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R Marthan

Publications and source records attributed to R Marthan.

89 records · Page 5Linked to original sources
PubMed1991

Contraction of vascular smooth muscle induced by phorbol 12,13 dibutyrate in human and rat pulmonary arteries.

1. The effect of phorbol 12,13 dibutyrate (PDB) on vascular tone was studied in both human and rat isolated pulmonary arterial strips (HPA and RPA, respectively). 2. PDB (1 nM to 2 microM) produced slowly developing, sustained and concentration-dependent contractions in HPA (mean EC50 = 3.5 nM, n = 5) and RPA (mean EC50 = 120 nM, n = 5). The maximal response was 185.6 +/- 25% and 207 +/- 27.5% (n = 5) of that induced by K(+)-rich (80mM) solution, and 223 +/- 34.5% and 176.5 +/- 38.6% of the noradrenaline (10 microM)-induced contraction in HPA and RPA, respectively. 3. PDB-induced contractions were not altered either by the presence of atropine (10 microM), propranolol (5 microM), phentolamine (5 microM) or tetrodotoxin (10 microM) in the bathing solution, or by the removal of endothelium from pulmonary arteries. 4. In HPA, the amplitude of PDB-induced contractions was significantly reduced by removal of external calcium ions, addition of verapamil (10 microM) or trifluoperazine (TFP, 5 microM) and significantly increased by Bay K 8644 (0.5 microM). In contrast, in RPA, calcium-free solution and verapamil had only a moderate effect on the maximal PDB-induced contraction (approximately 20% reduction), whereas Bay K 8644 and TFP had no significant effect. In both HPA and RPA, PDB-contractions in calcium-free solutions were not modified by ryanodine (25 microM) or by 8-(N,N diethylamino)octyl-3,4,5, trimethoxybenzoate hydrochloride (TMB-8, 50 microM). 5. PDB-induced contractions were inhibited by protein kinase C (PKC) antagonists. The maximal response was decreased by 60 +/- 10.5% and 35 +/- 11.5% (n = 5) by 145-isoquinolinesulphonyl)-2-methylpiperazine (H7, 50 microM), 70.5 +/- 12.2% and 56 +/- 18% (n = 5) by phloretin (100 microM) and 80.7 +/- 8.4% and 71 +/- 14% (n = 5) by staurosporine (25 nM) in HPA and RPA, respectively.6. Long term treatment (15-20 h) of arterial strips with phorbol esters (phorbol 12,13 didecanoate, or PDB) abolished the contractile response to subsequent addition of PDB.7. These results show that PDB is a potent vasoconstrictor agent in human and rat pulmonary arteries. Unlike the rat, part of the PDB response depends on calcium influx in human preparations. PDB action appears mainly mediated by the activation of protein kinase C. PKC could thus play a major role in the control of vascular pulmonary reactivity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Sensitization alters contractile responses and calcium influx in human airway smooth muscle.

Although an abnormality in airway smooth muscle has been promoted as a mechanism for airway hyperresponsiveness, there is, so far, little evidence to support this. We investigated whether in vitro hyperresponsiveness to pharmacologic agents could be induced in human airway tissue by passive sensitization and whether these changes in contractile responses were related to an alteration in calcium mobilization. Human bronchial tissue was incubated in serum with a high RAST titer to Dermatophagoides farinae. Control tissues were incubated in serum taken from a skin test-negative donor with a total IgE of less than 10 IU/ml. We compared contractile responses to histamine, KCI, and carbachol in nonsensitized and sensitized tissues and examined the effect on these responses of the calcium voltage-dependent channel agonist, BAY K8644 (10(-6) mol/L). We found that sensitization significantly increased responses to histamine, depressed responses to carbachol, and increased the involvement of the calcium voltage-dependent channel in contractions to KCl. These results suggest that airway hyperresponsiveness may be associated with altered calcium mobilization in airway smooth muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Calcium channel currents in isolated smooth muscle cells from human bronchus.

An electrophysiological study was carried out on smooth muscle cells that were enzymatically dissociated from bundles of muscle fibers dissected out of human bronchi obtained at thoracotomy. These cells that retain the contractile properties of intact bundles were voltage-clamped by means of the whole-cell patch-clamp technique. Upon voltage steps from a holding potential of -60 mV to more positive levels, the initial inward current was followed by large outward currents that inactivated slowly. These were subsequently reduced by substituting Cs+ for K+ in the internal solution and by using Ba2+ instead of Ca2+ as a charge carrier in the external solution. Under these conditions, the inward current did not completely inactivate in the course of 300-ms voltage steps. Inward current measured after leak subtraction was activated at a membrane potential of -25.8 +/- 5 mV, was maximum at +18 +/- 4 mV, and had an apparent reversal potential of +52.5 +/- 5.5 mV (n = 5). The potential at which steady-state inactivation was half-maximum was -28 mV (n = 5). This inward current was identified as a calcium current on the following basis: 1) it was not altered by 10 microM tetrodotoxin (TTX) or by lowering to 10 mM external Na+ concentration; 2) it was blocked by 2.5 mM Co2+ or 1 microM PN 200-110; 3) it was enhanced by 1 microM BAY K 8644, which in addition suppressed the PN 200-110 blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗
PubMed1989

Solubility of Freon 22 in human blood and lung tissue.

The solubility of Freon 22 in human blood and lung tissue was determined using the chromatographic method of Wagner et al. (J. Appl. Physiol. 36: 600-605, 1974). In normal human blood, the mean Bunsen coefficient of solubility (alpha B) was 0.804 cm3 STPD.cm-3.ATA-1 at 37 degrees C. It increased with hematocrit (Hct) according to the equation alpha B = 0.274 Hct + 0.691. Tissue homogenates were prepared from macroscopically normal lung pieces obtained at thoracotomy from eight patients undergoing resection for lung carcinoma. The Bunsen solubility coefficients were 0.537 +/- 0.068 and 0.635 +/- 0.091 in washed and unwashed lung, respectively. These values can be used in the determination of both cardiac output and pulmonary tissue volume in humans by use of the rebreathing technique.

Cardiac Output↗
PubMed1989

Is a myogenic response involved in deep inspiration-induced bronchoconstriction in asthmatics?

The mechanisms by which a deep inspiration (DI) induces bronchoconstriction in some asthmatic patients remain unclear. As a calcium-dependent myogenic response could be involved, we examined the effect of a potent voltage-dependent calcium channel (VDC) antagonist, nifedipine (20 mg administered sublingually) versus placebo, on the DI-induced change in plethysmographic specific airway conductance (SGaw) in six asthmatic patients and six healthy controls both before and after a bronchial challenge with methacholine (MCh). In the asthmatic group, when compared to those receiving placebo, nifedipine significantly reduced the decrease in SGaw induced by the DI at baseline (-34.2 +/- 5.6 and -12.7 +/- 3.6%, respectively) but it had no significant effect on mean SGaw baseline values (0.096 +/- 0.018 and 0.075 +/- 0.015 cm H2O-1.s.-1, respectively). When airway tone was increased with MCh, the DI-induced change in SGaw was reduced and nifedipine then had no further effect. In the control group, nifedipine had no significant effect on the weak changes in SGaw induced by the DI before or after the bronchial challenge. We conclude that nifedipine reduces DI-induced bronchoconstriction only in subjects with asthma and without altering baseline tone in airway smooth muscle. We suggest that this effect of nifedipine could be explained by the existence of a myogenic response in asthma, caused by the conversion of airway smooth muscle from intermediate to single unit function.

Airway Resistance↗
PubMed1989

[Calcium antagonists and chronic obstructive bronchopneumopathies].

Calcium ion acts as a second messenger in numerous cellular functions. The increase in its intracellular free concentration, which is brought about by influx from the extracellular source through voltage-dependent or receptor-operated channels and/or by release from intracellular sources, triggers the contraction of smooth muscle. The currently available calcium antagonists inhibit calcium movement through voltage-dependent channels. Tracheobronchial and pulmonary vascular smooth muscles play an important role in the symptomatic expression of chronic airflow obstruction. Whether an alteration in their functioning is involved in the pathogenic mechanism of the disease has not yet been established. The contraction of bronchial smooth muscle participates in bronchial obstruction and that of vascular muscle in pulmonary arterial hypertension, which complicates hypoxemic airflow obstruction. Numerous clinical and experimental studies show that bronchodilator or anti-bronchoconstrictor effects of calcium antagonists are limited. This limitation may be linked to either a low affinity of calcium antagonists for bronchial smooth muscle or a specificity of the mechanism of excitation-contraction coupling in this muscle. Calcium antagonists are powerful inhibitors of hypoxic pulmonary vasoconstriction. This inhibition may lead to a worsening of hypoxemia in relation to redistribution of blood flow towards low ventilation/perfusion ratio areas although the concomitant rise in cardiac output leads to increased oxygen transport. These effects seem to be maintained in the long term.

Bronchi↗
PubMed1988

Extracellular calcium and human isolated airway muscle: ionophore A23187 induced contraction.

In order to investigate the role played by extracellular calcium mobilization in activating human airway contraction, we studied the effects of A23187, a calcium ionophore, in human isolated bronchial spiral strips. In this preparation, ionophore induced a concentration dependent contraction from 10(-7) M to 10(-5) M which resulted from a direct effect on smooth muscle cells and was not a consequence of mediator release. Ionophore-induced contraction was dependent upon an entry of extracellular calcium which did not occur through the verapamil sensitive voltage dependent channel. Maximal ionophore contraction was 97 +/- 11% (n = 5) of the maximal histamine contraction but only 46 +/- 11% (n = 5) of the maximal carbachol contraction. However, when extracellular calcium concentration was doubled to 5 mM before addition of ionophore, the significant difference in amplitude between carbachol and ionophore maximal contraction was abolished. At physiological calcium concentrations addition of carbachol or histamine to the plateau of the ionophore maximal contraction produced a significant increase in the tension. Verapamil blocked the increase in ionophore tension produced only by histamine. These results suggest that (i) calcium mobilization from the extracellular source alone can produce contraction comparable in magnitude to that induced by histamine or carbachol. (ii) Extracellular calcium mobilization through different pathways has a cumulative effect on human airway contraction.

Calcimycin↗
PubMed1988

Prostaglandin F2 alpha augments the response to parasympathetic fibre stimulation in an isolated innervated preparation of rabbit trachea.

1. We have devised an isolated innervated preparation of rabbit trachea in which parasympathetic fibres can be stimulated either pre- or postganglionically. 2. Contractions induced by transmural stimulation of the tracheal smooth muscle and by stimulation of the proximal end of the vagus nerve were both inhibited by tetrodotoxin and atropine indicating that acetylcholine release from neural fibres was responsible for each contraction. 3. Only the contraction induced by stimulation of the vagus nerve was significantly inhibited by hexamethonium indicating that this response was mediated by preganglionic stimulation. 4. The contractions induced by both pre- and postganglionic stimulation were potentiated by prostaglandin F2 alpha (PGF2 alpha). The potentiation was short-lasting and could not be repeated in the same preparation. 5. In contrast prostaglandin D2 (PGD2) inhibited each form of stimulation-induced contraction in a dose-related manner. 6. In separate experiments PGF2 alpha also potentiated the contractile response to exogenous acetylcholine in isolated non-innervated tracheal segments. This localizes the action of PGF2 alpha to the smooth muscle. 7. These effects of PGF2 alpha may be important in the inflammation which accompanies airway disease.

Animals↗
PubMed1987

Acetylcholine-induced contraction in human isolated bronchial smooth muscle: role of an intracellular calcium store.

The aim of this study was to investigate the role played by an intracellular calcium store in human bronchoconstriction. Human isolated bronchial smooth muscle strips (5-6 mm long, 0.4-0.5 mm wide) were taken from lung specimens during pneumonectomy. Isometric contraction was recorded after stimulation by 10(-4) M acetylcholine in physiological solutions. The amplitude of acetylcholine-induced contractions was measured in the presence and absence of calcium ions in the perfusing medium. When the perfusing medium was switched to a calcium-free solution the amplitude of the acetylcholine-induced contraction was measured with respect to the duration of calcium-free perfusion. The amplitude of the contraction was 82.1 +/- 11.3%, 77.2 +/- 15.4%, 63 +/- 10.6% of the maximum contraction after the strips were perfused in calcium-free solutions for 1, 3 and 5 min respectively. Several successive contractions could be elicited, and even after 20 min of calcium-free perfusion, acetylcholine was still able to elicit contractions. These results suggest that an intracellular calcium store may be involved in human bronchoconstriction. This finding may help further our understanding of the effects of calcium antagonists on human airways.

Acetylcholine↗
PubMed1987

The calcium channel agonist BAY K8644 enhances the responsiveness of human airway muscle to KCl and histamine but not to carbachol.

The role of calcium channel antagonists in asthma remains controversial. A new compound BAY K8644 is an agonist at the calcium voltage-dependent channel (VDC). Therefore, we studied the effect of BAY K8644 on contraction to KCl, histamine, and carbachol in human bronchus in vitro to assess the role of the VDC in this tissue. Cumulative concentration response curves were obtained to the agonists in bronchial spiral strips in the absence and in the presence of BAY K8644. Contractile responses to histamine were significantly (p less than 0.05) enhanced by BAY K8644 (10(-6) M) at concentrations between 10(-7) M and 3 X 10(-6) M and there was a significant decrease in the histamine EC50 (the concentration producing half the maximal response). Responses to low concentrations of KCl (10(-4) M to 3 X 10(-3) M) were also potentiated. BAY K8644 did not affect carbachol-induced contractions. We conclude that calcium influx through VDC occurs in response to KCl and histamine but not to carbachol. Such findings could explain the variability in efficacy of calcium channel antagonists in inhibiting various forms of bronchospasm.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Gas exchange alterations in patients with chronic obstructive lung disease.

In a series of 23 patients with COPD, Wagner et al showed three distinct patterns of VA/Q distributions and a correlation between Burrows' clinical classification and the observed distribution patterns. Using the inert gas method, we studied 51 patients suffering from severe but stable COPD (FEV1 = 0.84 +/- 0.38 L; PaO2 = 58.5 +/- 10.5 mm Hg; PaCo2 = 48 +/- 6 mmHg; Ppa = 22 +/- 8 mmHg) breathing room air in a steady state. The H pattern (high mode of VA in high VA/Q) was found in 24 cases. There was an L pattern (Q mode in low VA/Q units) in nine cases and an HL (high-low) pattern in 16 cases (two patients were assigned another group). The analysis of the distribution data confirmed that VA/Q heterogeneity was the main factor underlying gas exchange disturbances in COPD. The PaO2 of the H subjects was higher than that of both HL (p less than 0.02) and L subjects. The true shunt value in the L group was significantly lower than in the H and HL groups. However, the relationship between clinical or functional aspects and distribution was not direct. The fraction of patients of H, HL, or (H + HL) types was nearly identical in the three clinical groups. The H pattern was found to be predominant in cases of COPD.

Aged↗
PubMed1985

[The inert gas method in respiratory physiopathology].

The main results obtained, in healthy or unhealthy man, with the inert gas method are gathered together. The major factor at the source of hypoxemia is the uneven distribution of VA/Q ratios. The fall in the partial pressure of oxygen in mixed venous blood amplifies this effect. Only hypoxemia, during muscular exercise, in patients with interstitial lung diseases could be explained, in part, by a decrease in membrane diffusion and a reduction in the transit time of blood in pulmonary capillaries. The differences between the methods used to analyse pulmonary gas exchange are discussed.

Adult↗
PubMedDate not supplied

Interaction of extracellular albumin and intravenous anaesthetics, etomidate and propofol, on calcium signalling in rat airway smooth muscle cells.

It has been shown in vitro that general anaesthetics modify airway responsiveness via, at least partially, a direct inhibitory effect on calcium signalling in airway smooth muscle cells. However, in vivo, these anaesthetic compounds bind serum proteins. We have investigated the effect of exposure to extracellular albumin of freshly isolated airway smooth muscle cells on the propofol- and etomidate-induced inhibitory effect on calcium signalling. [Ca2+]i was measured by microspectrofluorimetry in rat isolated tracheal smooth muscle cells using the fluorescent dye indo-1. Propofol (3 x 10(-4) M) and etomidate (10(-4) M) were the lowest 'effective' concentrations that altered the [Ca2+]i response. This alteration consisted of a decrease in both the amplitude of the [Ca2+]i peak (from 358 +/- 13 nM to 65 +/- 15 and 108 +/- 27 nM for propofol and etomidate, respectively) and the percentage of responding cells (from 80% to 37 and 25% respectively) in response to the low concentration of ACh and a decrease in the Ca2+ oscillation frequency (from 9.9 +/- 0.3 min(-1) to 4.7 +/- 0.4 and 6.9 +/- 0.4 min(-1), respectively) in response to the high concentration of ACh. Increasing the concentration of albumin reduced the inhibitory effect of etomidate and propofol on the [Ca2+]i response to ACh. When extracellular albumin concentration was kept constant (20 g/L), increasing the concentration of etomidate by one log restored its inhibitory effect on the calcium signal. This study indicates that increasing the concentration of extracellular albumin reduces the inhibitory effect of intravenous anaesthetics on calcium signalling in airway smooth muscle cells. This report suggests that, in extrapolating in vitro dose-response relationships to those from in vivo conditions, the effect of the concentration of extracellular protein can be estimated.

Acetylcholine↗
PubMedDate not supplied

[Cellular mechanism of muscle contraction of bronchial smooth muscle].

Airway smooth muscle is one of the main effector of bronchial reactivity. The understanding of the cellular mechanisms involved in the contraction of this muscle has advanced in the recent past since isolated cells in culture can now be studied. Extracellular messengers (neurotransmitters and mediators) as well as their specific membrane receptors have been analyzed in some details. The membrane transduction of extracellular messengers brings about the formation (or the increase in the concentration) of the intracellular second messenger which, in airway smooth muscle, is the cytosolic calcium (Ca2+i) via activation of calcium channels which depend on surface membrane potential changes (electromechanical coupling) on the one hand and mainly via mechanisms independent of surface membrane potential changes-so-called the pharmacomechanical coupling--which involves membrane phosphoinositides metabolism. Changes in Ca2+i activate contractile proteins leading the muscle to shorten and to develop force via several controlled steps such as phosphorylation of myosin or changes in the sensitivity to Ca2+ of the contractile elements. Experimental techniques that enable to simultaneously study different aspects of the cellular response are being developed in airway smooth muscle and are likely to provide complementary information about the cellular physiology and pathophysiology of this muscle.

Animals↗
PubMedDate not supplied

[Electrophysiology and calcium signalling in human bronchial smooth muscle].

Recently, cells isolated from airways have been used to characterize precisely the electrophysiological properties of this smooth muscle and to describe the changes in cytosolic calcium concentration ([Ca2+]i) occurring upon agonist stimulation. Although most studies have produced consistent results in terms of types of ion channel and pathways of calcium signalling implicated in the mechanical activity of airways, there are differences according to (i) the site along the bronchial tree (trachea vs. bronchi); (ii) the proliferating status of the cells (freshly isolated vs. cultured) and (iii) the species (human vs. animals). With regard to the electrophysiological properties of airway smooth muscle, the contribution to [Ca2+]i rise of Ca2+ influx through L-type voltage-dependent calcium channels depends on the balance between depolarization related to non-specific cation channel and/or chloride channel activation and hyperpolarization related to activation of a variety of potassium channels. Most of the above-mentioned channels appear to be controlled, directly or indirectly, by agonists in human bronchial smooth muscle. With regard to calcium signalling, the pattern of agonist-induced [Ca2+]i responses, the so-called [Ca2+]i oscillations, has been observed recently in freshly isolated airway smooth muscle cells. The role and the calcium sources involved in these oscillations in human bronchial smooth muscle are currently being investigated.

Animals↗