animals↗

Beta-adrenergic agonists that down-regulate receptor mRNA up-regulate a M(r) 35,000 protein(s) that selectively binds to beta-adrenergic receptor mRNAs.

In an effort to explore the molecular basis for agonist-induced destabilization of beta-adrenergic receptor mRNA, we investigated the nature of RNA-binding proteins both in untreated and agonist-treated DDT1-MF2 smooth muscle cells. Messenger RNAs for the alpha 1b-, beta 1-, and beta 2-adrenergic receptors as well as for beta-globin were transcribed in vitro, incubated with cytosolic fractions, covalently cross-linked by short-wave UV light, and analyzed by SDS-polyacrylamide gel electrophoresis. A prominent M(r) 35,000 radiolabeled protein(s) with the following characteristics was identified: (i) binds selectively to beta 1- and beta 2-adrenergic receptor mRNAs, both of which undergo agonist-induced down-regulation; (ii) does not bind to either alpha 1b-adrenergic receptor mRNA, which does not undergo agonist induced down-regulation, or to beta-globin mRNA; (iii) displays binding to beta 2-adrenergic receptor mRNA that is selectively competed by poly(U) RNA, but not poly(A), -(C), or -(G) RNA; and (iv) displays binding to receptor mRNA that can be competed by RNA harboring destabilizer sequences that are AU-rich and AUUUA pentamer-rich. The abundance of the M(r) 35,000 RNA-binding protein selective for beta-adrenergic receptor message, a factor we term beta ARB protein, varies inversely with the level of receptor mRNA, being induced by agonists that down-regulate receptor mRNA.

Adrenergic beta-Agonists↗

Cross-regulation between G-protein-mediated pathways. Acute activation of the inhibitory pathway of adenylylcyclase reduces beta 2-adrenergic receptor phosphorylation and increases beta-adrenergic responsiveness.

Cross-regulation from the stimulatory to the inhibitory adenylylcyclase pathways has been described (Hadcock, J. R., Ros, M., Watkins, D. C., and Malbon, C. C. (1990) J. Biol. Chem. 265, 14784-14790). More recently, persistent activation (48 h) of the inhibitory adenylylcyclase pathway has been shown to cross-regulate the stimulatory pathway (i) enhancing the maximal response of beta-adrenergic agonits, (ii) increasing the expression of beta-adrenergic receptor, and (iii) reducing the ED50 for the isoproterenol-stimulated response by 50-fold (Hadcock, J. R., Port, J. D., and Malbon, C. C. (1991) J. Biol. Chem. 266, 11915-11922). Here, we report that short term activation (60 min) of the inhibitory adenylylcyclase pathway of hamster smooth muscle DDT1MF-2 cells with the A1-adenosine receptor agonist N6-phenylisopropyladenosine (PIA) likewise enhances the stimulatory adenylylcyclase response to the beta-adrenergic agonist isoproterenol. The PIA effect was exerted at the level of the receptor, i.e., the beta-adrenergic receptor-mediated response was enhanced, whereas the guanosine 5'-O-(thiotriphosphate)- and forskolin-stimulated adenylylcyclase activities were largely unaffected. In contrast to longer term persistent activation of the inhibitory pathway, receptor number and affinity for 125I-labeled cyanopindolol were unaffected. Metabolic labeling of cells with [32P]orthophosphate and immuneprecipitation of beta-adrenergic receptors detected phosphorylation of the receptor in unstimulated cells and marked phosphorylation in cells challenged with epinephrine. When cells were challenged short term with PIA, the basal state of beta-adrenergic receptor phosphorylation was reduced by 75%. Treating cells with PIA in combination with the cAMP analog 8-(4-chlorophenylthio)adenosine cyclic AMP attenuated the enhanced receptor-mediated adenylylcyclase response observed in cells treated with PIA alone. These data suggest that short term cross-regulation from the inhibitory to stimulatory adenylylcyclase pathways results in the following: (i) decreased intracellular cAMP levels and protein kinase A activity, (ii) reduced phosphorylation of the beta 2-adrenergic receptor in the "basal" (i.e. unstimulated) state, and (iii) enhanced receptor-mediated activation of Gs.

Adenylyl Cyclases↗

The effects of dark-rearing on the electrophysiology of the rat visual cortex.

Our previous two studies have shown that dark-rearing affects the morphology and chemistry of adult rat primary visual cortex (area 17). In this study we demonstrate correlated physiological alterations with single unit recordings in the same preparation. Rats were raised from birth in either 14 h light/10 h dark (Lt/Dk) or in total darkness (Dk). At the age of 3 months, single units were recorded in area 17 of both groups. The cortical cells of Dk animals showed significantly more spontaneous activity during ambient lighting. The mean rate of randomly appearing spontaneous activity was greatly increased in Dk animals. Moreover, many cells in Dk animals also exhibited a particular type of spontaneous activity which occurred as 'bursts' of spikes, i.e. quantified groupings of fast firing spikes, separated by randomly appearing spontaneous activity. The mean number of bursts per min seen in Dk animals was also significantly more than any such activity seen in Lt/Dk animals. Visual stimuli consisted of white or dark bars moving with different orientations and directions at slow and fast speeds, and full field flashes. In response to moving stimuli, notably fewer cells were orientation- or direction tuned in dark-reared animals, and when they did respond to moving bar stimuli, the responses were of relatively longer duration. The pathologically high spontaneous activity rate, as well as lack of tuning and relatively prolonged duration of responses to moving stimuli indicate that intracortical inhibitory mechanisms are seriously compromised in both the unstimulated and stimulated states and is in agreement with our previous findings (Bakkum, B.W., Port, J.D., Cohen, R.S. and Benevento, L.A., Soc. Neursci. Abst., 15 (1989) 797) of a decreased number of synapses and GABA-containing cells in the visual cortex of the same preparation. Other evidence suggests that there may be a decrease in stimulus-bound excitatory drive. Significantly fewer cells in Dk animals were excited by all visual stimuli, and responses elicited by flashes had relatively longer 'on' latencies, relatively shorter durations, and were generally weaker. This may correlate with our finding of a significantly smaller number of perforated postsynaptic densities in the cortex of the same preparation (Bakkum, B.W., Benevento, L.A. and Cohen, R.S., J. Neurosci. Res., 23 (1991) 65-80).

Action Potentials↗

Effects of carvedilol on adrenergic receptor pharmacology in human ventricular myocardium and lymphocytes.

Carvedilol, a new beta-blocker with vasodilating properties due to alpha 1-blockade, was investigated in preparations of human ventricular myocardium. Carvedilol demonstrated a high affinity and is a slightly beta 1-selective competitive beta-blocking agent, with a KD for beta 1-receptors of approximately 4-5 nM and a mild selectivity for beta 1 vs. beta 2 receptors of 6- to 39-fold, depending on the method employed to assess subtype potency. In addition, carvedilol was also a potent alpha 1-blocking agent, with a beta 1:alpha 1 blocking relative potency of 1.7-fold. In human lymphocytes containing beta 2-receptors and in human myocardial membranes containing both beta 1- and beta 2-receptors carvedilol exhibited the unique property of guanine nucleotide modulatable binding. Despite this, no intrinsic sympathomimetic activity of carvedilol was detected in preparations of isolated human heart or in myocardial membranes. Vasodilation related to alpha 1-blockade and the lack of intrinsic activity should translate into improved tolerability and good efficacy in the treatment of heart failure.

Adrenergic beta-Antagonists↗

Receptor pharmacology of carvedilol in the human heart.

The beta-blocker and vasodilator carvedilol was examined in preparations of human ventricular myocardium. Carvedilol is a high-affinity, slightly beta 1-selective competitive beta-blocking agent, with a KD for beta 1-receptors of approximately 4-5 nM and a selectivity of sixfold to 39-fold for beta 1-receptors rather than beta 2-receptors, depending on the method used to assess subtype potency. Carvedilol also is a potent alpha 1-blocking agent, with a beta 1: alpha 1-blocking relative potency of 1.7-fold. In human lymphocytes containing beta 2-receptors and human myocardial membranes containing both beta 1- and beta 2-receptors, carvedilol exhibited the unique property of guanine nucleotide-modulatable binding. This is a property shared with bucindolol, another beta-blocker and vasodilator that is structurally similar to carvedilol. Despite the presence of guanine nucleotide-modulatable binding, no intrinsic activity of carvedilol was detected in preparations of isolated human heart or in myocardial membranes.

Adrenergic beta-Antagonists↗

Myocardial catecholamine and neuropeptide Y depletion in failing ventricles of patients with idiopathic dilated cardiomyopathy. Correlation with beta-adrenergic receptor downregulation.

BACKGROUND: Myocardial adrenergic neurotransmitters and beta-adrenergic receptor levels were measured in left and right ventricular myocardial specimens obtained from 30 patients with biventricular failure resulting from idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Nonfailing myocardium obtained from 12 organ donors provided control data. Norepinephrine, dopamine, and neuropeptide Y concentrations were significantly decreased in failing compared with nonfailing control hearts. The mean ratio of dopamine to norepinephrine and of dopamine to neuropeptide Y in failing hearts was also significantly decreased compared with nonfailing control hearts. Compared with nonfailing control hearts, Bmax and beta 1-receptor density were significantly decreased in failing hearts and there were weak but significantly positive correlations of Bmax and beta 1-adrenergic receptors with norepinephrine, dopamine, and neuropeptide Y. CONCLUSIONS: Norepinephrine and its cotransmitter neuropeptide Y are depleted in failing human ventricular myocardium. Decreased norepinephrine stores correlate weakly with beta 1-adrenergic receptor downregulation consistent with the hypothesis that norepinephrine depletion occurs in response to increased adrenergic drive. Decreased dopamine relative to norepinephrine implies that an abnormality of dopamine conversion to norepinephrine is not present in failing human heart.

Adult↗

Effect of therapeutic dopamine administration on myocardial catecholamine and neuropeptide Y concentrations in the failing ventricles of patients with idiopathic dilated cardiomyopathy.

The purpose of this study was to investigate the relationship between dopamine (DA) exposure and myocardial catecholamine and neuropeptide Y (NPY) concentrations in patients with severe congestive heart failure due to idiopathic dilated cardiomyopathy (IDC). Both nonfailing (NF) and failing (F) hearts were obtained in collaboration with the Utah Cardiac Transplantation Program and the Intermountain Organ Recovery System. The patients were stratified into five groups according to their preoperative exposure to dobutamine (DBT) and/or DA. Compared to 12 untreated, NF control hearts, norepinephrine (NE) concentrations were significantly decreased in 30 untreated F hearts obtained from patients with IDC. Norepinephrine concentrations were also significantly decreased in DA-treated NF hearts and in DA-treated F hearts compared to untreated NF and untreated or DBT-treated failing hearts, respectively. NPY concentrations were significantly decreased in untreated F hearts and were further decreased in dopamine-treated NF and DA-treated F hearts compared to untreated NF and untreated or DBT-treated F hearts. Thus, NE and NPY depletion related to DA administration was evident in both NF and F myocardium and was specific for DA in that it was not evident in patients who received the direct-acting beta-agonist inotrope DBT. These data suggest that the major inotropic mechanism of action of DA is through cardiac adrenergic neurotransmitter release. The data also provide further support for the concept that indirect acting inotropes such as DA may have limited inotropic potential in F hearts where neuronal NE has been depleted.

Adult↗

Pharmacological characterization of chick and frog beta adrenergic receptors in primary cultures of myocardial cells.

In membrane preparations derived from primary cultures of chick myocardial cells, beta adrenergic receptors modeled for a single low-affinity site for both betaxolol (beta-1-selective) and ICI 118551 (beta-2-selective) displacement of [125I]iodocyanopindolol (ICYP), indicating that the chick beta receptor is pharmacologically distinct from both mammalian beta-1 and beta-2 adrenergic receptors with respect to these antagonists. However, the highly beta-1-selective compound CGP 20712A was able to distinguish two binding sites on ICYP competition curves, a high-affinity "beta-1 site" (75%) and a low-affinity "beta-2 site" (25%). Also, in chick heart cell membranes the relative ability of agonists to displace ICYP produced a profile typical of beta-1 adrenergic receptors with a rank order of potency or efficacy of: isoproterenol greater than epinephrine = norephinephrine. When agonist-mediated adenylyl cyclase stimulation was assessed the order of potency was slightly different, isoproterenol greater than epinephrine greater than or equal to norepinephrine. Additionally, antagonism of isoproterenol stimulation of adenylyl cyclase by CGP 20712A yielded a Kb value (1.16 +/- 0.35 x 10(-7) M) intermediate between the high and low-affinity binding sites of CGP 20712A, suggesting that the low-affinity site is coupled to adenylyl cyclase. In membrane preparations of frog myocardial cells, ICYP/antagonist competition curves modeled for a mixed population of receptors, with subtype percentages varying from 50:50 beta-1:beta-2 to 100% beta-2 depending on the specific antagonist used and the individual cell preparation. For ICYP/agonist competition binding experiments the relative ability to displace ICYP was isoproterenol greater than epinephrine = norepinephrine, a profile typical of beta-1 adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

Cross-regulation between G-protein-mediated pathways. Activation of the inhibitory pathway of adenylylcylclase increases the expression of beta 2-adrenergic receptors.

Cross-regulation from the stimulatory (Gs alpha)-mediated) to the inhibitory (Gi alpha-mediated) pathways controlling adenylylcyclase has been described (Hadcock, J. R., Ros, M., Watkins, D. C., and Malbon, C. C. (1990) J. Biol. Chem. 265, 14784-14790). The extent to which cross-regulation occurs from inhibitory to stimulatory pathways for adenylylcyclase was explored. Persistent activation of the inhibitory pathway of adenylylcyclase by the A1-adenosine receptor agonist (-)-N6 (R-phenylisopropyl) adenosine (PIA) in hamster smooth muscle DDT1 MF-2 cells enhanced the stimulatory pathway of adenylylcyclase and its activation by the beta 2-adrenergic receptor agonist isoproterenol. PIA treatment (48 h) of cells increased isoproterenol-stimulated adenylylcyclase by 2-fold. In addition, the ED50 for stimulation of adenylylcyclase by isoproterenol decreased 50-fold to approximately 1 nM. Persistent activation of cells with PIA increased beta 2-adrenergic receptor number in a time- and dose-dependent manner. The steady-state levels of beta 2-adrenergic receptors (radioligand binding and immunoblotting) and receptor mRNA levels increased by more than 70%, while the half-life of the receptor (24 h) was unaltered. Both A1-adenosine receptor binding and Gi alpha 2 levels declined by half in cells persistently activated with PIA. Although Gi alpha 2 mRNA levels and the relative rate of synthesis of Gi alpha 2 protein upon persistent activation of the inhibitory pathway were found to increase, a decrease in the half-life of Gi alpha 2 from approximately 75 h in naive cells to approximately 40 in cells provides the basis for the decline in Gi alpha 2 levels. The steady-state level of mRNA and half-life of Gs alpha protein were unaltered in persistently activated cells. Thus, activation of the inhibitory pathway of adenylylcyclase cross-regulates the stimulatory, hormone-sensitive adenylylcyclase system by: (i) up-regulating beta 2-adrenergic receptors and enhancing the activation of the stimulatory adenylylcyclase pathway and (ii) down-regulating elements of the inhibitory adenylylcyclase pathway (Gi alpha 2 and A1-adenosine receptor binding).

Adenosine↗

Comparison of tidal ventilation and high-frequency jet ventilation before and after cardiopulmonary bypass in dogs using two-dimensional transesophageal echocardiography.

This study compared the use of high-frequency jet ventilation (HFJV) and tidal ventilation (TV) in a group of dogs with induced global myocardial ischemia before and after cardiopulmonary bypass. Transesophageal echocardiography was used to determine whether HFJV with its lower airway pressures could improve cardiac performance. The surgical procedure was separated into four study periods: closed chest before bypass, open chest before bypass, open chest after bypass, and closed chest after bypass. During each of these study periods, the dogs were randomly ventilated with alternate periods of TV and HFJV to maintain the PaCO2 at 34.3 +/- 3.3 mm Hg (mean +/- SEM). Cardiac output, stroke volume, systemic mean blood pressure, left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular dP/dt, left ventricular stroke work, and expiratory volumetric flows were higher during HFJV, whereas airway pressures and pulmonary vascular resistance were lower. Increases in cardiac output and stroke volume during HFJV were due to a combination of improved left ventricular contractility indicated by increased LV dP/dt and increased left ventricular end-diastolic volume accompanying decreased airway pressures. These data indicate that HFJV with its lower airway pressure is associated with significantly less impairment of cardiovascular function than TV in dogs with induced global myocardial ischemia.

Animals↗

Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy.

BACKGROUND: We measured the content and activities of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex and adrenergic neurotransmitter levels in left and right ventricular myocardial preparations derived from 77 end-stage failing human hearts from patients with idiopathic dilated cardiomyopathy (IDC) or ischemic dilated cardiomyopathy (ISCDC). METHODS AND RESULTS: The results were compared with data obtained in 21 nonfailing hearts removed from organ donors. Compared with ISCDC ventricles, IDC left and right ventricles exhibited a greater degree of total beta- or beta 1-receptor downregulation. In contrast, compared with IDC right ventricles, isolated tissue preparations of ISCDC right ventricles exhibited a greater degree of subsensitivity to the inotropic effect of isoproterenol, indicating a relatively greater degree of functional uncoupling of right ventricular ISCDC beta-receptors from mechanical response. In addition, relative to IDC left ventricles, preparations of ISCDC left ventricle exhibited greater subsensitivity to beta-agonist-mediated adenylate cyclase stimulation, indicating functional uncoupling of left ventricular ISCDC beta-receptors from cyclic AMP generation. The uncoupling of beta-receptors in ISCDC left and right ventricles may have been a result of abnormalities in G protein activation of adenylate cyclase; compared with age- and cardiac function-matched respective left or right IDC ventricles, ISCDC left ventricles exhibited less stimulation of adenylate cyclase by NaF or forskolin but no change in Mn2+ stimulation, whereas ISCDC right ventricles exhibited less stimulation by the nonhydrolyzable guanine nucleotide Gpp (NH)p. Also, IDC right ventricles exhibited a "selective" (not present in IDC left ventricles or ISCDC ventricles) decrease in stimulation of adenylate cyclase by Mn2+. Tissue neurotransmitter levels and pertussis toxin-catalyzed ADP ribosylation were altered to similar extents in IDC and ISCDC: CONCLUSIONS: These data indicate that potentially important differences exist in the regulatory behavior of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex in IDC versus ISCDC, differences that presumably relate to the distinct pathophysiologies of these two types of heart muscle disease.

Adenylyl Cyclases↗

Low-dose enoximone in subjects awaiting cardiac transplantation. Clinical results and effects on beta-adrenergic receptors.

During a 3-year period we administered enoximone, a phosphodiesterase inhibitor with positive inotropic and vasodilator properties, to 73 pretransplantation patients with end-stage heart failure who exhibited a clinical requirement for additional inotropic support. The clinical course and myocardial beta-adrenergic receptor status in the explanted hearts of these 73 patients was compared with results in 113 concurrently listed pretransplantation patients not requiring additional inotropic support. Only three patients required cessation of enoximone because of adverse effects, all from exacerbation of ventricular arrhythmias. Sixty-six of 73 (90.4%) enoximone-treated patients ultimately underwent cardiac transplantation a mean of 39.2 +/- 6.6 days (range 1 to 221 days) after starting enoximone, whereas seven patients (9.6%) died awaiting cardiac transplantation. The respective 1-, 3-, and 6-month pretransplantation survival rates of patients treated with enoximone calculated from their time on the waiting list for transplantation were 88.0%, 82.5%, and 82.5% compared with 92.1%, 83.8%, and 76.2% in control patients not receiving enoximone (all p = not significant). In 25 patients who received enoximone, ventricular myocardial beta-adrenergic receptors were measured at the time of transplantation and compared with values in failing ventricles from 52 pretransplantation patients not exposed to enoximone. Compared with ventricular myocardium of patients not given enoximone or intravenous beta-adrenergic agonists, total beta-adrenergic receptor (beta 1 plus beta 2) density was not decreased in patients treated with enoximone or enoximone plus intravenous beta-adrenergic agonists, but was decreased by 31% (p less than 0.05) in patients given intravenous beta-adrenergic agonists alone. Additionally, patients treated with enoximone had higher myocardial beta 2-adrenergic receptor densities than respective subgroups treated without (28% higher, p less than 0.01) or with (65% higher, p less than 0.01) intravenous beta-adrenergic agonists. Finally, isoproterenol- or calcium-mediated contractile responses in isolated right ventricular preparations from 14 patients treated with enoximone were similar to values in control patients not exposed to enoximone or intravenous beta-adrenergic agonists, suggesting that enoximone-related beta-adrenergic subsensitivity or damage to the contractile apparatus does not occur.

Adult↗

Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart.

To test the hypothesis that cardiac norepinephrine depletion related to heart failure alters contractile responses to beta-adrenergic agonists with a component of "indirect" action (acting by release of neuronal norepinephrine), we examined the inotropic potential of several pharmacologically distinct beta-agonists. Contractile responses to the nonselective beta-agonist isoproterenol, the beta 2-selective agonist zinterol, and the direct- and indirect-acting agonists dopamine and dopexamine were compared in isolated right ventricular trabeculae removed from failing, nonfailing innervated, and previously transplanted and, therefore, denervated nonfailing human hearts. In failing hearts, the contractile response to isoproterenol was significantly lower (41%) than that in nonfailing innervated hearts. The responses to the mixed agonists dopamine and dopexamine were even more attenuated in failing hearts, to a level 76-90% lower than those of nonfailing innervated hearts. In denervated, previously transplanted, nonfailing hearts, the contractile responses to the mixed agonists dopamine and dopexamine were 66-72% lower than those in the nonfailing innervated group, but the response to isoproterenol was not significantly different. The response to zinterol was not significantly different among the three groups. In subjects with severe heart failure, in vivo hemodynamic responses to dopexamine were compared with those of the direct-acting beta-agonist dobutamine. Responses to dopexamine and dobutamine were measured before and after prolonged continuous infusions of each drug. The response to dopexamine, but not to dobutamine, diminished over time. We conclude that a large component of the inotropic response to dopamine and dopexamine in human hearts is due to the ability of these agonists to promote the release of neuronal norepinephrine; when neuronal norepinephrine is depleted, indirect-acting agonists are less able to produce an inotropic response.

Adrenergic beta-Agonists↗