Biomedical subjects

R Einstein

Publications and source records attributed to R Einstein.

At least 37 records · Page 2Linked to original sources

PubMed1991

The effects of neuropeptide Y on myocardial contractility and coronary blood flow.

1. This study was designed to assess the effects of exogenous neuropeptide Y (NPY) on cardiac contractility and coronary blood flow (CBF) in anaesthetized dogs and to evaluate the effect of NPY on the responses to sympathetic and parasympathetic stimulation and to inotropic agents. 2. Bolus doses of NPY (500 micrograms), administered via the femoral vein, increased mean arterial pressure. The pressor effect was associated with reductions in heart rate, CBF and cardiac contractility. 3. The effects of NPY (500 micrograms) on contractility and CBF were compared with that of vasopressin (VP) (1 unit). For similar reductions in CBF, NPY and VP had similar negative inotropic effects. Thus, it is likely that the negative inotropic response to NPY is not due to a direct effect of NPY on the heart muscle but is largely due to coronary vasoconstriction. 4. In the presence of NPY (500 micrograms, i.v.), there was an inhibition of the positive inotropic response to stimulation of the left cardiac sympathetic nerve (2 or 5 Hz, 0.05 ms). NPY also inhibited the negative inotropic response and chronotropic response to vagal stimulation (2, 3 or 5 Hz, 0.05 ms). 5. Dose-response curves were obtained for the inotropic, chronotropic and pressor responses to cumulative infusions of noradrenaline (n = 6) and dobutamine (n = 6). NPY had no effect on these dose-response curves. 6. The effect of NPY on the responses to salbutamol and impromidine was assessed. NPY did not alter the positive inotropic, chronotropic or depressor responses to these agonists. 7. Our results indicate that NPY has direct, postsynaptic vasoconstrictor activity and the reduction in myocardial contractility and heart rate are due to a combination of coronary vasoconstriction, baroreceptor reflex activation and presynaptic inhibition of transmitter release from sympathetic nerves. The welldocumented inhibitory effect of NPY on the chronotropic response to parasympathetic stimulation was confirmed and similar inhibition of the inotropic response to both sympathetic and parasympathetic stimulation was demonstrated. Since there was no modulation of the inotropic effects of exogenous alpha- and beta-adrenoceptor or H2-receptor agonists, it is concluded that the effects of NPY on myocardial contractility are exerted presynaptically.

Albuterol↗

PubMed1991

Can changes in transcardiac impedance appropriately detect ventricular fibrillation?

Transcardiac impedance, as measured between two implanted defibrillator patches, has been shown to vary in peak-to-peak magnitude in response to the contractions of the ventricles. These variations in transcardiac impedance are known as delta Z. This study was aimed at determining if there was a significant change in the magnitude of delta Z between that during normal sinus rhythm, that during ventricular fibrillation (VF), and if this change could be used as a detector of the onset of VF. This study was performed acutely on 14 anesthetized dogs.

Animals↗

PubMed1990

Acidification-dependent dissociation of endocytosed insulin precedes that of endocytosed proteins bearing the mannose 6-phosphate recognition marker.

A key step in the sorting of endocytosed ligands from their receptors is dissociation, which is triggered by the acidic pH of endosomes. To determine whether dissociation occurs synchronously for all ligands, we compared in Chinese hamster ovary cells the intracellular dissociation of insulin, which dissociates between pH 6.3 and 7.0, with that of lysosomal hydrolases bearing the mannose 6-phosphate recognition marker (Man-6-P proteins), which dissociate around pH 5.8. Chinese hamster ovary cells were pulsed for 2 min with 125I-insulin, acid-washed to remove surface binding, and chased. During a 40-min period, about 50% of the internalized 125I-insulin was released intact via a retrocytotic pathway. Retrocytosis was not inhibited by monensin, suggesting that the release was not dependent on acidic endosomes. The remaining insulin dissociated from its receptor in an acidification-sensitive manner and was eventually degraded. Dissociation was 70% complete within 5 min of internalization. When cells were similarly incubated with 125I-Man-6-P proteins, about 35% of the internalized radioactivity was released during a 1-h chase, reflecting proteolytic maturation of the Man-6-P proteins. Dissociation of Man-6-P proteins was acidification-dependent (i.e. inhibited by monensin), and was 50% complete after about 11 min. The results indicate that acidification-dependent dissociation of ligands does not occur in a single step and suggest that multiple endocytic compartments are involved in receptor/ligand sorting.

Animals↗

PubMed1990

Increased sensitivity to isoprenaline following digoxin pretreatment in anaesthetised and conscious dogs.

STUDY OBJECTIVE: The aim of the study was to evaluate the effect of chronic digoxin therapy on cardiac sensitivity to isoprenaline. DESIGN: Responses to isoprenaline were examined in both conscious and anaesthetised dogs pretreated with digoxin, and compared with conscious or anaesthetised controls with no digoxin pretreatment. Isoprenaline infusion (0.001-0.1 micrograms.kg-1.min-1) in pretreated groups was performed 7 d after digoxin dosing was stopped, when plasma digoxin concentrations were zero. SUBJECTS: Mongrel dogs of either sex (15-25 kg) were used in the experiments, done under anaesthetic. They were divided into three groups (n = 6 per group): group A were controls; groups B and C were pretreated with digoxin 500-750 micrograms.d-1, for 14 d (B) and 7 d (C). For the experiments in conscious animals, six mongrel dogs (25-30 kg) and two greyhounds (25-30 kg) were used; group D (n = 6) were treated with digoxin for 20-40 d; group E (n = 2) were treated for 7 d. MEASUREMENTS AND RESULTS: Heart rate, blood pressure and myocardial contractility (dP/dt: integrated isometric tension) were measured during isoprenaline infusion. Digoxin pretreatment for 14 d did not significantly change the chronotropic or depressor responses to isoprenaline in anaesthetised dogs but there was a 10-fold increase in inotropic sensitivity to isoprenaline following withdrawal. When the pretreatment period was reduced to 7 d there was no change in any of the responses to isoprenaline. In conscious dogs there was also a significant increase in inotropic sensitivity to isoprenaline after digoxin withdrawal, but this was not so marked as in anaesthetised dogs. In conscious dogs chronotropic sensitivity to isoprenaline was also increased. CONCLUSIONS: It is possible that the inotropic effect maintained during the 2 weeks of digoxin treatment may cause substantial withdrawal of sympathetic tone to the heart, with a consequent increase in beta adrenoceptor number or sensitivity, which could be detected a week after digoxin withdrawal.

Anesthesia, General↗

PubMed1989

Serum factors alter the extent of dephosphorylation of ligands endocytosed via the mannose 6-phosphate/insulin-like growth factor II receptor.

Mouse L-cells that contain the cation-independent (CI) mannose 6-phosphate (Man 6-P)/insulin-like growth factor (IGF) II receptor endocytose acid hydrolases and deliver these enzymes to lysosomes. The postendocytic loss of the Man 6-P recognition marker from the cell-associated acid hydrolases was assessed by CI-Man 6-P receptor affinity chromatography. 125I-labeled acid hydrolases internalized by L-cells grown at high density were delivered to lysosomes but were not dephosphorylated. In contrast, the same 125I-labeled hydrolases internalized by L-cells maintained at low density were delivered to lysosomes and were extensively dephosphorylated. The dephosphorylation at low density required 5 h for completion suggesting that the phosphatase responsible for the dephosphorylation is located within the lysosomal compartment. Transition from the high to low density state was rapid and was not inhibited by cycloheximide. Medium substitution experiments indicated that serum factors were necessary to maintain the L-cells in the dephosphorylation-competent (low density) state, and that serum-free conditions led to a dephosphorylation-incompetent (high density) state. Addition of IGF II to cells in serum-free medium allowed acid hydrolases subsequently introduced by endocytosis to be dephosphorylated. The results indicate that the removal of the Man 6-P recognition marker from endocytosed acid hydrolases is regulated by serum factors in the growth medium, including IGF II.

Animals↗

PubMed1988

Inotropic activity of digitoxigenin glucoside and related glycosides.

The cardiovascular effects of digitoxigenin glucoside and two derivatives, digitoxigenin glucoside tetraacetate and 4',6'-isopropylidene digitoxigenin glucoside were studied in pentobarbital-anaesthetized dogs. Digoxin (0.112 mumol/kg) and digitoxigenin glucoside (0.056 mumol/kg) produced similar increases in myocardial contractility, although digitoxigenin glucoside was faster in onset of action and had a shorter duration of action. Digitoxigenin glucoside caused a significantly greater increase in blood pressure than digoxin. Digitoxigenin glucoside tetraacetate (0.056 mumol/kg) and isopropylidene digitoxigenin glucoside (0.112 mumol/kg) also increased myocardial contractility. Time to peak effect and duration of action were similar to those of digitoxigenin glucoside. The tetraacetate derivative of digitoxigenin glucoside was less hypertensive than the parent compound. The results suggest that the rapid onset and short duration of effect are a function of the glucose moiety. The rapid onset and, what appears to be, a reduced tendency to accumulate may confer clinical potential for these analogues.

Animals↗

PubMed1987

Positive inotropic effects of histamine in anaesthetized dogs.

1 The cardiovascular effects of histamine were examined in dogs anaesthetized with pentobarbitone 2 The effect of histamine on heart rate, blood pressure, left ventricular pressure, dP/dtmax and dP/dt: IIT (integrated isometric tension) was compared in the presence and absence of autonomic reflexes and blood pressure control. 3 In innervated animals with no attempt to control blood pressure, histamine produced dose-dependent decreases in blood pressure and heart rate and either positive or negative inotropic actions. 4 When autonomic reflexes were abolished, this variability in inotropic response was reduced and histamine produced a slight positive inotropic response. There was a decrease in blood pressure and a positive chronotropic response to histamine. 5 When blood pressure was controlled and the cardiac nerves were intact, histamine produced a decrease in heart rate. However, in the denervated animals, there was a slight increase in heart rate. 6 Inotropic responses to histamine in the blood pressure controlled groups were less variable than when blood pressure was uncontrolled. In all of these animals there was an increase in contractility, the increase being more marked in the denervated group. 7 The H2-receptor agonist impromidine produced a positive inotropic action in intact animals with uncontrolled blood pressure.

Anesthesia↗

PubMed1986

Putative diazepam binding inhibitor peptide: cDNA clones from rat.

cDNA clones corresponding to the polypeptide that has been shown to be an endogenous diazepam binding inhibitor and may act as a physiological ligand for the benzodiazepine/beta-carboline receptor have been isolated from bacteriophage lambda recombinant libraries from rat hypothalamus, total brain, and liver. The clones contain an open reading frame corresponding to 87 amino acids. A signal sequence is not present. In addition to high levels of mRNA in various brain regions, RNA blot analysis reveals an abundance of diazepam binding inhibitor mRNA in many peripheral organs (e.g., testes, kidney, liver, and heart) that are known to be rich in peripheral benzodiazepine recognition sites. The size of the mRNA in all tissue examined is approximately 0.7 kilobase. Southern blot analysis of genomic DNA suggests the presence of about six genes in the rat, some of which may be pseudogenes.

Amino Acid Sequence↗

PubMed1986

Comparison of the cardiac effects of beta-adrenoreceptor agonists in anaesthetised and conscious dogs.

The cardiovascular effects of some beta-adrenoreceptor agonists on heart rate, blood pressure and myocardial contractility (maximum rate of change of left ventricular pressure/integrated isometric tension) were measured in pentobarbitone-anaesthetised and conscious, instrumented greyhounds. In anaesthetised dogs isoprenaline increased heart rate and myocardial contractility and reduced blood pressure. Prenalterol and RO 363, in equiactive inotropic doses, induced greater increases in heart rate than isoprenaline if blood pressure fell by less than 25 mmHg. Salbutamol had hypotensive activity at all doses and appeared to be a relatively selective inotrope. None of the agonists caused blood pressure to fall in the conscious dogs. Prenalterol and RO 363 were more effective inotropic stimulants, producing smaller increases in heart rate and more pronounced increases in myocardial contractility. Salbutamol, however, elicited greater increases in heart rate in the conscious animals and the inotropic selectivity demonstrated in the anaesthetised animals was lost. The direct effects of the beta-adrenoreceptor agonists, without modification by reflexes could be observed in the anaesthetised animals. The differences in the actions of the agonists in the conscious animals appear to be attributable to the state of the baroreceptor reflex control system and the relatively enhanced responsiveness of the heart.

Albuterol↗

PubMed1985

Inotropic selectivity of salbutamol and terbutaline in anaesthetised, areflexic dogs.

The cardiovascular effects of the selective beta 2-adrenoceptor agonists salbutamol and terbutaline have been evaluated in anaesthetised, areflexic dogs. The preparation was designed to reduce the effects of changes in cardiac function mediated via reflex responses to changes in blood pressure. The effects of the selective beta 2-adrenoceptor agonists on heart rate, hindlimb blood flow, left ventricular pressure, max dP/dt and (dP/dt)/IIT (integrated isometric tension) were compared to those of isoprenaline, while blood pressure was held constant. All three drugs produced dose-dependent increases in heart rate, myocardial contractility and iliac blood flow. When equiactive inotropic doses of isoprenaline and salbutamol were compared, salbutamol produced a significantly lower chronotropic effect. A similar inotropic selectivity was found when terbutaline was compared to isoprenaline. beta 2-Adrenoceptor blockade abolished this selectivity. It is concluded that, in the absence of autonomic reflex activity, the beta 2-selective adrenoceptor agonists are relatively selective inotropic stimulants.

Albuterol↗

PubMed1984

The dependence of excitatory junction potential amplitude on the external calcium concentration in narcotic tolerant mouse vas deferens.

The dependence of neurotransmitter secretion on external calcium ions during development of opiate tolerance in the mouse vas deferens was studied. The writhing response of mice to an i.p. injection of acetylcholine was inhibited by morphine. Reversal of this antinociceptive effect of morphine during chronic treatment signalled the development of tolerance. Tolerance to morphine at the neuromuscular junction was shown as a reversal of the initial shift of the size of the excitatory junction potential (e.j.p.) vs extracellular calcium concentration relationship back towards the control without any change in the power of 2.4. Facilitation in the amplitude of the e.j.p. occurs with low frequency (2 Hz) stimulation. The initial increase in facilitation induced by morphine was reversed by chronic morphine treatment without any change in the plateau e.j.p. amplitude achieved after a long low frequency train of impulses. At high frequencies (10 Hz) the initial increase in e.j.p. amplitude was followed by a depression. Acute morphine administration decreased the size of the e.j.p., this was followed by an increase in facilitation and a decrease in depression. These effects were reversed after chronic morphine treatment. Tolerance to morphine involves a counteradaptive process which restores the normal entry of calcium ions or its actions within the release sites in promoting transmitter release.

Acetylcholine↗

PubMed1984

The dependence of excitatory junction potential amplitude on the external calcium concentration in mouse vas deferens during narcotic withdrawal.

The dependence of neurotransmitter release on calcium was evaluated in adrenergic terminals from mice that were acutely withdrawn from chronic morphine treatment (CMT). A two fold increase in the number of writhes in response to an i.p. injection of acetylcholine was induced in mice by CMT and subsequent withdrawal. A shift to the left in the relationship between the excitatory junction potential (e.j.p.) amplitude and extracellular calcium concentration ([Ca]o) was induced in vasa deferentia from CMT-withdrawn mice. A reduction in the degree of facilitation of transmitter release during a short low-frequency train of impulses and an increase in the amount of transmitter release during a high-frequency train of impulses was induced in vasa deferentia from CMT-withdrawn mice. The adaptive mechanism of the terminals to the sustained presence of morphine may involve an increase in the probability that the release sites will release transmitter either via increase in calcium influx or an increase in the affinity of calcium to the hypothetical X-receptor.

Acetylcholine↗

PubMed1983

Relative inotropic and chronotropic activity of beta-adrenoceptor stimulants in anaesthetised, areflexic dogs.

The use of different methods of measuring contractility and the effects of cardiovascular reflexes are among the factors which complicate the assessment of selective inotropic activity of beta-adrenoceptor agonists. The effects of dobutamine, prenalterol, noradrenaline and isoprenaline on heart rate, iliac blood flow, left ventricular pressure, max dP/dt and (dP/dt) divided by IIT (integrated isometric tension) were evaluated in anaesthetised dogs in which the hearts were denervated and blood pressure held constant. All the drugs caused dose-dependent increases in heart rate and contractility. The relative chronotropic and inotropic activity of each agonist was evaluated. At most doses studied the agonists exerted similar chronotropic and inotropic activity when compared to the non-selective agonist isoprenaline. It is likely that the inotropic selectivity observed with prenalterol and dobutamine in previous studies depends on factors other than direct drug action.

Adrenergic beta-Agonists↗

PubMed1983

Chronic haloperidol and adrenergic receptor sensitivity in the rat.

Rats were administered haloperidol (3-4 mg/kg/day) in their drinking water for 42 days, and experiments conducted on the seventh day of withdrawal. Anaesthetized haloperidol treated rats exhibited a similar mean blood pressure (BP) and heart rate (HR) response to control rats when challenged with phenylephrine (IV). When similarly pretreated rats were challenged with one of four possible doses of clonidine (IV), haloperidol treated rats were less sensitive than control rats to clonidine's hypertensive action, but there were no effects of treatment on the hypotensive (BP) effect of clonidine nor on its bradycardic effect. When one of six possible doses of tyramine was administered a similar mean BP response was seen in both treatment groups, but the positive HR response in the haloperidol-treated group was much less than in the vehicle-treated group. Atria isolated from haloperidol treated or control rats revealed a similar chronotropic response to noradrenaline and tyramine challenge. These data indicate that chronic haloperidol does not cause a generalized change in alpha-adrenergic receptor sensitivity. Nevertheless, it is clear that haloperidol has produced changes in the cardiovascular response of rats to these drugs.

Animals↗

PubMed1982

Phosphodiesterase activity of the lower urinary tract.

Cyclic AMP is believed to mediate the physiologic response of beta-receptor stimulation in the lower urinary tract. A possible novel therapy for specific dysfunctions might be via pharmacologic modification of cyclic AMP through regulation of phosphodiesterase, the enzyme responsible for metabolizing cyclic AMP. The present study characterizes the phosphodiesterase activity present in various sections of the lower urinary tract and determines the effect of calmodulin and the potency of a series of phosphodiesterase inhibitors. The results can be summarized as follows: the phosphodiesterase activity of all smooth muscle sections of the lower urinary tract were similar. They showed nonlinear kinetics with Vmax between 1.0 and 2.4 nmol./mg. protein/minute and apparent Km's around 100 microM. The external sphincter (skeletal muscle) displayed linear kinetics with a Vmax of 0.2 nmol./mg. protein/minute and a Km of 9 microM. Of the drugs tested, papaverine was the most potent inhibitor and theophylline was one of the weakest inhibitors. These studies also indicate that the major form of cyclic AMP phosphodiesterase is not sensitive to calmodulin.

Animals↗

PubMed1981

Vitamin C and the common cold: using identical twins as controls.

We analysed self-reported cold data for 95 pairs of identical twins who took part in a double-blind trial of vitamin C tablets. One member of each twin pair took vitamin C and the other took a well matched placebo each day for 100 days. Vitamin C had no significant effect except for shortening the average duration of cold episodes by 19%.

Adolescent↗

PubMed1981

Vitamin C and the common cold: a second MZ Cotwin control study.

Self-reported cold data have been analyzed for 95 pairs of identical twins aged 14-64 who took part in a double-blind trial of vitamin C tablets. One member of each twin pair took a tablet containing 1 g vitamin C and the other took a well-matched placebo each day for 100 days. In the total sample there was no effect of vitamin C in preventing colds. However, subdivision of the data showed a significant preventive effect of the placebo in the 51 pairs living together and an equal and opposite preventive effect of the vitamin C in the 44 pairs living apart. The placebo effect in the pairs living together may be attributed to the large proportion who wrongly perceived which treatment they were taking. The reduction of colds in the vitamin C group of the pairs living apart was about 20%. There were significant correlations between cold symptoms reported and the personality trait of neuroticism. No side effects of substantive changes in serum biochemistry could be attributed to the vitamin C dose.

Adolescent↗

PubMed1978

Effect of changing metabolic rate on local blood flow control in the canine hindlimb.

This study examined the effect of changing hindlimb metabolic rate on hindlimb blood flow control in anesthetized dogs. The hyperemias induced by graded levels of arterial hypoxia and the degree of steady state autoregulation evoked by changes in blood pressure were measured. Metabolic rate was increased above the resting value by direct electrical stimulation of hindlimb muscles at rates from 0.5 to 1.5 pulses/second, and in three dogs was reduced by cooling. In response to 6 minutes of arterial hypoxia, hindlimb blood flow steadily increased. At rest, and at each level of muscle stimulation, the steepness of the response increased as arterial oxygen saturation (SAO2) decreased. At all levels of SAO2, the response was steeper at increasing stimulation rates. For SAO2 greater than 50%, the relationship between the percentage increase in blood flow from control and SAO2, however, was unaffected by the degree of muscle activity, suggesting that during mild to moderate hypoxia the dynamics of the response were similar whether the muscles were at rest or exercising. The responses to severe hypoxia (SAO2 less than 50%) during stimulation were significantly enhanced compared with those at rest. Autoregulation of blood flow was measured in the steady state by comparing the relative change in blood flow from control with the relative change in blood pressure that produced it. Steady state autoregulation was weak at rest, but improved markedly with increasing muscle stimulation. Conversely, cooling the hindlimb depressed the resting steady state autoregulation. A close correlation was found between the degree of autoregulation and the hindlimb metabolic rate. The results suggest that tissue metabolic rate determines the precision of local blood flow control.

Animals↗