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It was established that the optimal dose ratio (high effectiveness and minimum toxicity) between the components in the combination: serotonin/AET/ATP was 1/3/45. It was shown that the radioprotective effect was conditioned by AET and serotonin the latter being more significant. ATP played a minor role in the total protective effect decreasing however, the toxicity of the combination.

The effect of the drug HR-6 containing adenosine triphosphate in three concentrations and of a placebo on nasal mucociliary function was studied in sixteen healthy subjects. Nasal mucociliary function was measured on both sides of the nose with a radioisotopic method before and after the drug administration. The nasal mucociliary transport rate was increased by the active drug, on the average, by 2.0-3.2 mm/min in all three concentrations and by 0.2 mm/min in the placebo group, when one side of the nose was taken into account. When the average of the mucociliary function rate on both sides of the nose was calculated, the active drugs were found to increase the transport rate from 6.0 to 8.9 mm/min. The results of this preliminary study indicate the need for further studies in patients with impaired mucociliary function.

Although a number of manipulations prior to or during the initiation phase of an acute renal injury will modify the degree of functional impairment, agents administered after the acute insult usually have been ineffective. In the present study, adenine nucleotides (AMP, ADP, or ATP) combined with magnesium chloride were infused after an ischemic renal injury. Twenty-four hours later: (1) rats that received no infusion or one of the components of the mixture alone had reduced CIn (355 +/- 40 microliter/min/100 g of body wt vs. 977 +/- 40 control value), decreased RBF (3550 +/- 205 microliter/min/100 g of body wt vs. 5095 +/- 171 control value), elevated FENa (0.65 +/- 0.10% vs. 0.17 +/- 0.04 control value), and diminished UOsm (862 +/- 110 mOsm/kg vs. 1425 +/- 132 control value); (2) rats given dopamine or phenoxybenzamine maintained low CIn (365 +/- 50) despite improved RBF (4678 +/- 222); (3) rats infused with either AMP, ADP, or ATP combined with magnesium chloride had markedly improved CIn (594 +/- 44, P < 0.01), increased RBF (4269 +/- 223, P < 0.01); normalized FENa (0.18 +/- 0.07%, P < 0.01), and improved UOsm (1201 +/- 106 mOsm/kg, P < 0.05). In animals given no infusion or only magnesium chloride, ultrastructural studies demonstrated focal cellular necrosis and marked generalized tubular cell and mitochondrial swelling, whereas rats infused with ATP and magnesium chloride had fewer ultrastructural changes with better preservation of cellular morphology. Rats treated with ATP and magnesium chloride had improved CIn despite ischemic periods of 30, 45, and 60- min; and the degree of improvement was directly related to the quantity of ATP and magnesium chloride administered. The cellular content of exogenously administered ATP was 2.5 times greater in previously ischemic kidneys than in nonischemic kidneys. The data indicate that adenine nucleotides combined with magnesium chloride when infused after the initiation of acute renal failure significantly improve both CIn and tubular function and suggest that these agents effectively enhance recovery following an ischemc renal insult.

Since previous studies have shown a protective effect of the administration of adenosine triphosphate-magnesium chloride (ATP-MgCl2) in shock, the present study was undertaken to determine the effect of the infusion of ATP-MgCl2 after 30 minutes of renal artery occlusion. In animals who received no infusion or only MgCl2, the combination of reduced glomerular filtration rate (GFR), marked diuresis, and reperfusion of the outer cortex suggested that these animals were in the early recovery phase of acute renal failure. In the animals who received ATP-MgCl2, there was improved GRF, no diuresis, and a normal pattern of cortical blood flow distribution. These findings would suggest that the infusion of ATP-MgCl2 appears to have either ameliorated the effect of renal ischemia, or to have accelerated the recovery process. While the precise mechanism of action of ATP-MgCl2 remains unknown, these observations may have important implications for future use in organ preservation and the management of acute renal failure.

Neurovascular island skin flaps are still hampered by occasional necrosis of their most distal aspect. Cells subjected to prolonged hypoxic conditions become intracellularly depleted of needed metabolic substrates and eventually die. Once hypoxic conditions are improved, ischemic tissue suffers further injury from the rapid accumulation of oxygen free radicals. This study showed 53% survival of a standard random flap constructed on the inferior epigastric neurovascular bundle of a rat. Random flap survival increased to 65% after intraarterial infusion of adenosine triphosphate--magnesium chloride (ATP-MgCl2); to 75% after superoxide dismutase infusion; and to 98% after combined ATP-MgCl2 and superoxide dismutase infusion. Neither substrate appeared to act by increasing blood flow to the ischemic tissue.

The effects of intra-carotid injections of adenosine, adenosine triphosphate (ATP) and alpha-beta-methylene ATP were studied on arterial blood pressure of anaesthetized cats. Adenosine and ATP decreased arterial blood pressure, whilst the ATP stable analogue, alpha-beta-methylene ATP caused a dose-dependent increase in arterial blood pressure. These results suggest that the hypotensive action of ATP might depend on its previous hydrolysis into adenosine.

1. Co-existence of NA and NPY-LI was observed in the dense network of sympathetic nerves around both resistance and capacitance vessels in the nasal mucosa from most species including man. NPY-LI seems also to be present together with VIP-LI and PHI-LI in periglandular and some perivascular parasympathetic fibres in some species. 2. A new in vivo model was developed in the pig which allowed parallel recordings of arterial blood flow (BF), capacitance function (V) and superficial movement of blood cells (LDF signal) of the nasal mucosa upon SNS and/or local intra-arterial injection of various pharmacological agents. SNS reduced both BF and V. The V response was maximal already at low frequency. The LDF signal was increased when the SNS-evoked BF reduction was under 40% but was reduced upon larger BF response. After pretreatment with the alpha-adrenoceptor antagonist PBZ, the vascular responses to SNS were significantly attenuated but clear-cut reductions of BF, V and LDF responses remained even to a single impulse. Exogenous NA induced dose-dependent reductions of the BF, V and LDF signal, which were abolished by PBZ treatment. ATP caused biphasic vascular effects with short-lasting vasoconstriction followed by vasodilatation. NPY and mATP caused reduction of the vascular parameters via non-adrenergic mechanisms. 3. A frequency-dependent increase of NA overflow was observed in the nasal venous effluent upon SNS in control pigs, whereas detectable release of NPY-LI occurred only at high frequency. Pretreatment with PBZ significantly increased the SNS-evoked NA and NPY-LI overflow, while DMI enhanced both the functional response and NA release but reduced the NPY-LI overflow. These data suggest that NA and NPY release in the pig nasal mucosa is regulated by prejunctional alpha-adrenoceptor mechanisms. During tachyphylaxis to mATP, the NA and NPY-LI overflow and the vasoconstrictor responses to SNS were unmodified in controls. 4. Reserpine pretreatment induced a marked depletion of both NA and NPY-LI in the pig nasal mucosa. The reduction of NA was not influenced by preganglionic denervation while the depletion of NPY then was prevented. Slowly developing, frequency-dependent and long-lasting vascular responses remained (up to 80% of control) upon SNS in reserpinized and decentralized animals. In these animals, the NA overflow was abolished while release of NPY-LI was enhanced. Stimulation with irregular bursts, caused both larger vascular responses and more NPY-LI overflow in comparison with continuous stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

In the present study the possibility of provoking an irreversible blockade of P2-receptors in vivo by photolyzing ANAPP3 was investigated. ANAPP3 administered as an intraarterial infusion produced a short-lived blockade of P2-receptor mediated contractions of cat urinary bladders in situ. However, irradiation of the bladders with visible light during the infusion of ANAPP3 resulted in a blockade of the response for at least 120 minutes. Thus, photoactivation of ANAPP3 in vivo produced an essentially irreversible blockade of P2-purinergic receptors.

The effect of phosphoenolpyruvate (PEP) and adenosine triphosphate (ATP) administered during ischemia was investigated, using the paracorporeal rat heart model. During 15 min of global ischemia the hearts were perfused twice with PEP and ATP (supplemented) or with NaCl only (non-supplemented). In hearts that were freeze-clamped after the ischemic period (group A), the myocardial content of high-energy phosphates showed only minor differences between hearts with and without supplemention. In the supplemented hearts there was increased myocardial content of pyruvate and, to some extent, of lactate, indicating that PEP was metabolized to pyruvate and partly to lactate. In groups B and C the hearts were reperfused for 40 min before freeze-clamping. The non-supplemented hearts showed higher energy content and better left ventricular performance and, concomitantly, the creatine kinase isoenzyme MB (CK-MB) efflux was less than for the supplemented hearts. A clear inverse relationship between left ventricular performance and CK-MB efflux indicated that CK-MB served as a marker of cell integrity. These results contrasted with previus finding of an unequivocally positive effect from PEP and ATP administration. Possible explanations are discussed.

The photolabeling of chloroplast F1 ATPase, following exposure to Mg2+ and 2-azido-ATP and separation from medium nucleotides, results in derivatization of two separate peptide regions of the beta subunit. Up to 3 mol of the analogue can be incorporated per mole of CF1, with covalent binding of one moiety or two moieties per beta subunit that can be either AMP, ADP, or ATP derivatives. These results, the demonstration of noncovalent tight binding of at least four [3H]adenine nucleotides to the enzyme and the presence of three beta subunits per enzyme, point to six potential adenine nucleotide binding sites per molecule. The tightly bound 2-azido nucleotides on CF1, found after exposure of the heat-activated and EDTA-treated enzyme to Mg2+ and 2-azido-ATP, differ in their ease of replacement during subsequent hydrolysis of ATP. Some of the bound nucleotides are not readily replaced during catalytic turnover and covalently label one peptide region of the beta subunit. They are on noncatalytic sites. Other tightly bound nucleotides are readily replaced during catalytic turnover and label another peptide region of the beta subunit. They are at catalytic sites. No alpha-subunit labeling is detected upon photolysis of the bound 2-azido nucleotides. However, one or both of the sites could be at an alpha-beta-subunit interface with the 2-azido region close to the beta subunit, or both binding sites may be largely or entirely on the beta subunit.

The efficacy, electrophysiologic effects, and side effects of adenosine triphosphate (ATP) and verapamil in the short-term management of paroxysmal reciprocating junctional tachycardia (PRJT) were compared in 20 patients. All patients had inducible sustained PRJT during control electrophysiologic study. Fourteen patients had PRJT involving a retrograde accessory pathway, and six patients had atrioventricular (AV) nodal reentrant tachycardia ("slow-fast" type). ATP, which has a very short half-life, was first administered (10 mg iv over 1 sec) during sustained PRJT. If PRJT did not terminate within 2 min, a bolus of 20 mg ATP was given. Verapamil (5 mg iv over 15 sec) was subsequently administered during sustained PRJT, and if the latter did not terminate within 3 min another bolus of 5 mg verapamil was given. The cycle lengths of PRJT before administration of 10 or 20 mg ATP and 5 mg verapamil were similar. The 10 mg dose of ATP terminated PRJT in 17 of the 20 patients, and 20 mg ATP was required to terminate PRJT in the three remaining patients. The 5 mg dose of verapamil terminated PRJT in 15 patients, whereas an additional bolus of 5 mg terminated PRJT in one of the remaining five patients. The overall efficacy of ATP (20/20, 100%) was significantly greater than that of verapamil (16/20, 80%) (p less than .05); however, there was no significant difference between the conversion rate of PRJT after administration of 10 mg ATP (17/20) and 5 mg verapamil (15/20). ATP terminated PRJT more quickly than verapamil (mean 24 sec vs mean 51 sec; p less than .01). Termination of PRJT by either ATP or verapamil was mainly related to a block in the AV node in patients with accessory pathways and to a block in the antegrade slow pathway in patients with AV nodal reentry. Cycle length alternans before termination of tachycardia was observed more frequently after verapamil than after ATP (7/16 vs 1/20; p less than .01). The total incidence of transient second-degree AV nodal block and various cardiac supraventricular and ventricular arrhythmias was higher after termination of PRJT by ATP than after verapamil (17/20 vs 5/16; p less than .001). A higher incidence of transient but frequently uncomfortable noncardiac side effects was observed after ATP. We conclude that ATP (10 to 20 mg) is more effective and more rapid than verapamil (5 or 5 + 5 mg) in terminating PRJT but results in a higher incidence of cardiac and noncardiac side effects.(ABSTRACT TRUNCATED AT 400 WORDS)

In 34 male patients with peripheral arterial occlusive disease of the lower extremities the individual responsibility to an intraarterial adenosine triphosphate infusion was tested with the help of Doppler-sonographic poststenotic measurements of the systolic blood pressure as well as comparatively to this by determination of the arterial blood-flow in rest in the region of the calf. While the greater part of the patients with occlusive disease reacted with a significant increase of the blood supply, nearly with the same frequency a decrease of pressure or no change could be established concerning the behaviour of the peripheral pressure. For the judgment of the efficacy of an intraarterial infusion treatment in the acute experiment plethysmographic measurements of the blood-flow are, therefore, more suitable and should be preferred to Doppler-sonographic pressure parameters. As to the controls of long-term therapy under conservative treatment as well as for the judgment of the success in the reconstructive surgery of vessels, however, the post-stenotic measurements of the pressure stood the test apart from further methods in clinical practice.

ATP entrapped into liposomes was administered intracarotidally to rats submitted to brain ischemics episodes by clamping of the carotid arteries and lowering of the systemic blood pressure. It was observed that when entrapped into liposomes, ATP greatly increased the number of ischemic episodes tolerated before brain electrical silence and death appeared. These results added to very similar previous data obtained by i.c.v. treatment excluding the prominent role of cardiovascular effects, could open new possibilities in brain antihypoxic protection. Here and now it cannot be stated if ATP provides direct energetic supply.

Basal, fluoride and follitropin stimulated activities of adenylate cyclase have been studied in the testes of immature rats. The enzyme was maximally activated (about twice the basal activity) by low concentrations of follitropin, with an apparent Km of about 9 . 10(-10) M. Both Mg2+ and Mn2+ activate the enzyme but the apparent Ka for Mg2+ is about 10 times that for Mn2+. However, the apparent Km values for MgATP2- and MnATP2- are nearly the same (1.4 . 10(-4) M) and the cation activation of the enzyme is mainly through an increase in V. Ca2+ inhibited all expressions of testicular adenylate cyclase activity. Follitropin and fluoride stimulated adenylate cyclase activity at all Mg2+ concentrations but did not significantly affect the apparent Ka for Mg2+ or the Km for the substrate (MgATP2-). The stimulatory effect of the hormone or fluoride is mainly through an increase in V. Testicular adenylate cyclase could be solubilized with Triton X-100 or Lubrol-PX. The detergent-solubilized enzyme exhibited Km for substrate and Ka values for divalent cations similar to those of the membrane-bound enzyme and remained responsive to stimulation by fluoride. The stimulatory effect of follitropin, however, was lost. Responsiveness to follitropin was also lost by membrane-bound adenylate cyclase after treatment with phospholipase, although the fluoride effect was unchanged. These results reflect the essential role of lipids in the regulation of the follitropin-specific response.

In this study we investigated the relationship between pulmonary and renal responses to a low dose infusion of adenosine triphosphate-magnesium chloride (ATP-MgCl2) in a newborn piglet model of hypoxic pulmonary hypertension (HPH). Three- to five-day-old piglets were cannulated for the measurement of pulmonary and systemic arterial pressure, pulmonary and renal artery flow, and urine output. The animals were then made hypoxic by ventilation with a mixture containing 10% oxygen, 4% CO2, and balance nitrogen. Serial infusions of ATP-MgCl2 at 0.01, 0.025, 0.05, 0.1, 0.5, and 1.0 mg/kg/min were compared to preinfusion hypoxia baselines. Hypoxia alone produced a significant elevation in pulmonary artery pressure (73%) and a reduction in pO2. All dose rates of ATP-MgCl2 greater than or equal to 0.05 mg/kg/min produced a significant decrease in mean pulmonary artery pressure. However, as baseline mean pulmonary artery pressure increased there was an increased sensitivity to ATP-induced vasodilation. Pulmonary artery flow did not change during ATP infusion, thus, the change in pulmonary vascular resistance accounted for the decrease in pulmonary artery pressure. In contrast to the response of the pulmonary vasculature, systemic pressure was significantly decreased only during the 1.0 mg/kg/min infusion. Renal blood flow decreased by 46% during hypoxia and decreased further only during the highest dose rate of ATP infused (i.e., 1.0 mg/kg/min). Creatinine clearance (Ccr) and fractional reabsorption of Na (FreNa) also fell during hypoxia, but were not further altered during all but the highest dose of ATP infused.(ABSTRACT TRUNCATED AT 250 WORDS)

In fourty patients with peripheric atherosclerosis obliterans blood flow was measured by means of venous occlusion plethysmography during an intraarterial and an intravenous infusion of ATP. The intraarterial application showed a significantly higher increase of blood flow than the intravenous in the sick extremities. The "borrowing-lending-phenomenon" happened more seldom than after an intravenous load. This withdrawal of blood occurred most frequently in patients with proximal occlusions, when the infusion reached casually the arteria femoralis profunda only. The "borrowing-lending-phenomenon" can be measured by the poststenotic pressure and by the volume of blood flow in time. Then the patients complain about a begining or an increasing of an ischemic pain at rest.

Surgical correction of the arterial duct and defects of the cardiac septa is followed in the nearest period after surgical correction by lung hypertension which considerably aggravates the postoperative period. The observation of 74 patients has shown that infusions of 1% solution of phosphobion (0.05 mg/kg/min) in the pulmonary artery decrease the pressure in the pulmonary artery, pulmonary-vascular resistance, make the incidence of disturbed heart rate less frequent, reduce the concentration of noradrenaline and prostaglandins.

Using experimental models of various disease states, the ability of the isolated perfused working rat heart to withstand and recover from a period of severe ischemia was investigated. The results revealed that the coexistence of a diabetic state, obesity, or left ventricular hypertrophy increased the susceptibility of the hearts to ischemic damage and reduced the rate or the extent of postischemic recovery. In contrast, hearts obtained from moderately hypertensive rats exhibited a greater resistance to, and a superior recovery from, ischemia than did hearts obtained from normotensive controls.

Infusion of phosphoenolpyruvate together with adenosine triphosphate early during reperfusion after ischemia increased the energy content and the left ventricular isovolumic performance in a paracorporeal rat heart model. Excised hearts were subjected to 15 min of complete global ischemia at 37 degrees C before reperfusion. During reperfusion they were either nonworking (empty-beating) or working (performing left ventricular isovolumic work) between 20 and 40 min of reperfusion before freeze-clamping. Early during reperfusion the excised hearts were either supplemented with 144 mumol phosphoenolpyruvate and 0.67 mumol adenosine triphosphate or nonsupplemented (plain saline) administered in a pulsatile arterial blood flow. The supplemented nonworking group showed significantly higher creatine phosphate and adenosine triphosphate contents compared to the nonsupplemented group. However, under postischemic working conditions there were no significant differences in high-energy phosphates between the supplemented and the nonsupplemented groups in spite of significantly better left ventricular isovolumic performance in the supplemented group. Concomitantly the efflux of creatine kinase isoenzyme MB indicating cellular damage was significantly less for this group. The data presented here favor the view of a possible compartmentalized adenosine triphosphate pool with a high metabolic turnover close to the plasma membrane.

The lipids of isolated Krebs perfused rabbit kidneys and hearts were labelled with [14C]arachidonic acid. Subsequent hormonal stimulation (e.g. bradykinin, ATP) of the pre-labelled tissue resulted in dose-dependent release of [14C]prostaglandins; little or no release of the precursor [14C]arachidonic acid was observed. When fatty acid-free bovine serum albumin was added to the perfusion medium as a trap for fatty acids substantial release of [14C]arachidonic acid was detected following hormonal stimulation. The release of [14C]arachidonic acid was dose-dependent and greater than 3 fold that of [14C]prostaglandin release. Indomethacin by inhibiting the cyclo-oxygenase, completely inhibited release of [14C]prostaglandins and only slightly inhibited release of [14C]arachidonic acid. These results demonstrate that in both rabbit kidney and heart much more substrate is released by hormonal stimulation than is converted to prostaglandins. This suggests that either the deacylation reaction is not tightly coupled to the prostaglandin synthetase system or that there are two deacylation mechanisms, one which is coupled to prostaglandin synthesis while the other is non-specific. It has previously been shown that prostaglandin release due to hormones such as bradykinin is transient despite continued presence of the hormone (tachyphylaxis). By utilizing albumin to trap released fatty acid, it was found that hormone-stimulated release of arachidonic acid is also transient. This directly demonstrates that tachyphylaxis occurs at a step prior to the cyclo-oxygenase.

There is controversy concerning the efficacy of ATP-MgCl2 in improving survival following hemorrhagic shock. To resolve this issue, the effect of ATP-MgCl2 infusion on survival following shock was reinvestigated. Rats were bled to and maintained at a mean arterial blood pressure of 40 mmHg for 90 min. Following reinfusion of the remaining shed blood, the animals were treated with ATP-MgCl2 (25 mumoles each) or saline. Survival was measured in one group of animals, and in another group of animals reticuloendothelial (RE) function was determined with 131I gelatinized test lipid emulsion in search of the mechanism of the beneficial effect of ATP-MgCl2 following hemorrhagic shock. The results indicate that survival was significantly improved if the animals were treated with ATP-MgCl2 following hemorrhagic shock. In addition, RE function, which was markedly depressed following hemorrhagic shock, was significantly improved by ATP-MgCl2 treatment, indicating that the beneficial effect of ATP-MgCl2 for hemorrhagic shock could be through the improvement of RE function.

The effect of HR-6 solution containing adenosine triphosphate 10 mg/ml on the impaired nasal mucocililary function in 13 patients was studied. The nasal mucociliary function measured with the radioisotopic method using 99Tc-labelled human serum albumin as a tracer substance was markedly impaired in all patients. The patients had had symptoms of upper and/or lower respiratory tract infections for 8 1/2 years, on the average. The nasal mucociliary function ranged from 0 to 5.0 mm/minute, mean 2.0 mm/minute. In this single dose study the test drug improved nasal mucociliary function by at least 1.4 mm/minute in 77% of the patients and by at least 2.8 mm/minute in 54% of the patients. This preliminary study indicates the need for further examinations with the HR-6 in patients with impaired mucociliary function.

Despite its importance, very little has been known on metabolic abnormalities in the patients with postoperative multiple organ failure (POMOF). The present study was undertaken to investigate the metabolic abnormalities and to establish effective nutritional management on these patients. Systemic energy metabolism and hepatocellular mitochondrial function were studied with indirect calorimetry and arterial ketone body ratio measurements on 30 POMOF patients treated between 1984 and 1985. The POMOF patients were hypermetabolic and their hepatic mitochondrial function was impaired. Their caloric intake was depleted for the limitation in administrable water volume due to renal failure. Some of them could not utilize exogenous glucose given by total parenteral nutrition (TPN). To overcome these problems, on 26 POMOF patients treated between 1986 and 1987 continuous hemofiltration (CHF) was applied to remove excess water and ATP-Mg was administered to improve hepatic mitochondrial function during TPN. The sufficiency rate of energy intake (caloric intake/energy expenditure) was improved from 73.3 +/- 14.7% to 92.0 +/- 8.1% with simultaneous CHF and the hepatic mitochondrial function was also improved with ATP-Mg resulting in better utilization of exogenous glucose. These results indicate that CHF and ATP-Mg administration are effective adjunctive treatments in the nutritional management for POMOF.

1. The response of the smooth muscle of the guinea-pig taenia coli to adenosine triphosphate (ATP) and related substances was compared with that to noradrenaline and dopamine. The effect of these substances on the inhibitory potential was investigated.2. ATP in concentration of 10(-6)-10(-5)M suppressed the spontaneous spike and relaxed the preparation. ATP in a concentration higher than 10(-4)M hyperpolarized the membrane, reduced the membrane resistance and decreased the inhibitory potential.3. Effects of noradrenaline (5 x 10(-6)M) and of dopamine (5 x 10(-4)M) were similar to those of ATP (10(-3)M). However, the effects of catecholamines were reduced in Cl-deficient solution and blocked by phentolamine (3.5 x 10(-6)M), while the effects of ATP were unaffected.4. A high concentration of phentolamine (3.5 x 10(-4)M) almost abolished the inhibitory potential as well as the effects of ATP. The inhibitory potential and the effect of high concentration of ATP (10(-3)M) were not impaired by imidazole (50 mM).5. Adenosine diphosphate, adenosine monophosphate and adenosine produced effects essentially similar to those of ATP. However, their potency was less compared with ATP.6. These electrophysiological observations support the hypothesis that ATP may be the transmitter of the non-adrenergic inhibitory nerves in the taenia coli. No evidence against the hypothesis was obtained.