Biomedical subjects

T M Wong

Publications and source records attributed to T M Wong.

At least 37 records · Page 2Linked to original sources

PubMed2000

Enhanced responses to 17beta-estradiol in rat hearts treated with isoproterenol: involvement of a cyclic AMP-dependent pathway.

We determined the effects of 17beta-estradiol, the most effective estrogen, acutely administered, on the heart/ventricular myocyte with or without treatment with isoproterenol (Iso). At 0.1 to 1 nM, 17beta-estradiol, which itself had no effect, reduced the heart rate and developed pressures in the isolated perfused heart treated with 10(-7) M Iso. One nanomolar 17beta-estradiol also inhibited the cyclic AMP (cAMP) production in Iso-treated ventricular myocytes. At 10 nM to 1 microM, 17beta-estradiol itself reduced the heart rate and incidence of ischemia/reperfusion-induced arrhythmias, with the exception of diastolic pressure. The effects of 17beta-estradiol on heart rate, systolic and mean pressures, and arrhythmias were significantly enhanced in the heart/ventricular myocyte treated with Iso. Tamoxifen, an estrogen receptor antagonist, did not antagonize the effect of 17beta-estradiol on the Ca(2+) current in ventricular myocytes treated with Iso, nor did it alter the effect of the hormone on the cAMP production augmented by Iso and forskolin. The effects of 17beta-estradiol on Ca(2+) current in the presence or absence of tamoxifen and/or Iso were similar in male rats, which do not possess the estrogen receptor, and female rats, which have the estrogen receptor. In conclusion, we have shown for the first time that estrogen at physiological concentrations modulates negatively the stimulatory actions of Iso on the heart rate and cardiac contractility. The effects may result from activation of an unknown membrane receptor and the adenylate cyclase/cAMP pathway, which enhances Ca(2+) influx across the L-type Ca(2+) channel.

Adrenergic beta-Agonists↗

PubMed2000

Cardiovascular actions of Radix Stephaniae Tetrandrae: a comparison with its main component, tetrandrine.

A comparison of the cardiovascular actions of the extract of Radix Stephaniae Tetrandrae (RST), the root of a Chinese hero Stephania tetrandra S Moore, in rats with those of tetrandrine (Tet), the best known active component of RST was reviewed. The RST extract inhibits Ca2+ influx into the myocyte and reduces protein release during reperfusion with a Ca2+ containing solution following perfusion with a Ca2+ free solution (Ca2+ paradox), and arrhythmia during reperfusion in the isolated perfused heart. It also reduces the infarct size induced by ischemia/reperfusion in vitro and in vivo. In addition, the RST extract suppresses elevation of arterial blood pressure in DOCA-salt hypertensive rats. It does not further reduce the heart rate and coronary flow significantly during myocardial ischemia. The effects are similar to those of Tet. When compared with the same doses of Tet alone, the RST extract, of which 9% is Tet, produces equally potent effects on infarction, arrhythmias, coronary flow and heart rate, and has a greater inhibitory effect on protein release during Ca2+ paradox. The combination at 1:1 ratio of Tet and fangchinoline (Fan), another main component, which constitutes 6% of the RST extract and has no significant effects on the heart, produces comparable effects on protein release during Ca2+ paradox as Tet alone. The observations suggest that the efficacy of the RST extract cannot be accounted for by Tet alone. Some of the effects may be due to an interaction between the components of the extract. The RST extract also produces similar effects as verapamil, a prototype Ca2+ channel antagonist widely used in the treatment of ischemic heart diseases and hypertension, except that verapamil, at 1 mumol/L, a concentration that produces similar cardiac effects as the RST extract, further reduces heart rate significantly during ischemia. So the RST extract may be a therapeutically better agent in the treatment of ischemic heart diseases and hypertension than Ca2+ channel antagonists because of the absence of the inhibitory effect on heart rate during myocardial ischemia.

Alkaloids↗

PubMed1999

Cardioprotection of preconditioning by metabolic inhibition in the rat ventricular myocyte. Involvement of kappa-opioid receptor.

To determine whether opioid receptors (ORs) are involved in the delayed cardioprotection of ischemic preconditioning (IP), the effect of severe metabolic inhibition (MI) with a glucose-free buffer that contained sodium cyanide and 2-deoxy-D-glucose on the viability of isolated rat ventricular myocytes was first determined 20 hours after preconditioning with a sublethal metabolic inhibition (MIP) with a glucose-free buffer that contained 2-deoxy-D-glucose and lactate for 30 minutes in the presence of OR antagonists. With the use of trypan blue exclusion as an index of cell viability, severe MI killed >60% of the cells and the value increased significantly after MIP. In the presence of 5x10(-6) mol/L nor-binaltorphimine (nor-BNI), a selective kappa-OR antagonist, but not 5x10(-6) mol/L CTOP, a selective mu-OR antagonist, or 5x10(-6) mol/L naltrindole, a selective delta-OR antagonist, the cardioprotection of MIP was significantly attenuated. To verify the role of kappa-OR, we studied the effects of severe MI after pretreatment with the kappa-OR agonist U50,488H (UP) for 30 minutes. U50,488H at 3x10(-6) to 1x10(-4) mol/L increased cell viability concentration-dependently with an EC50 of 3.311x10(-6) mol/L. In the presence of 5x10(-6) nor-BNI, the cardioprotection of UP (3x10(-5) mol/L) was blocked. A time course study showed that UP-induced cardioprotection occurred in 2 windows: the first occurred approximately 1 hour later and the other occurred 16 to 20 hours later. Additional studies on cell contraction and intracellular Ca2+ ([Ca2+]i) revealed that both UP and MIP attenuated the inhibitory effects of severe MI on contractility and electrically induced [Ca2+]i transient in single ventricular myocytes. On blockade of protein kinase C, the delayed cardioprotections of UP and MIP were significantly attenuated. In conclusion, the results of the present study have provided evidence that kappa-OR mediates the cardioprotection of MIP, which may involve protein kinase C and [Ca2+]i.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Cross-talk between cardiac kappa-opioid and beta-adrenergic receptors in developing hypertensive rats.

The kappa-opioid receptor exerts a negative modulatory action on the beta-adrenoceptor and the action is blunted in adult spontaneously hypertensive rats (SHR). In order to determine whether the blunted negative modulation of the beta-adrenoceptor by the kappa-opioid receptor contributes to the development of hypertension, the electrically induced intracellular calcium ([Ca2+]i) transient was measured in single ventricular myocytes of SHR at 4, 6, 8 and 13-week-old and the age-matched Wistar Kyoto (WKY) rats. The electrically induced [Ca2+]i transients were augmented by norepinephrine (NE), a beta-adrenoceptor agonist, over four-fold in WKY rats of all ages studied and in SHR of 4 and 6 weeks of age. The enhancing effect of NE in 8- and 13-week-old SHR was, however, only approximately three-fold, significantly lower than the corresponding values in age-matched WKY rats. Similarly, the electrically induced [Ca2+]i transients were also augmented by forskolin, an activator of adenylate cyclase, by approximately two-fold in WKY rats of all ages and SHR aged 4 and 6 weeks. In SHR aged 8 and 13 weeks, the effect of forskolin was only 1.5-fold, significantly lower than the two-fold increase in the corresponding WKY rats. The enhancing effects of NE and forskolin were attenuated by U50,488H, a selective kappa-opioid agonist, by approximately 50 and 25%, respectively, in both types of rats of all ages studied, with the exception of 13-week-old rats. In rats of this age group, the attenuations by U50,488H on the enhancing effects of NE and forskolin were 17 and 9% in SHR, respectively, significantly less than the corresponding 54 and 29% in WKY. The fact that attenuation of U50,488H on the enhancing effects of NE and forskolin only occurs in 13-week-old SHR when hypertension has been fully developed indicates that the attenuated inhibitory modulation of kappa-opioid receptor stimulation does not contribute to the initiation of hypertension. Interestingly, the enhancing effects of NE and forskolin on the electrically induced [Ca2+]i transient was attenuated in SHR aged from 8 weeks when the blood pressure was rapidly increasing. The different time courses of altered responses to U50,488H, and NE and forskolin suggest that the attenuated negative modulation of kappa-receptor stimulation on the beta-adrenergic receptor is not due to the signal transduction pathway activated by beta-adrenergic stimulation. In 13-week-old SHR with the arterial blood pressure restored to normal by pharmacological manipulations, the blunted responses to NE, U50,488H and forskolin still occurred, indicating that the altered responses to activation of beta-adrenergic and kappa-opioid receptors and adenylate cyclase are not secondary to hypertension.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Effects of U50488 and bremazocine on [Ca2+]i and cAMP in naive and tolerant rat ventricular myocytes: evidence of kappa opioid receptor multiplicity in the heart.

To explore the existence of multiplicity of kappa receptor in the heart, two series of experiments were performed. In the first we studied the antagonistic actions of nor-BNI, a selective kappa 1 antagonist, and quadazocine, a preferential kappa 2 antagonist, against the effects of U50488, a selective kappa 1 agonist, and bremazocine, a universal agonist preferentially binding to kappa 2 receptor, on the electrically stimulated [Ca2+]i transient and forskolin-stimulated cAMP accumulation in the rat ventricular myocyte. In the second series of experiments, we determined and compared the effects of above two kappa receptor agonists in the ventricular myocytes made insensitive to kappa 1 and kappa 2 agonists by prior exposure to the respective agonists. At the concentration range of 3 x 10(-6)-3 x 10(-5) M, both U50488 and bremazocine dose-dependently inhibited the [Ca2+]i transient induced by electrical stimulation. The inhibitory effects of U50488 and bremazocine were antagonized by nor-BNI and quadazocine. The antagonistic actions of nor-BNI were significantly greater against the effects of U50488, but smaller against the effects of bremazocine than those of quadazocine. At 1 x 10(-6)-5 x 10(-5) M, both U50488 and bremazocine dose-dependently and significantly inhibited the forskolin-induced cAMP accumulation. The inhibitory effect of 30 microM U50488 on cAMP accumulation was significantly attenuated by 5 microM nor-BNI, but not by quadazocine at the same concentration; whereas the effect of 30 microM bremazocine was significantly blocked by 5 microM quadazocine, but not by nor-BNI at the same concentration. The inhibitory effect of 30 microM U50488 on electrically stimulated [Ca2+]i was abolished by preincubation of myocytes with 10(-6) M U50488 for 24 h, but not with 10(-6) M bremazocine for h; whereas the inhibitory effect of 30 microM bremazocine on electrically stimulated [Ca2+]i transient was significantly attenuated after incubation of the myocyte with 10(-6) M bremazocine for 24 h, but not with 10(-6) M U50488 for 24 h. The observations indicate the existence of kappa receptor subtypes in the rat heart.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Anti-arrhythmic effect of kappa-opioid receptor stimulation in the perfused rat heart: involvement of a cAMP-dependent pathway.

During myocardial ischaemia the beta-adrenoceptor is activated, which contributes, at least partly, to cardiac arrhythmias via inducing [Ca2+]i oscillations. Since beta-adrenoceptor is negatively modulated by the kappa-opioid receptor in the heart, the present study attempted to determine if kappa-opioid receptor stimulation modulates the arrhythmogenic action of beta-adrenoceptor stimulation and to delineate the underlying mechanism. The effect of U50,488H, a selective kappa-opioid agonist, on arrhythmias in the isolated perfused rat heart subjected to low flow and 10(-6)mol/l norepinephrine (NE) were determined. Low flow induced arrhythmias, which were potentiated by NE, but not by 10(-6)mol/l U50,488H. The arrhythmia-potentiating effect of NE was antagonized by 10(-6)mol/l propranolol, a beta-adrenoceptor antagonist. U50,488H at 10(-6)mol/l also abolished the potentiation in arrhythmias by NE without affecting the arrhythmias induced by low flow. The anti-arrhythmic action of the kappa-opioid receptor agonist was abolished by 10(-6)mol/l nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by 10(-7)mol/l calphostin C, an inhibitor of protein kinase C. Similarly, kappa-opioid receptor stimulation with U50,488H also abolished the NE-induced [Ca2+]i oscillations which are believed to cause cardiac arrhythmias, in ventricular myocytes. To determine whether the inhibitory actions of U50,488H against the effects of beta-adrenoceptor stimulation was via a cAMP-dependent or a cAMP-independent pathway, we determined the effects of U50,488H on NE-enhanced cAMP production and [Ca2+]i oscillations induced by either forskolin, an activator of adenylate cyclase, or Bay K-8644, a selective L-type Ca2+ channel agonist, in the ventricular myocytes. We found that U50,488H abolished the effect of forskolin, but did not alter the effect of Bay K-8644, on [Ca2+]i oscillations in the ventricular myocyte. In addition, U50, 488H also attenuated significantly the NE-induced elevation in cAMP in the heart. The observations suggest that kappa-opioid receptor stimulation abolishes the effect of beta-adrenoceptor stimulation on arrhythmias and [Ca2+]i oscillation via a cAMP-dependent pathway. The finding may be useful for the prevention and treatment of ischaemic heart diseases.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Electrically induced intracellular Ca2+ transient in single ventricular myocytes: a useful parameter for the study of cardiac drugs.

1. Fluorescent Ca2+ indicators, such as fura-2/AM and calcium green-1, have become one of the most popular tools for measuring intracellular calcium ([Ca2+]i). 2. Electrical stimulation triggers a cascade of events in the cardiac muscle, which results in a [Ca2+]i transient and, eventually, contraction. The events that occur in electrically induced cardiac myocytes mimic the normal physiological events in vivo. 3. The electrically induced [Ca2+]i transient represents influx of Ca2+ from outside and mobilization of Ca2+ from the intracellular store and is directly related to contraction. Thus, it is more important to determine the electrically induced [Ca2+]i transient than [Ca2+]i. The [Ca2+]i transient can be easily measured with the spectrofluorescence method using fura 2/AM as the Ca2+ indicator in a single ventricular myocyte preparation. 4. We made use of the results of studies on carbachol, tetrandrine and cardiotoxin to illustrate the usefulness of the electrically induced [Ca2+]i transient in the study of actions of cardiac drugs.

Animals↗

PubMed1999

Pro- and anti-arrhythmic effects of a kappa opioid receptor agonist: a model for the biphasic action of a local hormone in the heart.

1. The effects of kappa opioid receptor stimulation on cardiac rhythm and the underlying signal pathways were investigated in the rat. 2. Stimulation of kappa opioid receptors with 40-50 mumol/L U50 488H, a selective kappa opioid receptor agonist, induced dysrhythmias and increased inositol 1,4,5-trisphosphate (IP3) production in rat isolated, perfused heart. The pro-arrhythmic effects of U50 488H were abolished by 5 mumol/L norbinaltorphimine (nor-BNI), a specific kappa opioid receptor antagonist. 3. The effect of U50 488H on cardiac dysrhythmia and IP3 production were abolished by 1 mmol/L neomycin and streptomycin, phospholipase C (PLC) inhibitors. 4. At 1 mumol/L, U50 488H, which itself has no effect on cardiac rhythm and IP3 production, significantly attenuated the potentiating effect of 1 mumol/L noradrenaline (NA) on dysrhythmias, which were induced by low flow in the isolated heart. The effects of U50 488H were abolished by 1 mumol/L nor-BNI. Cytosolic cAMP production was augmented by 1 mumol/L NA and this was significantly attenuated by 1 mumol/L U50 488H. 5. At 1 mumol/L, U50 488H also reduced [Ca2+]i oscillations induced by 0.5 mumol/L NA and 0.5 mumol/L forskolin, an activator of adenylate cyclase (AC). 6. In conclusion, U50 488H exerted pro- and anti-arrhythmic actions at high and lower concentrations, respectively. The former effect was mediated via the PLC/IP3 pathway, while the latter was mediated via the AC/cAMP pathway.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study.

The objective of the current study was to determine the efficacy of amantadine in improving cognitive and behavioural performance in a traumatic brain injury (TBI) rehabilitation sample. The design was a prospective, randomized, double-blind, placebo-controlled, crossover design. Subjects were 10 adult traumatic brain injury patients in an acute brain injury rehabilitation unit. Subjects received a 2-week trail of amantadine or placebo, followed by a 2-week washout, then a 2-week trail of the alternative (placebo or amantadine). Neuropsychological outcome measures included orientation, attention, executive function, memory, orientation, behaviour, and a composite variable. Results of repeated measures ANOVA and regression analysis of slope/change showed a main effect of time, but no significant difference for amantadine versus placebo. In conclusion, although patients generally improved, this initial exploratory study found no differences in rate of cognitive improvement between subjects given amantadine versus those given placebo. However, the small sample size, heterogeneous population, acute time course, and large number of dependent variables limit power and generalizability. Implications are discussed for further research to better answer questions regarding efficacy of amantadine post-TBI.

Adult↗

PubMed1999

Acidosis antagonizes intracellular calcium response to kappa-opioid receptor stimulation in the rat heart.

To study the effects of kappa-opioid receptor stimulation on intracellular Ca2+ concentration ([Ca2+]i) homeostasis during extracellular acidosis, we determined the effects of kappa-opioid receptor stimulation on [Ca2+]i responses during extracellular acidosis in isolated single rat ventricular myocytes, by a spectrofluorometric method. U-50488H (10-30 microM), a selective kappa-opioid receptor agonist, dose dependently decreased the electrically induced [Ca2+]i transient, which results from the influx of Ca2+ and the subsequent mobilization of Ca2+ from the sarcoplasmic reticulum (SR). U-50488H (30 microM) also increased the resting [Ca2+]i and inhibited the [Ca2+]i transient induced by caffeine, which mobilizes Ca2+ from the SR, indicating that the effects of the kappa-opioid receptor agonist involved mobilization of Ca2+ from its intracellular pool into the cytoplasm. The Ca2+ responses to 30 microM U-50488H were abolished by 5 microM nor-binaltorphimine, a selective kappa-opioid receptor antagonist, indicating that the event was mediated by the kappa-opioid receptor. The effects of the agonist on [Ca2+]i and the electrically induced [Ca2+]i transient were significantly attenuated when the extracellular pH (pHe) was lowered to 6.8, which itself reduced intracellular pH (pHi) and increased [Ca2+]i. The inhibitory effects of U-50488H were restored during extracellular acidosis in the presence of 10 microM ethylisopropyl amiloride, a potent Na+/H+ exchange blocker, or 0.2 mM Ni2+, a putative Na+/Ca2+ exchange blocker. The observations indicate that acidosis may antagonize the effects of kappa-opioid receptor stimulation via Na+/H+ and Na+/Ca2+ exchanges. When glucose at 50 mM, known to activate the Na+/H+ exchange, was added, both the resting [Ca2+]i and pHi increased. Interestingly, the effects of U-50488H on [Ca2+]i and the electrically induced [Ca2+]i transient during superfusion with glucose were significantly attenuated; this mimicked the responses during extracellular acidosis. When a high-Ca2+ (3 mM) solution was superfused, the resting [Ca2+]i increased; the increase was abolished by 0.2 mM Ni2+, but the pHi remained unchanged. Like the responses to superfusion with high-concentration glucose and extracellular acidosis, the responses of the [Ca2+]i and electrically induced [Ca2+]i transients to 30 microM U-50488H were also significantly attenuated. Results from the present study demonstrated for the first time that extracellular acidosis antagonizes the effects of kappa-opioid receptor stimulation on the mobilization of Ca2+ from SR. Activation of both Na+/H+ and Na+/Ca2+ exchanges, leading to an elevation of [Ca2+]i, may be responsible for the antagonistic action of extracellular acidosis against kappa-opioid receptor stimulation.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Spontaneous activity and barosensitivity of the barosensitive neurons in the rostral ventrolateral medulla of hypertensive rats induced by transection of aortic depressor nerves.

In order to determine the role of the rostral ventrolateral medulla (RVLM) in the development of neurogenic hypertension, the aortic depressor nerves of rats were transected (tADN) to produce neurogenic hypertension. The rate and pattern of firing of the barosensitive RVLM neurons of the treated rats were studied. In neurogenic hypertensive rats, the RVLM barosensitive neurons exhibited a faster firing rate and a shorter interspike interval (ISI) than the corresponding values of the control and sham groups, indicating an enhanced spontaneous activity of these neurons in the hypertensive rats. The coefficient of variation (cv) and skewness (sk) of the ISI histogram, parameters reflecting the regularity of neuronal firing, were smaller in neurogenic hypertensive than in the control and sham-operated rats. Following tADN, the responsiveness of these neurons to blood pressure changes was attenuated, suggesting a reduced intrinsic barosensitivity of neurons and/or a reduced baroreceptor input. The increase in spontaneous activity and firing regularity of RVLM barosensitive neurons imply an enhancement in the efficacy of outflow from these neurons. The increased efficacy of the outflow from the RVLM barosensitive neurons and the resetting of the baroreflex may contribute to the genesis of neurogenic hypertension.

Animals↗

PubMed1998

U50,488H inhibits effects of norepinephrine in rat cardiomyocytes-cross-talk between kappa-opioid and beta-adrenergic receptors.

In order to determine the effect of kappa-opioid receptor agonist on the beta1-adrenoceptor stimulation in the heart, the effects of norepinephrine (NE), a beta1-adrenoceptor agonist, on contraction and electrically induced intracellular calcium ([Ca2+]i) transient in the single rat ventricular myocyte pretreated with a kappa-opioid receptor agonist, trans-(+/-)-3, 4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)-benzeneacetamide (U50,488H), at 0.01-1 microM were studied with a video edge tracker method and a spectrofluorometric method using fura-2 as calcium indicator, respectively. NE at 0.01-10 microM augmented both twitch amplitude and electrically induced [Ca2+]i transient dose-dependently, which were abolished by propranolol at 1 microM, a beta-adrenoceptor antagonist. The effects of NE on both contraction and [Ca2+]i transient were attenuated in a dose-dependent manner by U50,488H at 0.01-1 microM, which itself had no effect at all. The maximum response ( Emax) was decreased, while the concentration that produces 50% of the maximum response (EC50) was enhanced, by U50, 488H. The inhibitory effects of U50,488H on beta-adrenoceptor stimulation were completely blocked by pretreatment with norbinaltorphimine, a specific kappa-opioid receptor antagonist at 1 microM, or preincubation with pertussis toxin (PTX) at 200 ng/ml for 6 h. On the other hand, the inhibition on NE-induced augmentation in electrically induced [Ca2+]i transient by U50,488H was not affected by pretreatment with U73122, a specific inhibitor of phospholipase C (PLC), at 10 microM for 30 min. U50,488H attenuated the augmentation of the electrically stimulated [Ca2+]i transient induced by forskolin at 0.1 and 0.5 microM. It did not, however, affect the augmentation of the electrically induced [Ca2+]i transient by N6, 2'-O-dibutyryl adenosine cyclic monophosphate (DB-cAMP). The results suggest that kappa-opioid receptor stimulation by U50,488H at 10(-6 )M or lower may inhibit the effects of beta-adrenoceptor stimulation by acting at a PTX-sensitive G-protein and AC, but not via the phosphoinositol pathway.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Phospholipase C inhibitors attenuate arrhythmias induced by kappa-receptor stimulation in the isolated rat heart.

To determine whether the phospholipase C (PLC)/inositol 1,4,5 trisphosphate (IP3)/Ca2+ pathway mediates cardiac arrhythmias induced by kappa-opioid receptor stimulation, the effects of U50,488H, a selective kappa-opioid receptor agonist, on cardiac rhythm in a isolated perfused rat heart, intracellular calcium ([Ca2+]i) in a single ventricular myocyte and IP3 production in myocytes were studied in the presence and absence of PLC inhibitors. U50,488H, the effects of which had been shown to be abolished by a selective kappa-receptor antagonist, nor-binaltorphimine, induced arrhythmias dose-dependently and increased both [Ca2+]i and IP3-production in the heart. More importantly, the effects of U50,488H were blocked by PLC inhibitors, neomycin and streptomycin. To further confirm the selectivity of action of the PLC inhibitor, the effects of another PLC inhibitor U73122 and its inactive structural analog, U73343, on cardiac rhythm in the isolated perfused rat heart were compared. The former did, while the latter did not, block the arrhythmogenic effect of U50,488H. We also determined whether the effects of kappa-receptor stimulation involves a pertussis toxin (PTX)-sensitive G-protein. We found that pretreatment with PTX at 4 microg/l for 10 min, a treatment shown to affect PTX sensitive G-protein-mediated functions, attenuated significantly the U50,488H-induced arrhythmias. The present study provides evidence that kappa-receptor stimulation-induced cardiac arrhythmias involves, at least partly, the PLC/IP3/Ca2+ pathway as well as a PTX sensitive G-protein.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Continuous nebulization therapy for asthma with aerosols of beta2 agonists.

BACKGROUND: Various studies have demonstrated the benefits of continuous nebulization therapy for delivering aerosols of the beta2 agonists such as terbutaline sulfate or albuterol sulfate to patients with severe asthma and/or impending respiratory failure. OBJECTIVE: The purpose of this investigation was to explicate the operational factors associated with the use of nebulizers for extended aerosol respiratory therapy including those factors that affect the prescribed aerosol dosages and the relationship to actual delivery of prescribed drugs to the respiratory airways of the lungs of a patient under treatment conditions. METHODS: Operational characteristics and methods have been investigated for use of long-running nebulizers for continuous nebulization therapy. Factors considered were particle size distribution, setup conditions, aerosolization concentrations and rates, delivery fraction of aerosol reaching patient, and changes in medication concentration during extended operation. With a large volume nebulizer, aerosols can be delivered to the patient without dilution via a standard open mask for up to eight hours without refill. The pneumatic HEART nebulizer with 240 mL reservoir was evaluated. RESULTS: The nebulizer was operated from a single compressed air or oxygen source and found to provide from 10 to 15 L/min of aerosol with 38 to 50 microL of aerosolized medicine per liter of air (or oxygen) and utilize from 30 to 56 mL/hour of medicinal liquid. The mass median aerodynamic diameter of the aerosol droplets was found to be about 2.0 microm (sigma(g) = 2.7). Delivery efficiency to the patient mask was about 90%. The aerosolized medicine delivered to the patient can be increased by adjusting the flow rate of the gas source or changing the solution concentration of medicine. Typically, several milligrams of drug can be delivered to the patient as inhaled aerosol per hour of treatment of which about one-quarter can be expected to be deposited in the lungs. During eight hours of operation the concentration of medicinal solution increased by about a factor of two because of water evaporation. CONCLUSIONS: Continuous nebulization therapy is an important means of treating patients with severe asthma. Dosage criteria can be established based on the operating characteristics of the nebulizer system, drug solution concentration, and patient respiration.

Adrenergic beta-2 Receptor Agonists↗

PubMed1998

Effects of kappa-opioid receptor stimulation in the heart and the involvement of protein kinase C.

1. The role of protein kinase C (PKC) in mediating the action of kappa-receptor stimulation on intracellular Ca2+ and cyclic AMP production was determined by studying the effects of trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulphonate (U50,488H), a selective kappa-receptor agonist, and phorbol 12-myristate 13-acetate (PMA), a PKC agonist, on the electrically-induced [Ca2+]i transient and forskolin-stimulated cyclic AMP accumulation in the presence and absence of a PKC antagonist, staurosporine or chelerythrine, in the single rat ventricular myocyte. 2. U50,488H at 2.5-40 microM decreased both the electrically-induced [Ca2+]i transient and forskolin-stimulated cyclic AMP accumulation dose-dependently, effects which PMA mimicked. The effects of the kappa-agonist, that were blocked by a selective kappa-antagonist, nor-binaltorphimine, were significantly antagonized by the PKC antagonists, staurosporine and/or chelerythrine. The results indicate that PKC mediates the actions of kappa-receptor stimulation. 3. To determine whether the action of PKC was at the sarcoplasmic reticulum (SR) or not, the [Ca2+]i transient induced by caffeine, that depletes the SR of Ca2+, was used as an indicator of Ca2+ content in the SR. The caffeine-induced [Ca2+]i transient was significantly reduced by U50,488H at 20 microM. This effect of U50,488H on caffeine-induced [Ca2+]i transient was significantly attenuated by 1 microM chelerythrine, indicating that the action of PKC involves mobilization of Ca2+ from the SR. When the increase in IP3 production in response to K-receptor stimulation with U50,488H in the ventricular myocyte was determined, the effect of U50,488H was the same in the presence and absence of staurosporine, suggesting that the effect of PKC activation subsequent to kappa-receptor stimulation does not involve IP3. The observations suggest that PKC may act directly at the SR. 4. In conclusion, the present study has provided evidence for the first time that PKC may be involved in the action of kappa-receptor stimulation on Ca2+ in the SR and cyclic AMP production, both of which play an essential role in Ca2+ homeostasis in the heart.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Hypoxic brain injury with motor apraxia following an anaphylactic reaction to hymenoptera venom.

Hypoxic brain injury can be a complication following several well known situations or disorders. The neurological and neuropsychological characteristics of patients who suffer hypoxic brain injury depend on the mechanism of injury and the structures of the brain that are particularly vulnerable to hypoxia. Injury to the hippocampus with resultant memory impairment is a well described clinical feature. Motor apraxia has not been described as a common feature following hypoxic injury. This paper describes an unusual case of hypoxic brain injury that resulted from an anaphylactic reaction to hymenoptera venom. The patient presented with severe ideomotor apraxia as he emerged from coma after cardiorespiratory arrest. Surprisingly, the patients memory was relatively preserved in relation to other cognitive impairments. A brief discussion of the pathophysiology of hypoxic brain injury and the patient's rehabilitation outcome is presented.

Adult↗

PubMed1998

Reduced responsiveness of [Ca2+]i to adenosine A1- and A2-receptor stimulation in the isoproterenol-stimulated ventricular myocytes of spontaneously hypertensive rats.

To determine the modulatory action of adenosine-receptor stimulation on [Ca2+]i responses to beta-adrenoceptor stimulation in the heart of the spontaneously hypertensive rat (SHR), the electrically induced [Ca2+]i transient in response to isoproterenol (ISO) in single ventricular myocytes pretreated with adenosine agonists in SHRs and its normotensive control Wistar-Kyoto (WKY) rats was measured with a spectrofluorometric method by using fura-2/AM as the calcium indicator. In both types of rat, ISO at 0.001-1 microM augmented the electrically induced [Ca2+]i transient, and the effect was blocked by a beta-adrenoceptor blocker, propranolol. In SHRs that did not exhibit cardiac hypertrophy, the resting level of [Ca2+]i and the amplitude of the electrically induced [Ca2+]i transient were the same as those in WKY rats, whereas the augmentation of the electrically induced [Ca2+]i transient in response to ISO was significantly lower than that in WKY rats. In WKY rats, the effects of ISO on the electrically induced [Ca2+]i transient were inhibited by the adenosine A1-receptor agonist, R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA) at 0.01-10 microM. In contrast, the effects of ISO were further enhanced by the adenosine A2-receptor agonist, N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl)]adenosine (DPMA) at 1-10 microM. In SHRs, the inhibitory effect of R-PIA was significantly reduced, whereas the excitatory effect of DPMA was absent. The effects of both adenosine-receptor agonists in both types of rat were abolished by the respective adenosine-receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 3,7-dimethyl-1-propargylxanthine (DMPX). The results indicate that the modulatory actions of adenosine-receptor stimulation on [Ca2+]i response to beta-adrenoceptor stimulation in the hearts of SHRs are reduced, which is independent of cardiac hypertrophy.

Adenosine↗

PubMed1998

Suppression of cAMP by phosphoinositol/Ca2+ pathway in the cardiac kappa-opioid receptor.

To determine whether the phosphoinositol/Ca2+ pathway interacts with the adenylate cyclase/adenosine 3',5'-cyclic monophosphate (cAMP) pathway in the cardiac kappa-receptor, the effects of U-50488, a specific kappa-receptor agonist, on the intracellular Ca2+ concentration ([Ca2+]i) and forskolin-induced accumulation of cAMP in rat ventricular myocytes were determined after interference of the phosphoinositol/Ca2+ pathway. U-50488 suppressed the forskolin-induced accumulation of cAMP and elevated [Ca2+]i, which were blocked by norbinaltorphimine, a specific kappa-receptor antagonist, and pertussis toxin. The effects of U-50488 were qualitatively similar to those of A-23187, a Ca2+ ionophore, but opposite to those of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-acetoxymethyl ester (AM), a [Ca2+]i chelator. Abolition of U-50488-induced elevation of [Ca2+]i by BAPTA-AM also abolished the effect of U-50488 on forskolin-induced accumulation of cAMP. Inhibition of the phospholipase C by specific inhibitors, U-73122 and neomycin, abolished the effects of U-50488 on both [Ca2+]i and forskolin-induced accumulation of cAMP. The results showed for the first time that kappa-receptor stimulation may suppress cAMP accumulation via activation of the phosphoinositol/Ca2+ pathway in the rat heart.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗