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Biomedical subjects

A Bobik

Publications and source records attributed to A Bobik.

At least 109 records · Page 6Linked to original sources
PubMed1988

The effects of alterations in membrane sodium transport on rat aortic smooth muscle proliferation.

The univalent cations Na+, K+ and H+ are known to play a critical role in regulating growth in a number of mammalian cell types. In this study we used tissue culture to explore the ways in which two cation transport processes, known to affect the intracellular concentrations of these ions, and Na-H exchange and the Na-K pump, affect serum proliferation of rat aortic smooth muscle. Exposure of quiescent serum-deprived smooth muscle to 10% serum increased both the Na-H exchange and the activity of the Na-K pump. This activation of Na-H exchange increased intracellular pH in proliferating cells by 0.22 units. Attenuation of exchange activity by 40 mumol/l ethylisopropylamiloride (EIPA) reduced the smooth muscle replication rate by 79%. Attenuation of the Na-K pump activity also reduced the replication rate. These results indicate that alterations in the activities of either Na-H exchange or Na-K pump activity will influence smooth muscle cell replication.

Amiloride↗
PubMed1988

Relationships between the cardiovascular effects of alpha-methyldopa and its metabolism in pontomedullary noradrenergic neurons of the rabbit.

We compared the biotransformation of equipotent intracisternal (i.c., 600 micrograms/kg) and intravenous (i.v., 50 mg/kg) doses of alpha-methyldopa (alpha-MD) to alpha-methylnorepinephrine (alpha-MeNE) in the five major (A1, A2, A5, A6, and A7) noradrenergic nuclei of the rabbit brain, in relation to their cardiovascular effects. Peak effects on blood pressure and heart rate occurred 2-3 h after administration and persisted for 8 h. Three hours after i.v. alpha-MD, norepinephrine (NE) content throughout the five cell group regions was greatly reduced. However, total catecholamine (CA) content (NE plus alpha-MeNE) in the five cell groups increased by up to 300% due to accumulated alpha-MeNE. Eight hours after the i.v. dose, CA content throughout all five cell groups remained elevated. Following i.c. alpha-MD, a similar pattern of effect was observed in the A1, A2, and A5 regions. In the A6 and A7 regions, the effects were small and transient. Three hours after the i.c. dose, there was some biotransformation of alpha-MD but CA content was not affected. By 8 h, alpha-MeNE accounted for only a small fraction of the CA content. These results suggest that A1, A2, and A5 areas could be contributing to alpha-MD's cardiovascular effects. The elevation in CA content may be responsible for the activation of noradrenergic depressor pathways and blood pressure reduction.

Animals↗
PubMed1988

Effect of antihypertensive therapy on the cardiovascular amplifiers.

1. In established chronic hypertension the amplifier properties of vessels and heart contribute about 70% to the maintenance of the elevated blood pressure (BP). Recent studies in spontaneously hypertensive rats (SHR) suggest that the structural changes occur very early and their amplifier properties may be critical for the development of hypertension. 2. In patients with primary hypertension, the greater the regression of cardiac and vascular hypertrophy, the slower the subsequent redevelopment of hypertension. Following regression of hypertrophy, the antihypertensive action of moderate regular exercise can maintain BP in the normal range in a proportion of patients. 3. Early treatment of SHR with enalapril greatly reduces the subsequent 'steady-state' BP in SHR. This produces virtually complete regression of vascular hypertrophy, but somewhat lesser degrees of regression of cardiac hypertrophy. 4. These studies serve as models for primary and secondary prevention of hypertension. A strategy based on intermittent drug and non-pharmacological therapy in man may contribute to the secondary prevention of atherosclerosis, in view of the adverse effects on lipid profiles of many antihypertensive drugs.

Animals↗
PubMed1988

Spontaneous oscillations in cytoplasmic free calcium concentration in vascular smooth muscle: a potential mechanism associated with myogenic tone.

1. The cytoplasmic free calcium concentration was monitored in primary rat aortic smooth muscle cells, grown in culture and serum-deprived for 24-48 h, with the calcium sensitive fluoroprobe, Fura-2. 2. In the absence of external stimuli, spontaneous increases in the cytoplasmic free calcium concentration were observed which averaged 60 +/- 11 nmol/l and lasted approximately 30 s. 3. The calcium transients were in part dependent on intracellular calcium and were abolished when the temperature was lowered to 10 degrees C. 4. It is concluded that vascular smooth muscle cells have an inherent ability to initiate spontaneous transient increases in cytoplasmic free calcium concentration via membrane calcium channels.

Animals↗
PubMed1988

Vascular smooth muscle polyploidy in the development and regression of hypertension.

1. Two groups of spontaneously hypertensive rats (SHR) were treated with enalapril (25-30 mg/kg per day): Group I received treatment from 4 to 14 weeks of age to inhibit development of hypertension and Group R received the drug from 14 to 20 weeks of age to reverse established hypertension. 2. Systolic blood pressure, ploidy of aortic smooth muscle cells (flow cytometric DNA analysis) and aortic hypertrophy (medial cross-sectional area) were determined at times both during and after enalapril treatment (up to 30 weeks). 3. Enalapril treatment normalized blood pressure to that of age-matched Wistar-Kyoto rats in both groups. Blood pressure rose again following cessation of treatment. 4. In untreated SHR the incidence of polyploid cells increased concomitantly with increasing pressure throughout the time studied, whereas in Group I the incidence remained low. In Group R, the incidence of polyploidy directly paralleled both the decrease (normalization) and the rise in blood pressure following cessation of treatment. 5. Hence, the incidence of vascular smooth muscle cell polyploidy is not simply a result of growth of the vessel with increasing age of the SHR, but parallels inhibition, reversal, and redevelopment of hypertension.

Aging↗
PubMed1988

Effects of 5,6-dihydroxytryptamine on the release, synthesis, and storage of serotonin: studies using rat brain synaptosomes.

5,6-Dihydroxytryptamine is a neurotoxic analogue of serotonin which can have profound cardiovascular effects within minutes of administration in vivo (Korner and Head, 1981). These effects have been attributed to 5,6-dihydroxytryptamine-induced serotonin release, although there has been no biochemical assessment of the extent to which this occurs. The present study utilized an in vitro synaptosomal assay to determine the short-term effects of 5,6-dihydroxytryptamine on endogenous serotonin release, synthesis, storage, and metabolism. 5,6-Dihydroxytryptamine produced a rapid depletion of serotonin. At lower concentrations of 5,6-dihydroxytryptamine (0.1-1 microM), this depletion was associated primarily with an increase in the levels of 5-hydroxyindoleacetic acid, the deaminated metabolite of serotonin, with small increases in the amount of serotonin release. At higher concentrations (10-100 microM), a greater proportion of the depleted serotonin was released with less metabolism occurring. When metabolism was prevented by inhibiting monoamine oxidase, the amount of serotonin which was released equalled the amount of serotonin depletion. Thus monoamine oxidase activity was important in controlling the amount of serotonin which could be released by 5,6-dihydroxytryptamine. Further studies demonstrated that an impairment in serotonin synthesis and vesicular storage could account for the rapid depletion produced by 5,6-dihydroxytryptamine. Taken together, the results indicate that 5,6-dihydroxytryptamine acts to displace serotonin from vesicular stores into the cytoplasm where it can either be deaminated by monoamine oxidase or be released. Moreover, it is hypothesized that the intraneuronal concentration of 5,6-dihydroxytryptamine is important in determining the extent of serotonin release, because it can inhibit the deamination of serotonin by monoamine oxidase.

5,6-Dihydroxytryptamine↗
PubMed1987

Effect of autonomic blockade on the hemodynamic responses of normal human subjects to acute intravenous milrinone.

We studied the hemodynamic effects of four doses of milrinone, administered by intravenous (i.v.) infusion alone and after autonomic blockade with prazosin, propranolol, atropine, and clonidine. Plasma concentrations of milrinone (50-600 ng/ml) were similar to those used for the treatment of cardiac failure and were unaltered by autonomic blockade. When given alone, milrinone induced dose-dependent increases in heart rate (maximum increase 21 +/- 4, SEM, beats/min) and cardiac output (CO) (maximum 44 +/- 9%) and reduced systemic vascular resistance (SVR) by a maximum of 32 +/- 5%. After autonomic blockade, milrinone caused a similar fall in SVR and a smaller but significant (7 +/- 2 beats/min) rise in heart rate, but no change in CO. The increase in CO produced in normal humans by acute i.v. infusions of milrinone depends on intact cardiovascular reflexes.

Adult↗
PubMed1987

Regulation of sodium influx and sodium, potassium pump activity by a sodium-hydrogen antiport in rat vascular smooth muscle.

1. The effects of Na-H antiport inhibitors on sodium influx, intracellular pH and Na,K-pump activity were examined in vascular smooth muscle from rats. 2. Amiloride and 5-(N-ethyl-N-isopropyl)amiloride inhibited Na accumulation following inhibition of the Na,K-pump. 3. Inhibition of Na influx was associated with a reduction in basal Na,K-pump activity and intracellular pH. 4. It is concluded that a Na-H antiport system in vascular smooth muscle regulates Na influx rate, contributes to intracellular pH regulation and influences basal levels of Na,K-pump activity.

Amiloride↗
PubMed1987

Effects of five non-steroidal anti-inflammatory drugs on the renal and systemic responses to arachidonate in conscious dogs.

1. The effects of five different non-steroidal anti-inflammatory drugs (NSAID) on the renal blood flow responses to arachidonate were compared. 2. Arachidonate (5-200 micrograms/kg) injected into the renal arteries of conscious dogs caused dose-related renal vasodilatation with no systemic effects. 3. Aspirin (35 mg/kg), phenylbutazone (12 mg/kg) and ibuprofen (25 mg/kg) all markedly reduced arachidonate-induced renal vasodilatation. 4. In contrast, neither indomethacin (3 mg/kg) or its related drug sulindac sulphide (6 mg/kg) significantly reduced arachidonate-induced renal vasodilatation. 5. All NSAID abolished the hypotensive response to intravenous injection of arachidonate (10 mg). 6. Thus, indomethacin and sulindac did not block the effects of renal artery injections of arachidonate but did abolish the systemic effects. Aspirin, phenylbutazone and ibuprofen greatly reduced responses to both renal artery and intravenous arachidonate. 7. Indomethacin and aspirin both reduced the production of prostaglandin E2 and 6-keto-PGF1 alpha by dog renal cortical microsomes in vitro. 8. Thus, indomethacin and sulindac had different effects to other NSAID on arachidonate-induced renal vasodilatation. The results are compatible with the hypothesis that some sites of prostaglandin production in the kidneys of conscious dogs may be relatively resistant to inhibition by indomethacin and sulindac.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

The cardiovascular amplifiers in human primary hypertension and their role in a strategy for detecting the underlying causes.

The present review considers evidence that in chronic hypertension, hypertrophy of the muscles of the resistance vessels and left ventricle (LV) accounts for their intrinsic properties as haemodynamic amplifiers. In spontaneously hypertensive rats (SHR) there is early hypertrophy of both vessels and LV, suggesting that they may initiate hypertension; slow development of alpha-adrenoceptors may contribute to the early preponderance of the LV amplifier. In human hypertension LV hypertrophy occurs in most patients, including a high proportion of mild hypertensives. In Goldblatt one-kidney hypertension the stenosis resistance, which is the initiating cause, accounts for 25% of the rise in blood pressure throughout, with 75% initially due to systemic constrictor action of angiotensin II and later due to the amplifier properties of the hypertrophied heart and vessels. The cardiovascular amplifiers must be important in all chronic hypertension, so that if hypertrophy can be reversed, detection of the initiating mechanism should be easier. Studies in patients indicate that drug therapy can reverse hypertrophy and that subsequent redevelopment of hypertension is markedly slowed. We postulate an intrinsic disturbance of muscle performance in all primary hypertension, which may be triggered through the sympathetic nervous system in some patients and through altered cation transport in others.

Animals↗
PubMed1987

Na-H antiport in cultured rat aortic smooth muscle: its role in cytoplasmic pH regulation.

We have investigated the role of the Na-H antiport in the regulation of intracellular pH (pHi) in vascular smooth muscle. Experiments were conducted on contractile-state rat aortic smooth muscle cells grown in primary culture and loaded with the pH-sensitive, fluorescent indicator 2',7',-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF). Cells equilibrated in a normal physiological salt solution (PSS) containing 135 mM Na, pH 7.4 at 37 degrees C, had a pHi of 7.16 +/- 0.04 (means +/- SE; n = 8). 5-(N-ethyl-N-isopropyl)amiloride (EIPA) caused a concentration-dependent fall in pHi. Removal of extracellular Na caused an intracellular acidification that was rapidly reversed on replacement of Na. The rate of recovery from NH4Cl-induced intracellular acidosis was dependent on extracellular Na concentration (Km 14.6 +/- 2.8 mM) and was accelerated by increasing the transmembrane Na gradient and slowed by decreasing it. Recovery from acidosis was completely abolished by either EIPA or the absence of extracellular Na. These results demonstrate that the Na-H antiport is an important mechanism for the maintenance and regulation of pHi in vascular smooth muscle cells. The BCECF fluorescence technique provides an ideal method for further studies on the mechanisms for pHi regulation in these cells.

Acidosis↗
PubMed1987

Role of brain amine transmitters and some neuromodulators in blood pressure, heart rate, and baroreflex control.

We studied the acute effects of transmitter release induced by intracisternal (i.c.) 6-hydroxydopamine (6-OHDA) from mainly noradrenergic (NA) neurons and by 5,6-dihydroxytryptamine (5,6-DHT) from serotonergic (5HT) neurons. Each group of neurons affects blood pressure and heart rate in conscious rabbits through both suprapontine and bulbospinal pathways that alter both sympathetic and vagal function. Some of the pathways are complex with 5HT neurons and NA neurons in series with one another, while in others a given autonomic function is altered through parallel independent mechanisms. The central effects of alpha-methyldopa and clonidine on blood pressure and heart rate are mediated through both groups of neurons. We examined the role of the main bulbar NA neuron groups by producing bilateral electrolytic lesions of the A1, A2, A1 + A2, A5, and A6 + A7 regions, allowing time for degeneration and noting which component of the 6-OHDA transmitter release response had become affected by the lesion. These studies suggest that each is an integrative site with distinctive NA projections to the different autonomic motoneuron pools. We also examined how physiological changes in plasma levels of angiotensin II (AII) modulate the properties of the baroreceptor-heart rate reflex. The vagal component of the reflex is depressed and this is mediated through the action of AII on peripheral vagal ganglia, so that less acetyl choline is released per nerve impulse. This provides one model of the mechanisms by which central peptide transmitters may alter the action of other transmitters.

Angiotensin II↗
PubMed1986

High-performance liquid chromatographic analysis of norepinephrine and alpha-methylnorepinephrine in microdissected noradrenergic cell groups of the rabbit brain.

A high-performance liquid chromatographic method with electrochemical detection has been developed to measure norepinephrine (NE) and alpha-methylnorepinephrine (alpha-MeNE) in microdissected noradrenergic cell groups of the rabbit brain stem. The method is shown to be specific, accurate and precise and has a sensitivity of 0.5 pmol per sample. The method has been applied to the measurement of NE and alpha-MeNE levels in the A1, A2, A5, A6 and A7 noradrenergic cell groups after administration of the antihypertensive drug alpha-methyldopa (alpha-MD), so that the sites of action of alpha-MD within the central nervous system may be localised.

Animals↗
PubMed1986

Forskolin-mediated activation of cardiac, liver and lung adenylate cyclase in the rat. Relation to [3H]forskolin binding sites.

We investigated whether differences in binding sites for [3H]forskolin could account for the low potency of forskolin on adenylate cyclase (EC 4.6.1.1) from rat lung compared with heart or liver adenylate cyclase. Forskolin (0.1 mM) increased basal adenylate cyclase activity 41-fold in heart, 27-fold in liver, but only 3-fold in lung. The low potency in lung could not be accounted for by any lack of enzyme or stimulatory nucleotide-binding protein, since sodium fluoride (10 mM) increased basal activity 9-12-fold in all three tissues. The effectiveness of forskolin on adenylate cyclase appears to be related to the presence of specific [3H]forskolin binding sites. [3H]Forskolin binding in both heart and liver membranes was consistent with single binding sites with dissociation constants of 0.74 +/- 0.25 microM and 1.43 +/- 0.21 microM respectively. No such binding sites were detected in lung membranes. The binding was of low affinity (greater than 100 microM) and showed no tendency to saturate. These results are not consistent with the hypothesis that the nucleotide-binding protein influences stimulation of adenylate cyclase by forskolin, rather [3H]forskolin binding sites appear to be an important determinant of the effect of forskolin in different tissues.

Adenylyl Cyclases↗
PubMed1986

Differential effects of sino-aortic denervations on cardiac noradrenaline stores, turnover and neuronal re-uptake in normotensive and renal hypertensive rabbits.

The effects of sino-aortic denervation (SAD) on cardiac noradrenaline stores, turnover and neuronal re-uptake were examined in normotensive rabbits and rabbits with two-kidney, two wrapped hypertension. Ten to 12 days after SAD, left ventricular (LV) noradrenaline stores were reduced in renal hypertensives to 43% of that of the sham-operated rabbits, although there was no overt evidence of heart failure. This did not occur after SAD of normotensive rabbits. The reduction in noradrenaline content was accompanied by a reduction in [3H]-noradrenaline turnover time (4.4 h) compared with renal hypertensive (7.4 h) and the normotensive subgroups (9.3 h). Noradrenaline turnover rates were elevated by 25% in hypertensive compared with normotensive rabbits. Left ventricular tyrosine hydroxylase, dopamine-beta-hydroxylase and type A monoamine oxidase activities were similar in normotensive and hypertensive rabbits and were unaffected by SAD. Following SAD of hypertensive rabbits cardiac neuronal uptake for alpha-methylnoradrenaline was reduced by 33% compared with either the hypertensive or the normotensive rabbits. Sino-aortic denervation did not affect neuronal uptake in normotensives. These results suggest that following SAD of hypertensive rabbits, cardiac noradrenaline stores are depleted by enhanced cardiac sympathetic activity (reduction in [3H]-noradrenaline turnover time) and a reduction in neuronal re-uptake. It appears that the hypertensive hypertrophied heart is less able to tolerate chronic sympathetic overactivity and/or liability in coronary oxygen supply brought about by SAD.

Animals↗