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Biomedical subjects

A Bobik

Publications and source records attributed to A Bobik.

At least 127 records · Page 7Linked to original sources
PubMed1986

Na-H exchange is a major pathway for Na influx in rat vascular smooth muscle.

Rat aortic segments and aortic smooth muscle cells in primary culture were used to examine the importance of the Na-H exchange system in transporting Na into smooth muscle. Ethylisopropylamiloride was approximately 100 times more potent than amiloride at inhibiting Na influx into smooth muscle. In a 135 mM Na-containing medium approximately 80% of the Na influx rate could be inhibited by 100 microM ethylisopropylamiloride. The rate of Na entry into cells was markedly influenced by extracellular and intracellular pH. Elevating extracellular pH from 6.0 to 8.0 increased the Na influx rate. The dependence of the Na influx rate on intracellular pH was demonstrated by acidification of cells with nigericin or preincubation with ammonium chloride. These two procedures increased 22Na+ influx rate by about 3.5-fold. In both instances the increases in 22Na+ influx rate could be completely attenuated by ethylisopropylamiloride. Increases in Na influx rate via the Na-H exchange also increased the activity of the Na-K pump, thereby maintaining intracellular Na content approximately constant. These results indicate that Na-H exchange is a major influx pathway for Na in rat vascular smooth muscle. Activation of this system activates the Na-K pump, which maintains intracellular Na constant.

Amiloride↗
PubMed1986

Evidence for a predominantly central hypotensive effect of alpha-methyldopa in humans.

We examined the time course and extent to which central and peripheral mechanisms contribute to the short-term effects of a 500-mg oral dose of alpha-methyldopa on supine mean arterial pressure, cardiac output, and total peripheral resistance, as well as its effects on total urinary excretion of norepinephrine and its metabolites, in five subjects with essential hypertension. Total peripheral resistance was reduced significantly 1 hour after alpha-methyldopa administration and remained so for the ensuing 7 hours of the study (p less than 0.05). A small but significant reduction in mean arterial pressure occurred 7 hours after the dose (p less than 0.05), while cardiac output did not change significantly. Total 24-hour urinary norepinephrine and metabolite excretion was reduced by 8.1 mumol (35% compared with placebo). The relative distribution of urinary norepinephrine metabolites was unaffected by alpha-methyldopa, and the catecholamine metabolites of alpha-methyldopa, alpha-methylnorepinephrine and alpha-methylnormetanephrine did not account for this reduction. Competitive inhibition of methyldopa transport across the blood-brain barrier and into the central nervous system by large oral doses of isoleucine antagonized most of the effect of alpha-methyldopa. The effects on total peripheral resistance were completely abolished, and small, insignificant changes during the 7-hour study were similar to those observed after placebo. Changes in mean arterial pressure were not significant; however, 24-hour total urinary norepinephrine and metabolite excretion increased by 6.1 mumol to 22.7 mumol (24.7 mumol excreted after placebo). Adding benserazide to the alpha/methyldopa-isoleucine dose regimen in an attempt to inhibit any residual, presumably peripheral, effects of alpha-methyldopa caused little, if any, further antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Effects of alterations in cell phenotype and hypokalemia on sodium-potassium pump activity in rabbit vascular smooth muscle.

We investigated in cell culture, how alterations in phenotype accompanying proliferation of rabbit aortic smooth muscle and chronic hypokalemia could affect the Na,K pump. Total rubidium-86 uptake as well as ouabain and frusemide-sensitive uptake into cells was measured in physiological salts solution (PSS), PSS containing 5% foetal calf serum and PSS containing foetal calf serum plus 15 microM monensin. In physiological salts solution 90% of the rubidium-86 uptake into contractile or synthetic state cells was frusemide-sensitive and less than 8% ouabain-sensitive. Total and frusemide-sensitive rubidium-86 uptakes, measured in PSS or PSS containing foetal calf serum were similar in cells cultured and maintained in the contractile phenotype, cells in the synthetic phenotype and those which had recently reverted from the synthetic to contractile phenotype. When cells were sodium loaded in the presence of monensin and foetal calf serum, ouabain-sensitive rubidium-86 uptake was 50% higher in cells which were maintained in culture in the contractile phenotype. Frusemide-sensitive rubidium-86 uptake was similar in each cell phenotype. To examine how cell culture in hypokalemic media would affect the Na,K pump, we determined ouabain-sensitive rubidium-86 uptake in the presence of monensin plus foetal calf serum in cells incubated for 24 hours in low and normal potassium containing culture media. Ouabain-sensitive uptake was 20% higher in cells cultured in a 0.76 mM potassium medium than in those cultured in 5.4 mM potassium medium. Frusemide-sensitive rubidium-86 uptake was unaffected. These results demonstrate that 'maximal' Na,K pump activity in sodium-loaded cells is reduced when cells change from the contractile to synthetic phenotype. This reduction appears only very slowly reversible when cells revert from the synthetic to contractile phenotype. Prolonged hypokalemia increases 'maximal' activity of the Na,K pump.

Animals↗
PubMed1984

Cardioselectivity, kinetics, hemodynamics, and metabolic effects of xamoterol.

Xamoterol is a new orally active partial beta-adrenoceptor agonist. Its kinetics, hemodynamic and metabolic effects, and cardioselectivity were investigated in eight normal subjects. Plasma xamoterol concentrations after 100 micrograms/kg iv declined biexponentially over 8 hr and t 1/2 beta averaged 2.6 hr. Resting heart rate (HR) increased slightly in the supine position but was unchanged on sitting. Systolic blood pressure (SBP) rose by 5 to 10 mm Hg and cardiac index (CI) rose 15% to 20%. Both parameters were above control values 6 hr after dosing, when plasma xamoterol concentrations had fallen to about 10 ng/ml. There were no changes in diastolic or mean arterial pressure (MAP). During graded exercise the effects of xamoterol on HR and SBP were the reverse of those at rest, with lowering of exercise HR and SBP at higher work loads. CI during exercise was not altered by xamoterol. Doses of xamoterol were calculated from the kinetic data to give plasma concentrations of 100, 200, 400, and 800 ng/ml. HR and blood pressure effects at each xamoterol level were compared before and after inhibition of cardiovascular reflexes with prazosin, atropine, and clonidine. Hemodynamic effects of xamoterol and isoproterenol were compared. Before autonomic block xamoterol increased HR by 10 bpm and MAP by 7 mm Hg at the highest dose. After autonomic block there was a 200% to 300% rise in HR at each dose and MAP still rose. The rise in MAP after block could be entirely accounted for by a 23% increase in CI because total peripheral resistance did not change. The effects of isoproterenol after autonomic block were a rise in HR and a fall in MAP. Metabolic responses to xamoterol were measured at the four dose levels. There was a dose-related increase in nonesterified fatty acids and a fall in plasma lactate levels but no changes in plasma renin activity or blood glucose. Results suggest that xamoterol is a cardioselective partial beta-adrenoceptor agonist in man.

Adrenergic beta-Agonists↗
PubMed1984

Role of auto-inhibitory feed-back in cardiac sympathetic transmission assessed by simultaneous measurements of changes in 3H-efflux and atrial rate in guinea-pig atrium.

Guinea-pig right atria were labelled with [3H]-noradrenaline or [3H]-dopamine before superfusion in a flow-cell. Choice of label did not significantly alter either the relationship between 3H-efflux and number of electrical field pulses or the inhomogeneity of labelling. The relationship between 3H-efflux and frequency of 4 field pulses (0.125-2 Hz) was hyperbolic and similar to the tachycardia-frequency relationship measured simultaneously. No evidence was found for a U shaped 3H-efflux-frequency relationship (Story, McCulloch, Rand & Standford-Starr, 1981). Phentolamine (1 microM) did not alter the 3H-efflux or atrial rate responses to 4 field pulses at stimulus levels that gave 50-60% of the maximum rate response. In the presence of neuronal uptake inhibition (desipramine, DMI 0.1 microM), rate and 3H-efflux responses to 4 field pulses were enhanced at all frequencies and were further increased by phentolamine. In the absence of DMI, prolonged trains of field pulses (8 and 12 pulses) at low frequency (0.25 Hz) were not sufficient to activate auto-inhibitory feed-back. At 2 Hz phentolamine enhanced both 3H-efflux and rate responses at 12 field pulses. We conclude that in guinea-pig right atrium auto-inhibitory feed-back plays little role in the modulation of transmitter release at levels of stimulation that cause 50-60% of maximum tissue response. This is because neuronal uptake normally prevents synaptic concentrations of noradrenaline from activating prejunctional alpha 2-adrenoceptors. Stimulation sufficient to induce a near-maximal response or the presence of neuronal uptake inhibition are necessary to evoke autoinhibitory feed-back.

Animals↗
PubMed1984

Role of autoinhibitory feedback in cardiac sympathetic transmission.

The relationship between two indices of transmitter release measured simultaneously and the frequency of 4 field pulses (0.125-2 Hz) were obtained from superfused guinea pig right atria after labelling with 3H-noradrenaline. The relationships between 3H-efflux or rate responses and frequency were hyperbolic. Autoinhibitory feedback did not play a role since phentolamine (1 microM) did not alter the 3H-efflux or rate responses to 4 field pulses that gave 50-60% of the maximum rate response. In the presence of neuronal uptake block (desipramine (0.1 microM) phentolamine enhanced 3H-efflux and rate responses to 4 field pulses at all frequencies. In the absence of desipramine prolonged trains of field pulses (8-12 pulses) at low frequency (0.25 Hz) were not sufficient to activate autoinhibitory feedback. At 2 Hz phentolamine enhanced both responses at 12 field pulses. We conclude that in the right atrium autoinhibitory feedback plays little role in the modulation of transmitter release at levels of stimulation that cause 50-60% of maximum tissue response. The presence of neuronal uptake inhibition or high stimulus strengths are necessary to evoke autoinhibitory feedback.

Animals↗
PubMed1983

Influence of sympathectomy on alpha 2 adrenoceptor binding sites in canine blood vessels.

The effects of denervation of alpha 2 adrenoceptor binding sites were examined in canine arteries and veins. Denervation of the lower abdominal aorta, renal and femoral arteries and femoral veins marked reduced vessel norepinephrine concentrations. Denervation had little effect on the concentration of alpha 2 adrenoceptor binding sites or the affinity of (3H)yohimbine for these sites. The apparent lack of any significant reduction in receptor binding sites suggests that the majority of these sites are located on smooth muscle cells of blood vessels. The failure of any appreciable rise in receptor concentration following denervation is consistent with the hypothesis from functional studies that postsynaptic alpha 2 adrenoceptors on blood vessels are located extra-synaptically and hence not influenced by neurally released norepinephrine.

Animals↗
PubMed1983

The effects of endogenous phospholipase A2 activation on beta adrenoceptor function in cardiac cells.

The effects of endogenous phospholipase A2 activation by melittin on components of the beta adrenoceptor linked adenylate cyclase system were examined in cultured cardiac cells. Exposure of cardiac cells for one hour to melittin concentrations ranging from 0.125 microgram/ml to 5.0 micrograms/ml induced a concentration dependent hydrolysis of radioactively labelled phospholipids and loss of lysophospholipids from the cell membrane. Melittin concentrations of 2.5 micrograms/ml or greater markedly attenuated the isoprenaline induced rise in cyclic AMP. In vitro studies using cell homogenates suggest that phospholipase A2 activation by the higher concentration of melittin (5 micrograms/ml) partially uncoupled the beta adrenoceptor from adenylate cyclase. Beta adrenoceptor number estimated by 125I-iodohydroxybenzylpindolol specific binding as well as the affinity of isoprenaline for these binding sites were unaffected by melittin pre-exposure. The percentage stimulation of adenylate cyclase by sodium fluoride or guanylylimidodi-phosphate was not significantly affected by activation of endogenous phospholipase A2. Phosphodiesterase activity in the soluble fraction of cell homogenates increased marginally (9%, P = 0.05) in cells exposed to melittin. These results suggest that activation of endogenous phospholipase A2 within the sarcolemma can modulate the activity of the beta adrenoceptor linked adenylate cyclase system of intact cardiac cells. The reduced beta adrenoceptor responsiveness of the cells appears to be primarily due to an alteration in coupling between the beta adrenoceptor and the guanine nucleotide binding protein components of the adenylate cyclase system and not between the latter and the catalytic subunit.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Cardioselectivity of prenalterol and isoproterenol.

We examined the hemodynamic effects and kinetics of prenalterol, a new beta-adrenoceptor agonist, in 10 normal subjects. There is some doubt whether prenalterol is selective for beta 1 adrenoceptors in animals; therefore, we also compared its cardioselectivity with that of the nonselective agonist, isoproterenol, with respect to heart rate (HR) and blood pressure (BP) responses after inhibition of cardiovascular reflexes with atropine, clonidine, and phentolamine. After intravenous (2.5 mg) and oral (10 mg and 100 mg) dosing, t 1/2 beta was 2 to 3 hr. Oral bioavailability averaged 33% and was independent of dose. Oral prenalterol, 10 mg and 100 mg, increased resting HR, systolic BP, and cardiac index by up to 27% but had no significant effects during graded exercise. Prenalterol infusions were calculated to attain steady-state plasma concentrations of 10, 20, and 40 ng/ml. HR and BP effects of the levels (10.8, 23.6, and 47.4 ng/ml) were compared with those of 0.5, 1.5, and 2.5 micrograms isoproterenol. Before autonomic block, prenalterol increased HR by 10 bpm at the highest dose and mean arterial pressure (MAP) by 10 mm Hg. In contrast, HR rose and MAP fell after isoproterenol. After block, at the highest doses of prenalterol and isoproterenol, there was an average rise in HR of 42 and 27 bpm; BP was almost maintained after the former but fell by 33 mm Hg after the latter. Prenalterol is an inotropic drug that has the effects of a full cardioselective beta-adrenoceptor agonist. Its inotropic effects are evident at doses that have little effect on HR because of the modifying effect of cardiovascular reflexes. The hemodynamic effects are most obvious at rest when sympathetic tone is low.

Administration, Oral↗
PubMed1982

Effects of noradrenergic neuronal activity on 3,4-dihydroxyphenylethylene glycol (DHPG) levels. Quantitation by high performance liquid chromatography.

We describe a sensitive specific and simple high pressure liquid chromatographic procedure for determining 3,4-dihydroxyphenyl-ethylene glycol (DHPG) in both plasma and tissue. DHPG is extracted from plasma or tissue extracts by adsorption onto alumina. DHPG in the alumina eluate is detected electrochemically following chromatography on a C18 reverse phase column. The method is sensitive enough to detect approximately 20 pg/ml of plasma DHPG. Both clonidine (100 micrograms/kg) and desmethylimipramine (2.5 mg/kg) when administered to rabbits for 3 days induced significant falls in both cardiac and plasma DHPG concentrations. These experiments indicate that both tissue and plasma DHPG concentrations may be of value in assessing both the release and re-uptake of norepinephrine at peripheral sympathetic nerve endings in vivo.

Animals↗
PubMed1982

Identification of alpha adrenoceptor subtypes in dog arteries by (3H) yohimbine and (3H) prazosin.

Binding of the alpha adrenergic antagonists (3H)prazosin and (3H) yohimbine to membranes of dog arteries exhibit the characteristics expected of alpha adrenoceptors. Binding of both ligands is saturable with dissociation constants of 0.19nM and 1.15nM for (3H)prazosin and (3H)yohimbine respectively. A series of catecholamines inhibit binding of both ligands with a potency in the order epinephrine greater than norepinephrine much greater than isoproterenol, corresponding with the activity of these agents at alpha adrenoceptors in blood vessels. Competition for binding in both instances is stereoselective. l-Phenylephrine has similar potencies in inhibiting (3H)prazosin and (3H)yohimbine specific binding whilst the imidazoline related partial alpha adrenergic agonists clonidine and guanfacine are more potent in inhibiting (3H) yohimbine specific binding. The affinity of prazosin for the (3H)yohimbine binding site is approximately 2500 times less than for the (3H)prazosin site whilst yohimbine is approximately 150 times more potent in inhibiting (3H)yohimbine than (3H)prazosin specific binding. Non-selective alpha adrenergic antagonists have similar affinities for both binding sites. The concentration of (3H)yohimbine binding sites in different arteries vary about two fold whilst for (3H)prazosin in the variation was about three fold. These results indicate that there are two discrete noradrenergic binding sites in the major arteries of dog which have binding properties expected of alpha 1 and alpha 2 adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1982

The peripheral kinetics of norepinephrine in depressive illness.

Sympathetic nervous system function was studied in patients with primary depressive illness. Tritiated norepinephrine was used to measure the rate of entry to plasma of norepinephrine released from sympathetic nerves ("norepinephrine spillover rate"), and to assess the neuronal uptake of norepinephrine by studying the removal of norepinephrine from plasma. Norepinephrine spillover was elevated in five of 11 patients. This abnormality, which was unrelated to the presence of individual vegetative symptoms, occurred exclusively in patients with endogenous depression. The rapid-removal phase of the disappearance of tritiated norepinephrine from plasma, which seemed to correspond with neuronal uptake of norepinephrine, was accelerated in patients with depressive illness, providing presumptive evidence of increased neuronal uptake. If norepinephrine uptake is also accentuated within the brain, a functional deficiency of the transmitter at adrenergic receptor sites might result.

Adult↗
PubMed1982

Bioavailability of dihydroergotamine in man.

1 The pharmacokinetics of dihydroergotamine (DHE) in plasma were examined in six normotensive subjects after single acute doses of dihydroergotamine, 10 micrograms/kg i.v. and 10, 20 and 30 mg orally. 2 The mean apparent half-time of elimination was 2.37 +/- 0.29 h and plasma clearance of dHE was 1002 +/- 169 ml/min. 3 Mean apparent absorption of DHE determined from the 10 mg dose was 26.6 +/- 10% and ranged from 8.9 to 60.3%. The oral bioavailability after the 10, 20 and 30 mg doses averaged 0.47 +/- 0.07%, 0.59 +/- 0.13% and 0.52 +/- 0.14% respectively. Inter-patient variability in bioavailability was 6-fold. 4 The results indicate that pre-systemic 'first-pass' extraction of DHE is the main determinant of its oral bioavailability. Oral doses of the drug up to 30 mg do not saturate this extraction process resulting in apparently linear kinetics for the drug.

Administration, Oral↗