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Biomedical subjects

A Bobik

Publications and source records attributed to A Bobik.

174 records · Page 10Linked to original sources
PubMedDate not supplied

Mechanism of isoprenaline-induced refractoriness of the beta-adrenoceptor--adenylate cyclase system in chick embryo cardiac cells.

We examined the role of beta-adrenoceptors in regulating cardiac cell cyclic adenosine monophosphate (cyclic AMP) in concentrations during beta-receptor activation. Chick embryo cardiac cells in primary tissue culture respond to 50 microM isoprenaline with a rapid, but transient, increase in intracellular cyclic AMP. Continued exposure of these cells to this concentration of isoprenaline results in a rapid time-dependent decrease in maximum beta-receptor responsiveness. In vitro determination of adenylate cyclase and 125I-iodohydroxybenzyl pindolol specific beta-receptor binding sites in 35,000 x g particulate cell fractions and phosphodiesterase activity in cell homogenates suggest that the decrease in the cells' ability to raise intracellular cyclic AMP concentration is mainly due to an initial "uncoupling" of the beta-receptor--adenylate cyclase system. During 16 hr exposure of cells to varying isoprenaline concentrations, the magnitude of the cells' ability to increase intracellular cyclic AMP and the concentration of beta-receptor binding sites were inversely related to the isoprenaline concentration to which they had been previously exposed. On removal of isoprenaline, both beta-receptor response and receptor concentration returned slowly towards control levels over the next 24 hr. These results suggest that loss of beta-receptor responsiveness of cardiac cells during prolonged exposure to isoprenaline involves both alterations in receptor number and alterations of the adenylate cyclase system distal to the receptor.

Adenylyl Cyclases↗
PubMedDate not supplied

Role of cyclic AMP in cardiac beta-adrenoceptor desensitization: studies using prenalterol and inhibitors of phosphodiesterase.

We examined the effects of prolonged exposure of cardiac cells in primary culture to the partial beta-adrenoceptor agonist prenalterol and inhibitors of phosphodiesterase on their subsequent ability to increase intracellular cyclic AMP during a 5-min exposure to 50 microM isoprenaline (receptor responsiveness). Although prenalterol possesses only 7% of the agonist activity of isoprenaline on adenylate cyclase, it induces extensive beta-adrenoceptor desensitization. Three hours after exposing the cells to 1 microM prenalterol, beta-adrenoceptor responsiveness was reduced by 40% (p less than 0.05), whereas after 12 h the reduction averaged 55%. Prolonging the incubation time to 48 h had no further effect on the magnitude of receptor desensitization. The magnitude of the desensitization was concentration dependent. On exposure of cells to 10(-8) M prenalterol for 16 h, receptor responsiveness was reduced by 19%, and at concentrations of 1 microM and higher responsiveness was reduced by 60% (p less than 0.01). Receptor desensitization appeared to be due to an inability of receptors to activate adenylate cyclase as well as to receptor loss. To investigate if beta-adrenoceptor desensitization as well as receptor loss could be mediated by cyclic AMP, the cells were exposed for 16 h to inhibitors of phosphodiesterase. Exposure of cells to the phosphodiesterase inhibitor isobutylmethylxanthine (0.1 mM) (which increased intracellular cyclic AMP by between 50 and 150%) also induced receptor desensitization. The reduction in receptor responsiveness averaged 62% (p less than 0.01). The loss in responsiveness could be accounted for by an inability of receptors to activate adenylate cyclase as well as by receptor loss.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Effects of histamine bolus injections and continuous infusions on the H1- and H2-receptors in the hindlimb vessels of the rabbit.

1. Hindlimb vascular resistance (HVR) was continuously measured after pharmacological block of the autonomic effectors in unanesthetized rabbits with previously implanted Doppler ultrasonic flowmeters. 2. Histamine bolus injections caused a dose-related short lived fall in HVR followed by a more sustained rise. The fall was due to H2-receptor stimulation (blocked by burimamide or metiamide) and the rise to H1-receptor stimulation (blocked by mepyramine). At the doses of histamine tested the magnitude of the H1-mediated vasoconstriction had a larger peak effect than the H2-mediated vasodilatation. 3. Histamine infusions up to 200 microgram kg-1 min-1 did not alter HVR significantly but both increases and decreases in HVR were observed after giving H2- or H1-antagonists, respectively. 4. From the double reciprocal plots of 1/peak HVR change and 1/dose of histamine the magnitude of the predicted H1- and H2-mediated peak HVR effects at large doses were the same. This suggested that the number of H1- and H2-receptors were similar in the hindlimb vascular bed, in agreement with the infusion data.

Animals↗
PubMedDate not supplied

Pharmacokinetics of methyldopa. Plasma levels following single intravenous, oral and multiple oral dosage in normotensive and hypertensive subjects.

1. The pharmacokinetics of methyldopa after oral and intravenous administration was studied in hypertensive and normotensive patients. After intravenous administration methyldopa plasma concentrations decayed according to a two-compartment open model. 2. For intravenous administration the overall elimination constant Ke1 was 0.56 +/- 0.03 h-1, the volume of distribution of the central compartment 0.29 +/- 0.80 1 kg-1 and the plasma clearance rate 11.2 +/- 0.6 1 h-1. 3. Plasma half-times during the beta-phase of the methyldopa plasma decay curve following intravenous and oral administration were 2.8 +/- 1.3 and 2.1 +/- 0.7 h, respectively. 4. Maximal plasma levels in hypertensive out-patients show great variation and range from 0 to 1.9 microgram ml-1. 5. No relationships were found between maximal methyldopa plasma levels in patients under treatment and control of hypertension.

Administration, Oral↗
PubMedDate not supplied

Assessment of neuronal uptake of noradrenaline in humans: defective uptake in some patients with essential hypertension.

1. Disappearance of tritiated noradrenaline from plasma, after infusion to steady-state, was studied to assess neuronal uptake of noradrenaline inessential hypertension. 2. Plasma tritiated noradrenaline disappearance was biexponential. Rapid removal was dependent on neuronal uptake, being slowed both in normal subjects after desipramine, and in patients with sympathetic nerve dysfunction (autonomic insufficiency). 3. In nine of thirty-eight hypertensive patients the t1/12 similarly was prolonged. Endogenous noradrenaline escaping uptake after release, and spilling over into plasma, was increased in these patients. 4. Defective neuronal uptake of noradrenaline, by exposing adrenergic recepotors to high local transmitter concentration, may be important in the pathogenesis of essential hypertension in some patients.

Adult↗
PubMedDate not supplied

Differing noradrenaline kinetics in essential hypertension and depressive illness, two diseases in which the plasma concentration of noradrenaline is sometimes elevated.

1. The rate of spill-over of noradrenaline to plasma, and neuronal noradrenaline uptake, which influences spill-over, were studied in patients with essential hypertension and depressive illness. 2. Noradrenaline spill-over was increased in seven of thirty-four patients with essential hypertension and five of eleven patients with primary depressive illness, compared with values in seventeen normal subjects (range 1.0-3.63 nmol/min per m2). 3. Faulty neuronal reuptake of noradrenaline seemed to be the cause of higher noradrenaline spill-over in patients with essential hypertension. Increased sympathetic nerve firing rates apparently were responsible in the primary depressives, despite their normal blood pressure. 4. These puzzling findings suggest that hypertension occurs when neurotransmitter excess is due to defective noradrenaline reuptake (in essential hypertension), but not chronically increased nerve firing (in depressive illness).

Adult↗
PubMedDate not supplied

Regulation by protein kinase C of transforming growth factor-beta 1 action on the proliferation of vascular smooth muscle cells from spontaneously hypertensive rats.

1. This study examined the role of protein kinase C (PKC) on the action of transforming growth factor-beta 1 (TGF-beta 1) to regulate the proliferation of vascular smooth muscle cells (VSMC) isolated from the aorta of the spontaneously hypertensive rat (SHR). 2. Down-regulation of PKC by prolonged exposure to phorbol 12-myristate 13-acetate (PMA) completely inhibited the ability of TGF-beta 1 to potentiate epidermal growth factor-stimulated proliferation of VSMC. 3. In contrast, the inhibitory effect of TGF-beta 1 on serum-stimulated proliferation of VSMC was not altered by PMA action. 4. These results suggest that PKC-dependent signalling pathways involved in the regulation of growth by TGF-beta 1 may be important in any proliferative component of vascular hypertrophy that develops in the SHR.

Animals↗
PubMedDate not supplied

Norepinephrine kinetics in essential hypertension. Defective neuronal uptake of norepinephrine in some patients.

To assess sympathetic nervous system function in essential hypertension, we measured the rates of release to and removal from plasma of the sympathetic neurotransmitter, norepinephrine. In normal subjects, disappearance of tritiated l-norepinephrine from plasma, after infusion to steady state, was biexponential, with t1 1/2 = 2.0 +/- 0.4 minutes (mean +/- standard deviation) and t2 1/2 = 33 +/- 15 minutes. The rapid component of removal seemed to represent neuronal uptake of norepinephrine: the t1 1/2 was lengthened by the selective inhibitor of neuronal norepinephrine uptake, desipramine; it was not changed by the extraneuronal uptake blocker, cortisol; and it was prolonged in patients with peripheral sympathetic nerve dysfunction (idiopathic autonomic insufficiency). In eight of 37 hypertensive patients, the t1 1/2 was greater than 2.8 minutes (range, 3.3-6.0 min), longer than in any normal subject; this appears to be presumptive evidence of the existence of defective neuronal norepinephrine uptake. In these patients the rate of spillover of norepinephrine to plasma, of transmitter escaping uptake after release, was 0.73 +/- 0.39 micrograms/m2/min (4.3 +/- 2.3 nmoles/m2/min), higher than in normal subjects, 0.36 +/- 0.14 micrograms/m2/min (2.1 +/- 0.8 nmoles/m2/min) (p less than 0.01). A defect in neuronal uptake of norepinephrine, by exposing adrenergic receptors to high local norepinephrine concentration, may be important in the pathogenesis of blood pressure elevation in some patients with essential hypertension.

Adolescent↗
PubMedDate not supplied

Central and peripheral autonomic mechanisms involved in the circulatory actions of methyldopa.

Intracisternal (i.c.) and intravenous (i.v.) administration of methyldopa in conscious rabbits produced closely similar changes in hemodynamics, heart rate, and falls in plasma norepinephrine levels. Two weeks after giving i.c. 6-hydroxydopamine (6-OHDA), when there is widespread destruction of central noradrenergic neurons, the effects of i.c. methyldopa virtually were abolished. This suggests that noradrenergic neurons are the major central site of biotransformation into active metabolites. The circulatory and norepinephrine effects of i.v. methyldopa were attenuated but not completely abolished after giving i.c. 6-OHDA. Hence, in the rabbit about 70% of the action of methyldopa was central and about 30% was peripheral in the human therapeutic range of methyldopa concentrations. Preliminary lesion experiments suggest that the A5 nucleus plays an important role in the bradycardia. Two weeks after giving 5,6-dihydroxytryptamine (5,6-DHT) to destroy serotonergic (5HT) neurons the effects of i.c. methyldopa on mean arterial pressure (MAP) and heart rate were attenuated to approximately 50% of control effects. Therefore, some of the central effects of methyldopa apparently are mediated through 5HT pathways. We also compared the effects of i.c. methyldopa with those of i.c. clonidine (an alpha 2-adrenergic receptor agonist) and with the effects of transmitter release from the endings of noradrenergic and 5HT neurons during the first few hours after either 6-OHDA or 5,6-DHT administration. Our findings suggest that after biotransformation of methyldopa its active metabolites increase the activity of the bulbospinal noradrenergic neurons that control MAP and heart rate and reduce the activity of bulbospinal 5HT neurons.

5,6-Dihydroxytryptamine↗
PubMedDate not supplied

Contribution of central and peripheral mechanisms to the antihypertensive effects of alpha-methyldopa in the rabbit.

We compared the effects of one intracisternal (0.6 mg/kg i.c.) and two intravenous (25 and 50 mg/kg i.v.) doses of alpha-methyldopa (alpha-MD) on blood pressure, heart rate, and plasma catecholamines in rabbits before and 2-3 weeks after intracisternal administration of 6-hydroxydopamine (6-OHDA). Intracisternally administered alpha-MD lowered heart rate, blood pressure, and plasma noradrenaline levels. Peak effects on heart rate and blood pressure were observed 2-3 h after administration. Three hours after intracisternally administered alpha-MD, plasma noradrenaline levels were reduced by 58%. Two to three weeks after 6-OHDA administration, the central mechanism responsible for the falls in heart rate, blood pressure, and plasma noradrenaline levels was abolished. The effects of intravenously administered alpha-MD (50 mg/kg) on heart rate, blood pressure, and plasma noradrenaline levels were attenuated but not completely abolished by destruction of central catecholaminergic neurons with 6-OHDA. These residual effects of alpha-MD most probably represent the peripheral effects of alpha-methylnoradrenaline at sympathetic terminals. The relative magnitudes of central to peripheral effects of alpha-MD on heart rate and blood pressure are dose dependent. After the lower intravenous dose (25 mg/kg), which achieves plasma alpha-MD concentrations similar to those found in humans, central mechanisms predominant. At higher doses, central and peripheral mechanisms contribute equally to these effects.

Animals↗
PubMedDate not supplied

Mechanism of isoprenaline induced desensitization of rabbit aortic smooth muscle beta-adrenoceptor responses.

The effects of short term (1 h) as well as prolonged (16 h) activation of beta-adrenoceptors by isoprenaline on the functioning of the beta-adrenoceptor linked adenylate cyclase system of rabbit aortic smooth muscle cells in the contractile phenotype in primary culture was examined. Smooth muscle cells responded to 50 mumol/l isoprenaline with a rapid increase in intracellular cAMP. Continued exposure of these cells to this concentration of isoprenaline results in a rapid time dependent reduction in maximum beta-adrenoceptor responsiveness. In vitro analyses of adenylate cyclase activities, phosphodiesterase activity and 125I-iodocyanopindolol specific (beta-adrenoceptor) binding sites suggest that the decrease in the cells' ability to increase intracellular cAMP may be due to a reduction in beta-adrenoceptor binding sites. The loss in cell receptor responsiveness and membrane receptor concentration was only very slowly reversible. These results suggest that following prolonged exposure of vascular smooth muscle cells to beta-adrenoceptor agonists, beta-adrenoceptors are rapidly internalized and degraded. This mechanism may account for the haemodynamic tolerance observed to chronic therapy with beta-adrenoceptor agonists.

Adenylyl Cyclases↗