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PubMed1991

Relationship between cyclic guanosine monophosphate accumulation and relaxation of canine trachealis induced by nitrovasodilators.

The role of cyclic GMP (cGMP) in mediating relaxation of canine trachealis produced by nitrovasodilators (NVDs), compounds that activate guanylate cyclase, was examined. Sodium nitroprusside (SNP) produced a concentration-dependent relaxation of the canine trachealis that was accompanied by a concentration-related increase in cGMP content. In time course studies, relaxation of isolated trachealis strips induced by 30 microM SNP was paralleled by an increase in cGMP that reached a maximum of 18-fold above basal levels within 2 min. Zaprinast, an inhibitor of the cGMP-specific phosphodiesterase, potentiated both SNP-induced relaxation and cGMP accumulation. A cell-permeable analog of cGMP, 8-bromo-cGMP, mimicked the relaxant effects of SNP. Also assessed were the effects of methylene blue, an agent that inhibits soluble guanylate cyclase activity, and hemoglobin, an agent that competitively binds NO-containing compounds. In these experiments, tissues were pretreated with the above agents for 10 min, contracted with 1 or 3 microM methacholine, and then relaxed by the cumulative addition of SNP or two other NVDs, S-nitroso-N-acetyl-penicillamine (SNAP) and glyceryl trinitrate (GTN). Tissues were flash-frozen after adding the final concentration of the various NVDs and assayed for cGMP. Methylene blue and hemoglobin suppressed both cGMP accumulation and relaxation in response to SNAP and GTN. in contrast, methylene blue and hemoglobin inhibited SNP-induced cGMP accumulation but, paradoxically, potentiated SNP-induced relaxation. The results of this study generally support a role for cGMP in NVD-induced relaxation of airway smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1990

Physiologic aspects of relaxation of the myocardium.

To understand relaxation in the intact heart, an appreciation of myocardial relaxation in controlled isometric and isotonic twitches is a prerequisite. Load dependence of myocardial relaxation is manifest as the temporal separation of relaxation in isotonic and isometric twitches, i.e. rapid isotonic lengthening in contrast to slower isometric force decline. Although both isotonic and isometric relaxation modes are governed by the same determinants of crossbridge kinetics (life cycle of individual crossbridges along with regulatory properties of the contractile proteins, and calcium sequestration particularly by the sarcoplasmic reticulum), the contribution of these determinants in controlling onset and rate of relaxation is different in isometric force decline and in isotonic lengthening. In an isometric twitch, cooperative activity will, through a process of force development-induced increased sensitivity of the contractile proteins, upgrade the development and maintenance of force throughout contraction and relaxation. On the other hand, a functional calcium sequestration by the sarcoplasmic reticulum will, in the presence of a reduced effect of cooperative activity in the isotonic twitch, allow for load-induced rapid lengthening. Marked mechanical nonuniformity is observed in intact cardiac muscle. Nonuniformity in cardiac muscle mechanics is usually considered as a nuisance. Uniform behaviour of overall muscle does occur, however, despite or perhaps through nonuniform behaviour of longitudinal muscle segments. A limited but variable degree of nonuniformity therefore probably constitutes an essential property of the heart. A quantitative analysis of nonuniformity in isolated cat papillary muscle is proposed. Pathological considerations require extrapolation of our understanding from isolated muscle relaxation to ventricular relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMedDate not supplied

Comparative study in mice of tetrazepam and other centrally active skeletal muscle relaxants.

Tetrazepam is a 1,4 benzodiazepine (BZD) clinically used in France and Germany as a muscle relaxant. The activity of tetrazepam was compared to that of diazepam, baclofen, mephenesin and chlormezanone in mice, in pharmacological models which are predictive of muscle relaxant and sedative properties. Tetrazepam was active in all the 6 tests of muscle relaxation (traction, chimney, inclined screen, grip force, horizontal grid and morphine-induced Straub tail). The overall muscle relaxant potency of tetrazepam was inferior to that of diazepam, but was clearly superior to that of chlormezanone and mephenesin. Baclofen was less active than tetrazepam in 3 tests (traction, horizontal grid, and grip strength), but more active in the other 3 tests. The administration of the benzodiazepine receptor antagonist Ro 15-1788 blocked the effects of tetrazepam and diazepam in 2 representative tests, morphine-induced Straub tail and the rotarod test, but did not modify the activities of the other centrally acting muscle relaxants in these same models. The selectivity ratio (ED50 rotarod or ED50 locomotor activity/ED50 in each muscle relaxant test) for tetrazepam was superior to that of diazepam and all the other muscle relaxant drugs examined. It is concluded that tetrazepam exerts its muscle relaxant activity by stimulating central BZD receptors, and presents the advantage of a wide dissociation between muscle relaxant and sedative potencies.

Animals↗
PubMed1987

Arachidonic acid-induced endothelial-dependent relaxations of canine coronary arteries: contribution of a cytochrome P-450-dependent pathway.

Arachidonic acid (AA, 10(-8)-5 X 10(-6) M) induced dose-dependent relaxations of canine coronary arterial rings precontracted with dinoprost that were significantly greater (P less than .001) if the endothelium was intact. Cyclooxygenase inhibition with indomethacin displaced the dose-response curve to AA to the right but did not prevent the relaxant effects of the fatty acid. SKF-525A, an inhibitor of cytochrome P-450-dependent enzymes, also attenuated the response to AA although the combination of SKF-525A and indomethacin prevented any relaxant effect. Induction of cytochrome P-450-dependent enzymes in the coronary artery with 3-methylcholanthrene and beta-naphthoflavone given in vivo (40 mg/kg/day for 3 days) or depletion of these enzymes with cobalt chloride (24 mg/kg/day for 2 days) resulted in an enhancement or diminution, respectively, of AA-induced endothelial-dependent relaxations. These results implicate a cytochrome P-450-dependent mixed function oxidase in the endothelial-dependent relaxations to AA in the canine coronary artery. Precontraction of coronary arteries with U46619 in contrast to dinoprost failed to display endothelial-dependent relaxations to AA, whereas the responses to bradykinin and acetylcholine were also partially attenuated. Pharmacologic manipulations of AA metabolism via cyclooxygenase and cytochrome P-450-dependent monooxygenases indicate that the endothelial-dependent relaxations induced by bradykinin are partially dependent upon metabolites of AA, whereas the relaxations produced by acetylcholine are independent of AA metabolites, suggesting that a number of potential relaxing factors may be released from the endothelium.

Animals↗
PubMed1988

Relaxant effect of amiloride on canine tracheal smooth muscle.

Amiloride, a K+-sparing diuretic, relaxed canine tracheal smooth muscle strips contracted isometrically with high potassium (KCl), carbachol, serotonin and histamine. This indicated that relaxation was not linked to an interaction with an agonist specific receptor. Amiloride-induced relaxation was also not mediated through the production of relaxant prostaglandins, or by the endogenous release of catecholamines. During potassium contractions, amiloride addition produced a slow monophasic, dose-dependent relaxation (IC50 = 12.3 microM). In carbachol contracted strips, 1 and 10 microM amiloride induced a slow monophasic relaxation. With 35 to 250 microM, an initial rapid phase (IC50 = 75.5 microM) was superimposed onto this slow phase (IC50 = 23.5 microM), producing a biphasic relaxation. The rates of relaxation decreased with increased external [Na+] regardless of stimulus, suggesting possible competitive inhibition of a sodium-dependent process. Exposure caused a rapid decline in tension followed by a recovery phase. Tension maintenance during potassium contraction decreased transiently upon the addition of acid to a much lesser extent. Amiloride (100 microM) depressed tension recovery after acid exposure in both cases. Based on the known actions of this drug, inhibition of the Na+-H+ antiporter appears to be consistent with these data. This suggests amiloride may well belong to a new class of smooth muscle relaxants.

Airway Resistance↗
PubMed1983

Endothelium-dependent and nitrovasodilator-induced relaxation of vascular smooth muscle: role of cyclic GMP.

The mechanisms by which endothelium-dependent relaxants and nitrovasodilators cause relaxation of vascular smooth muscle has been reviewed. A model explaining these observations is summarized in Fig. 1. The endothelium-dependent vasodilators through interaction with their appropriate receptors are thought to activate phospholipase A2 and cause the release of an unsaturated fatty acid. The released unsaturated fatty acid or a metabolite is thought to be the "endothelial relaxant factor" that interacts with the smooth muscle component to cause relaxation. While the unsaturated fatty acid may be oxidized in either the endothelial cell or smooth muscle cell, the lability of the endothelial relaxant factor suggests that at least some of this processing occurs before its release from the endothelium. the model in Figure 1 suggests that an oxidized fatty acid or a derived free radical is responsible for activation of smooth muscle guanylate cyclase and increases in cyclic GMP levels. As pointed out above, the use of various inhibitors of fatty acid release and metabolism has not allowed us or others to predict the structure of the active material. To date the best evidence suggests that the unsaturated fatty acid is a product of either the lipoxygenase or P-450 pathways. Nitrovasodilators are thought to form nitric oxide free radical and directly activate guanylate cyclase as described above. Activated guanylate cyclase, whether by endothelium dependent agents or the nitrovasodilators, then increases the formation of cyclic GMP, which activates cyclic GMP-dependent protein kinase. The phosphorylation state of various proteins is then altered and, eventually, myosin light chain is dephosphorylated and relaxation occurs. Whether this mechanism involves cyclic GMP-dependent changes in activities of myosin light chain kinase and/or myosin light chain phosphatase remains to be determined. Although the altered phosphorylation state of myosin light chain that results from cyclic GMP accumulation may explain the mechanisms of action of cyclic GMP in smooth muscle relaxation, other mechanisms can not be excluded. For example, some additional studies which we have not summarized here indicate that the integrity of the membrane and Na+-K+ pump can modify both cyclic GMP synthesis and relaxation in rat aorta (38 and unpublished observations). Apparently complex interactions may exist in smooth muscle and other tissues which regulate cyclic GMP accumulation and/or its expression on some process. While several functions for cyclic GMP have been suggested, there is considerable evidence which suggests that one of its roles is relaxation of airway and vascular smooth muscle.

Animals↗
PubMed1995

Involvement of K+ channels in the relaxant responses to various agonists in estrogen primed rat uterus.

The present investigation was undertaken to study the effects of K+ channel openers in the relaxant responses to various agonists in estrogen primed rat uterus. Adrenaline and isoprenaline produced a dose-dependent relaxation in the estrogen primed rat uterus. The relaxant responses were found to be significantly potentiated when the preparations were exposed to PSS devoid of calcium. The responses to isoprenaline were found to be greater in the preparations depolarized with 40 mM KCl instead of 80 mM KCl. KCl failed to produce any contractile effect in the presence of D-600. Further, the addition of D-600 completely relaxed the KCl depolarized rat uterus. Pinacidil and cromakalim failed to relax 80 mM KCl depolarized rat uterus. However, they produced dose-dependent relaxation in the preparations depolarized with 40 mM KCl. The relaxant responses to pinacidil and cromakalim were competitively blocked by procaine. However, they were not altered by either propranolol or cimetidine. The relaxant responses to isoprenaline and histamine were found to be potentiated by pinacidil and cromakalim. These results indicate that in rat uterus in addition to adenylate cyclase c-AMP, potassium channels are also involved in the relaxant responses to isoprenaline and histamine.

Animals↗
PubMed1993

Calcitonin gene-related peptide relaxes porcine coronary arteries via cyclic AMP-dependent mechanisms, but not activation of ATP-sensitive potassium channels.

We investigated the relaxant mechanisms of calcitonin gene-related peptide (CGRP) in endothelium-denuded porcine coronary arteries. Intracellular free calcium concentration ([Ca++]i) was measured simultaneously with force by the fura-2 microfluorimetric method. CGRP (10(-9) to 10(-7) M) or isoproterenol (10(-8) to 10(-5) M) produced a concentration-dependent relaxation of arterial rings precontracted with 30 mM KCl with only a slight decrease in [Ca++]i. In contrast, cromakalim (3 x 10(-7) to 3 x 10(-5) M), an ATP-sensitive potassium channel opener, reduced [Ca++]i and force in a parallel manner. When the arteries were precontracted with 90 mM KCl, the relaxant effects of CGRP and isoproterenol were attenuated, whereas that of cromakalim was abolished. In arteries precontracted with 90 mM KCl, reduction of extracellular calcium concentrations from 2.5 to 0.1 mM recovered the relaxant effects of CGRP and isoproterenol, but not that of cromakalim. All three relaxants reduced both [Ca++]i and force in arteries precontracted with endothelin-1 (10(-8) M). Glibenclamide (10(-5) M) inhibited the decrease in [Ca++]i and the relaxation caused by cromakalim, but had virtually no effect on those produced by CGRP or isoproterenol. In arteries precontracted with 30 mM KCl and relaxed maximally by isoproterenol (10(-5) M), CGRP (10(-7) M) failed to produce any relaxant effect, whereas cromakalim (10(-5) M) reduced [Ca++]i and force further. The inhibitor of phosphodiesterase, 3-isobutyl-1-methylxanthine, potentiated the decreases in [Ca++]i and relaxations caused by CGRP and isoproterenol, but not those by cromakalim.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1976

The management of chronic hysteria: a review and double-blind trial of electrosleep and other relaxation methods.

The effectiveness and mode of action of electrosleep therapy in chronic hysteria was evaluated in a double blind trial with a 1 month follow-up. Matched groups of hysterics were treated with central electrical stimulation and relaxation, peripheral electrical stimulation and relaxation, or relaxation only. Autogenic training exercises were used initially to standarize the relaxation instructions for all the patients. Central electrical stimulation has no specific benefit for hysteria. Rhythmic peripheral stimulation does increase the effect of verbal suggestions to relax initially but has no long term advantage over relaxation alone. Regular brief periods of relaxation can improve the mood and diminish the anxiety level of psychiatric outpatients with hysteria but have no persistant benefit for sleep disturbance or hypochondriasis. The best treatment of depression in chronic hysterics was found at follow-up to be relaxation without electrostimulation. Specialized somatic and psychotherapeutic methods have no advantage over treatment with low doses of anxiolytic drugs, reassurance, suggestion, and regular periods of relaxation.

Anxiety↗
PubMed1994

Selective pulmonary and venous smooth muscle relaxation by furosemide: a comparison with morphine.

Furosemide and morphine reduce pulmonary edema associated with congestive heart failure. It is uncertain whether furosemide or morphine are direct-acting relaxants of arterial and venous smooth muscle. The authors compared the effect of furosemide and morphine on isolated rings of canine pulmonary artery (PA) and vein (PV) and mesenteric, splenic and anterior tibial arteries and their corresponding veins precontracted with norepinephrine or (15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid. Furosemide (10-300 microM) selectively relaxed veins by an endothelium-independent mechanism, with its greatest efficacy on the PV. Morphine (10-1000 microM) relaxed both arteries and veins. The mechanism of relaxation by furosemide and morphine was examined in the PV and PA. Morphine-induced relaxation of the PV and PA was dependent on prostanoid release from endothelium and smooth muscle because it was attenuated in endothelium-rubbed and ibuprofen-treated PV and PA but not in blood vessels treated with inhibitors of nitric oxide system/cyclic GMP system (I-NG-nitroarginine and methylene blue). Furosemide-mediated relaxation of the PV was refractory to each of these interventions. Similarly, furosemide- and morphine-induced relaxation of the PV were unaffected by 4-aminopyridine, tetraethylammonium, glibenclamide, dendrodotoxin and apamin and, thereby, were independent of an action on K+ channels. Reduction of extracellular K+ or Cl- attenuated furosemide-mediated relaxation of, and inhibition of 86Rb+ uptake by, PV even in the presence of ouabain. It was concluded that furosemide relaxes veins by an effect on Na+/K+/Cl- cotransport or chloride-mediated refilling of intracellular calcium stores.

Animals↗
PubMed1993

Potassium channel-mediated relaxation to acetylcholine in rabbit arteries.

Endothelium-dependent relaxation is associated with smooth muscle hyperpolarization in many arteries which may account for relaxation that persists in the presence of nitric oxide inhibitors such as NG-nitro-L-arginine methyl ester (L-NAME). Acetylcholine (ACh)-induced relaxations of the rabbit thoracic and abdominal aorta and iliac and carotid arteries were studied for the relative contribution of nitric oxide-dependent and -independent mechanisms in rings suspended for measurement of isometric tension. Although relaxation of the thoracic aorta to ACh (10(-6) M) was almost blocked completely by L-NAME (3 x 10(-5) M), the maximal relaxation in the abdominal aorta, carotid and iliac arteries was only reduced by 28, 26 and 62%, respectively. In rings of abdominal aorta, L-NAME blocked the ACh-stimulated (10(-6) M) rise in cyclic GMP verifying that relaxation which persists in L-NAME-treated rings is not mediated by nitric oxide. The L-NAME resistant response was nearly abolished by elevated external K+ in rings of abdominal aorta and carotid artery, suggesting this relaxation may be mediated by a membrane potential sensitive mechanism. Furthermore, tetraethylammonium (10(-3) M) partially and charybdotoxin (5 x 10(-8) M) completely inhibited the remaining L-NAME-resistant relaxation in both abdominal aorta and carotid artery, suggesting a role for Ca(++)-activated K(+)-channels. Blockers of ATP-sensitive K+ channels also inhibited the L-NAME resistant relaxation in the abdominal aorta only.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1997

Relaxation by bradykinin in porcine ciliary artery. Role of nitric oxide and K(+)-channels.

PURPOSE: To assess the effects of K(+)-channel blockers on bradykinin-induced relaxations in porcine ciliary artery. METHODS: Vascular isometric forces were measured with a myograph system. Ciliary vascular rings were precontracted with thromboxane A2 analog (U 46619, 10(-7) M) to assess dose-dependent (10(-10)-3 x 10(-6) M) bradykinin-induced relaxation after addition of one of the following: the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or inactive enantiomer (D-NAME, 10(-4) M); the nonspecific K(+)-channel blocker tetra-ethylammonium (TEA, 10(-2) M); or the ATP-sensitive K(+)-channel blocker glibenclamide (10(-5) M). The effect of TEA on relaxations to the NO donor, sodium nitroprusside (SNP, 10(-10)-10(-4) M) was investigated. The membrane potential of vascular smooth muscle cells (VSMC) was recorded after exposure to bradykinin (2.5 x 10(-7) M). RESULTS: Endothelium-dependent relaxations to bradykinin (maximal [max], 99% +/- 3%) were strongly inhibited by L-NAME (max, 39% +/- 4%, P < 0.01) and partially by TEA (max, 62% +/- 3%, P < 0.01) or glibenclamide (max, 77% +/- 4%, P < 0.01). Administration of glibenclamide plus L-NAME further suppressed bradykinin-induced relaxation (max, 23% +/- 6%; P < 0.01), whereas TEA and L-NAME (max, 6% +/- 2%; P < 0.01) abolished the relaxation. SNP relaxations were unaffected by TEA. Bradykinin had no effect on the membrane potential of VSMC. CONCLUSIONS: In porcine ciliary artery, the endothelium-dependent relaxations to bradykinin are primarily mediated by NO and involve K(+)-channels. As only relaxations to bradykinin, but not those mediated by SNP, were inhibited by TEA, this implies that K(+)-channel blockers most likely affect the bradykinin-evoked NO production or release by the endothelium.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMedDate not supplied

Relaxation kinetics of rat aorta during pregnancy.

OBJECTIVE: To examine the hypothesis that kinetics of vasorelaxation are altered during pregnancy. METHODS: Rings of aorta from rats at different stages of pregnancy (early, late, and term) and from nonpregnant female rats were precontracted with high-K+ and then allowed to relax in normal-K+ physiologic saline solution. The time to reach 50% and 80% relaxation were determined in the absence or presence of a cyclooxygenase inhibitor (indomethacin) and a nitric oxide synthase inhibitor (N omega-nitro-L-arginine methyl ester) or after removal of the endothelium. RESULTS: The aortic relaxation was progressively faster in later stages of gestation. N omega-nitro-L-arginine methyl ester and indomethacin had no significant effect whereas removal of the endothelium caused a slowing of relaxation in all the groups. Even in the presence of N omega-nitro-L-arginine methyl ester and indomethacin or after de-endothelization, the relaxation remained faster at term as compared with the other groups. CONCLUSION: Aortic relaxation is faster in the presence of endothelium. The effect of endothelium on relaxation is independent of nitric oxide synthase or cyclooxygenase systems. Progression of gestation is associated with acceleration of aortic relaxation, which cannot be totally ascribed to an endothelial factor and may involve a change intrinsic to the vascular smooth muscle. Faster relaxation kinetics of the vasculature during pregnancy may be a mechanism to decrease peripheral vascular resistance.

Animals↗
PubMed2000

Interpretation of relaxation time constants for amorphous pharmaceutical systems.

The molecular mobility of amorphous pharmaceutical materials is known to be a key factor in determining their stability, reactivity, and physicochemical properties. Usually such molecular mobility is quantified using relaxation time constants. Typically relaxation processes in amorphous systems are non-exponential and relaxation time constants are usually obtained from experimental data using a curve fitting procedure involving the empirical Kohlrausch-Williams-Watts (KWW) equation. In this article we explore the possible relationship between the KWW curve fitting parameters (tau(KWW), beta(KWW)) and common statistical measures of the average and the distribution (e.g., median, standard deviation) of the relaxation time values. This analysis is performed for several common statistical distributions (e.g., normal, lognormal, and Lorentzian), and the results are compared and analyzed in the context of pharmaceutical product stability predictions. The KWW function is able to describe relaxation processes stemming from several different statistical distribution functions. Under some circumstances the "average" relaxation time constant of the KWW equation (tau(KWW)) is significantly different from common statistical measures of the central value of a distribution (e.g., median). Simply knowing the relaxation time constants from the fit of the KWW equation is not sufficient to completely characterize and quantify the molecular mobility of amorphous pharmaceutical materials. An appreciation of the distribution of relaxation times and the resulting effects upon the KWW constants should be considered to be essential when working with amorphous pharmaceutical materials, especially when attempting to use relaxation time constants for predicting their physical or chemical stability.

Algorithms↗
PubMed2006

Influence of sucrose and water content on molecular mobility in starch-based glasses as assessed through structure and secondary relaxation.

Molecular mobility is known to be a key parameter in controlling the physical properties of materials and thus their quality and performance. Beyond glass transition related changes, attention should be called to the impact of local motions remaining in the glassy state. Gelatinized waxy maize starch at different sucrose contents (0-20% solids) was equilibrated between 0 and 14% water and sorption isotherms determined at 25 degrees C. The effect of water and sucrose content on the molecular mobility of glassy starch was investigated by differential scanning calorimetry through enthalpy relaxation studies and dynamical mechanical thermal analysis. The existence of sucrose-starch interactions was suggested by the sorption isotherms not following the expected additivity of the single component sorption curves. Contrary to the glass transition or associated alpha relaxation, water and sucrose affected differently the secondary relaxations. Indeed, the beta relaxation observed around -15 degrees C was shifted to lower temperature upon increasing hydration, and to higher temperature when sucrose content increased, suggesting a hindering of these local motions. Enthalpy relaxation of the ternary mixtures was studied following aging up to 668 h at Tg -15 degrees C. Ternary mixtures exhibited an enthalpy relaxation upon aging lower than starch alone as a sign of lower polymer mobility in the presence of small molecules, contrary to the free volume theory. Relaxation kinetics were characterized with the Cowie-Ferguson model and compared to literature data. The extent of the enthalpy relaxation appeared to be controlled by the distance between the aging temperature and the beta relaxation temperature.

Adsorption↗
PubMed2005

Rotational dynamics account for pH-dependent relaxivities of PAMAM dendrimeric, Gd-based potential MRI contrast agents.

The EPTPA5) chelate, which ensures fast water exchange in GdIII complexes, has been coupled to three different generations (5, 7, and 9) of polyamidoamine (PAMAM) dendrimers through benzylthiourea linkages (H5EPTPA = ethylenepropylenetriamine-N,N,N',N'',N''-pentaacetic acid). The proton relaxivities measured at pH 7.4 for the dendrimer complexes G5-(GdEPTPA)111, G7-(GdEPTPA)253 and G9-(GdEPTPA)1157 decrease with increasing temperature, indicating that, for the first time for dendrimers, slow water exchange does not limit relaxivity. At a given field and temperature, the relaxivity increases from G5 to G7, and then slightly decreases for G9 (r1 = 20.5, 28.3 and 27.9 mM(-1) s(-1), respectively, at 37 degrees C, 30 MHz). The relaxivities show a strong and reversible pH dependency for all three dendrimer complexes. This originates from the pH-dependent rotational dynamics of the dendrimer skeleton, which was evidenced by a combined variable-temperature and multiple-field 17O NMR and 1H relaxivity study performed at pH 6.0 and 9.9 on G5-(GdEPTPA)111. The longitudinal 17O and 1H relaxation rates of the dendrimeric complex are strongly pH-dependent, whereas they are not for the [Gd(EPTPA)(H2O)]2- monomer chelate. The longitudinal 17O and 1H relaxation rates have been analysed by the Lipari-Szabo spectral density functions and correlation times have been calculated for the global motion of the entire macromolecule (tau(gO)) and the local motion of the GdIII chelates on the surface (tau(lO)), correlated by means of an order parameter S2. The dendrimer complex G5-(GdEPTPA)111 has a considerably higher tau(gO) under acidic than under basic conditions (tau(298)gO = 4040 ps and 2950 ps, respectively), while local motions are less influenced by pH (tau(298)lO = 150 and 125 ps). The order parameter, characterizing the rigidity of the macromolecule, is also higher at pH 6.0 than at pH 9.9 (S2 = 0.43 vs 0.36, respectively). The pH dependence of the global correlation time can be related to the protonation of the tertiary amine groups in the PAMAM skeleton, which leads to an expanded and more rigid dendrimeric structure at lower pH. The increase of tau(gO) with decreasing pH is responsible for the pH dependent proton relaxivities. The water exchange rate on G5-(GdEPTPA)111(k(298)ex = 150 x 10(6) s(-1)) shows no significant pH dependency and is similar to the one measured for the monomer [Gd(EPTPA)(H2O)]2-. The proton relaxivity of G5-(GdEPTPA)111 is mainly limited by the important flexibility of the dendrimer structure, and to a small extent, by a faster than optimal water exchange rate.

Chelating Agents↗
PubMed2005

Gadolinium(III)-loaded nanoparticulate zeolites as potential high-field MRI contrast agents: relationship between structure and relaxivity.

The effects of dealumination, pore size, and calcination on the efficiency (as expressed in the relaxivity) of Gd3+-loaded zeolites for potential application as magnetic resonance imaging (MRI) contrast agents were studied. Partial dealumination of zeolites NaY or NaA by treatment with (NH4)2SiF6 or diluted HCl resulted in materials that, upon loading with Gd3+, had a much higher relaxivity than the corresponding non-dealuminated materials. Analysis of the 1H NMR dispersion profiles of the various zeolites showed that this can be mainly ascribed to an increase of the amount of water inside the zeolite cavities as a result of the destruction of walls between cavities. However, the average residence time of water inside the Gd3+-loaded cavities did not change significantly, which suggests that the windows of the Gd3+-loaded cavities are not affected by the dealumination. Upon calcination, the Gd3+ ions moved to the small sodalite cavities and became less accessible for water, resulting in a decrease in relaxivity. The important role of diffusion for the relaxivity was demonstrated by a comparison of the relaxivity of Gd3+-loaded zeolite NaY and NaA samples. NaA had much lower relaxivities due to the smaller pore sizes. The transversal relaxivities of the Gd3+-doped zeolites are comparable in magnitude to the longitudinal ones at low magnetic fields (<60 MHz). However at higher fields, the transversal relaxivities steeply increased, whereas the longitudinal relaxivities decreased as field strength increased. Therefore, these materials have potential as T1 MRI contrast agents at low field, and as T2 agents at higher fields.

Aluminum↗
PubMed2002

Dynamics of pharmaceutical amorphous solids: the study of enthalpy relaxation by isothermal microcalorimetry.

The structural relaxation time is a measure of the molecular mobility involved in enthalpy relaxation, and thus, is a measure of the dynamics of amorphous (glassy) pharmaceutical solids that determines physicochemical properties and reactivity of drugs in amorphous formulations. In this article we describe a novel method for characterization of structural relaxation using isothermal microcalorimetry, which directly measures the rate of heat release during the relaxation processes. The structural relaxation time is then obtained from a fit of the power data to the derivative version of the Kohlrausch-Williams-Watts (KWW) equation. The relaxation times of quenched and lyophilized samples of saccharides were studied using an isothermal microcalorimeter, the Thermal Activity Monitor (TAM). In addition to the KWW derivative function, a derivative equation of the modified stretched exponential function (MSE) was employed to evaluate TAM data. The later (MSE) appeared to have numerical advantages over the KWW equation. The data demonstrate, as expected, that structural relaxation times of amorphous solids depend on a number of variables, including nature of material, temperature, moisture content, thermal history, etc. Isothermal microcalorimetry with the TAM provides a very fast and reliable way to characterize the dynamics of glassy materials, which in many respects is superior to the conventional DSC approach. To the extent stability and structural relaxation dynamics in the glass are correlated, structural relaxation parameters derived by isothermal microcalorimetry may provide data useful for rational development of stable peptide and protein formulations and for the control of their processing.

Algorithms↗