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PubMed1996

Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro.

The mechanisms producing long duration of action for formoterol and salmeterol are not fully understood. The aim of the current study was to examine how the concentration of long and short acting beta 2-adrenoceptor agonists affects their relaxation kinetics in airway smooth muscle. Onset (time to peak relaxation) and offset of action (reassertion of reversible relaxation followed repeated beta-adrenoceptor blockade and washout) were measured in the guinea pig trachea precontracted postjunctionally by carbachol 0.3 microM in vitro. At 10-1,000% (C10-C1,000) of the maximally effective concentration (C100: 150 nM formoterol, 10 microM salbutamol, 30 microM salmeterol), salbutamol had a shorter time to peak relaxation than did salmeterol. Formoterol and salmeterol had a similar time to peak relaxation at C10, but, in contrast to salmeterol, formoterol's time to peak relaxation became markedly shorter and similar to that of salbutamol as the concentration was increased up to C1,000. Significant reversible reasserted relaxation was demonstrated for salmeterol alone at C10. At C30-C1,000, however, salmeterol produced irreversible relaxation only, in spite of repeated beta-adrenoceptor blockade by sotalol 10 microM followed by washout. In contrast, formoterol produced an increasing reversible reasserted relaxation at C30-C1,000. Salbutamol produced significant, reversible reasserted relaxation at C1,000 only. In conclusion, the concentration determines the onset and offset of action for formoterol and to a lesser extent for salbutamol, but not for salmeterol. To cause sustained action, a submaximally effective concentration is sufficient for salmeterol, whereas formoterol requires a maximally effective concentration. The rank order of concentration dependence for the relaxation kinetics is not paralleled by the rank order of lipophilicity for formoterol, salbutamol, and salmeterol. Therefore, factors other than lipophilicity may also play a role in determining the relationship between concentration and relaxation kinetics for the investigated beta 2-agonists.

Adrenergic beta-Agonists↗
PubMed2004

Modulation of the distance dependence of paramagnetic relaxation enhancements by CSA x DSA cross-correlation.

Paramagnetic metal ions with fast-relaxing electronic spin and anisotropic susceptibility tensor provide a rich source of structural information that can be derived from pseudo-contact shifts, residual dipolar couplings, dipole-dipole Curie spin cross-correlation, and paramagnetic relaxation enhancements. The present study draws attention to a cross-correlation effect between nuclear relaxation due to anisotropic chemical shielding (CSA) and due to the anisotropic dipolar shielding (DSA) caused by the electronic Curie spin. This CSA x DSA cross-correlation contribution seems to have been overlooked in previous interpretations of paramagnetic relaxation enhancements. It is shown to be sufficiently large to compromise the 1/r6 distance dependence usually assumed. The effect cannot experimentally be separated from auto-correlated DSA relaxation. It can increase or decrease the observed paramagnetic relaxation enhancement. Under certain conditions, the effect can dominate the entire paramagnetic relaxation, resulting in nuclear resonances narrower than in the absence of the paramagnetic center. CSAxDSA cross-correlation becomes important when paramagnetic relaxation is predominantly due to the Curie rather than the Solomon mechanism. Therefore the effect is most pronounced for relaxation by metal ions with large magnetic susceptibility and fast-relaxing electron spin. It most strongly affects paramagnetic enhancements of transverse relaxation in macromolecules and of longitudinal relaxation in small molecules.

Anisotropy↗
PubMed2005

Electron spin relaxation of copper(II) complexes in glassy solution between 10 and 120 K.

The temperature dependence, between 10 and 120 K, of electron spin-lattice relaxation at X-band was analyzed for a series of eight pyrrolate-imine complexes and for ten other copper(II) complexes with varying ligands and geometry including copper-containing prion octarepeat domain and S100 type proteins. The geometry of the CuN4 coordination sphere for pyrrolate-imine complexes with R=H, methyl, n-butyl, diphenylmethyl, benzyl, 2-adamantyl, 1-adamantyl, and tert-butyl has been shown to range from planar to pseudo-tetrahedral. The fit to the recovery curves was better for a distribution of values of T1 than for a single time constant. Distributions of relaxation times may be characteristic of Cu(II) in glassy solution. Long-pulse saturation recovery and inversion recovery measurements were performed. The temperature dependence of spin-lattice relaxation rates was analyzed in terms of contributions from the direct process, the Raman process, and local modes. It was necessary to include more than one process to fit the experimental data. There was a small contribution from the direct process at low temperature. The Raman process was the dominant contribution to relaxation between about 20 and 60 K. Debye temperatures were between 80 and 120 K. For samples with similar Debye temperatures the coefficient of the Raman process tended to increase as gz increased, as expected if modulation of spin-orbit coupling is a major factor in relaxation rates. Above about 60 K local modes with energies in the range of 260-360 K (180-250 cm-1) dominated the relaxation. For molecules with similar geometry, relaxation rates were faster for more flexible molecules than for more rigid ones. Relaxation rates for the copper protein samples were similar to rates for small molecules with comparable coordination spheres. At each temperature studied the range of relaxation rates was less than an order of magnitude. The spread was smaller between 20 and 60 K where the Raman process dominates, than at higher temperatures where local modes dominate the relaxation. Spin echo dephasing time constants, Tm, were calculated from two-pulse spin echo decays. Near 10 K Tm was dominated by proton spins in the surroundings. As temperature was increased motion and spin-lattice relaxation made increasing contributions to Tm. Near 100 K spin-lattice relaxation dominated Tm.

Copper↗
PubMed1999

Pharmacological characterisation of endothelium-dependent relaxation in human radial artery: comparison with internal thoracic artery.

OBJECTIVE: The aim of this study was to investigate the contribution of nitric oxide/prostanoid-independent pathways to endothelium-dependent vasorelaxation in human conduit arteries. METHODS: Rings of internal thoracic artery (ITA) and radial artery (RA) taken from patients undergoing coronary artery bypass graft surgery were suspended in 10-ml organ baths and relaxation to carbachol and bradykinin studied in the presence and absence of nitric oxide synthase (NOS) inhibitors and potassium channel blockers. RESULTS: No significant relaxation to carbachol or bradykinin was observed in ITA after NOS inhibition. In contrast, in RA less than 40% attenuation of relaxation to carbachol or bradykinin was achieved with any of the NOS inhibitors. In the presence of 20 mM K+ relaxation to carbachol and bradykinin was inhibited by 28 +/- 9% and 42 +/- 9% while in the presence of L-NAME 200 microM + 20 mM K+ relaxation was inhibited by 66 +/- 6% and 70 +/- 4% respectively in this artery. Tetraethylammonium, glibenclamide, apamin and iberiotoxin had little effect on relaxation to carbachol but charybdotoxin alone and charybdotoxin plus apamin attenuated relaxation to carbachol by 23 +/- 4% and 49 +/- 9% in RA. In the presence of L-NAME 200 microM attenuation of these relaxations were increased to 60 +/- 4% and 78 +/- 4%. CONCLUSION: In ITA relaxations to carbachol and bradykinin were mediated via nitric oxide. In contrast in RA, a conduit vessel of similar diameter, both nitric oxide-dependent and independent pathways appeared to contribute to vascular relaxation. This nitric oxide-independent relaxation involved opening of Ca2+ activated potassium channel(s). The existence of alternative pathways mediating endothelium-independent relaxation could be important under pathological conditions and may contribute to the long term survival of radial artery grafts.

Bradykinin↗
PubMed2000

Guanylate cyclase and not ATP-dependent K(+) channels seems temperature-dependent in smooth muscle relaxation of human umbilical arteries.

The effects of K(+) channel opener, nicorandil [N-(2-hydroxyethyl)-nicotinamide nitrate], on isolated human umbilical arteries were investigated at two temperatures: 37 degrees C and 25 degrees C. The purpose of this investigation was: (1) to confirm the relaxant effect of nicorandil, (2) to elucidate the influence of endothelium and temperature on nicorandil-induced relaxation, (3) to determine which of guanylate cyclase or ATP-sensitive K(+) channels was implicated in temperature-induced relaxation of smooth muscles. Rings, 3-mm-wide, were suspended in organ chambers for isometric force measurement. All solutions were aerated with 95% O(2)-5% CO(2) and maintained at 37 degrees C or 25 degrees C (cooling), pH 7.4. The presence of an intact endothelium was confirmed by immunohistochemistry. During the first set of experiments after contraction with 5-hydroxytryptamine (5-HT 10(-5) M), nicorandil (10(-9)-10(-4) M) was added to the organ chambers with controls and in with rings incubated with L-arginine, N-nitro-L-arginine (L-NNA) an inhibitor of nitric oxide (NO) synthase, [1-H-(1,2,4) oxadiazole (4,3-a) quinoxalin-1-one] (ODQ), a specific inhibitor of guanylate cyclase, or glibenclamide, an antagonist of nicorandil, all at 10(-5) M. In another set of experiments, rings were contracted with 5-HT (10(-5) M) and relaxed with 3-morpholinosydnonimine [SIN-1 (10(-9)-3x10(-5) M) or cromakalim (10(-9)-3x10(-5) M)]. Our results showed that nicorandil induced concentration-dependent relaxation. At 37 degrees C, in the control, the maximum relaxation was 90+/-5%, and 60+/-8% at 25 degrees C (P<0.01). However, the relaxation at 37 degrees C or 25 degrees C remained unchanged after pretreatment with L-arginine, L-NNA, this suggests that the same concentration of drugs used in this type of vessel does not appear to modulate the relaxant effect of nicorandil. On the other hand, we observed that the relaxant effect of SIN-1 was 72+/-5% at 37 degrees C and only 28+/-7% at 25 degrees C (P<0.01). However, relaxations with cromakalim were partly influenced by cooling. In the presence of ODQ, the nicorandil-induced relaxation observed at 37 degrees C or 25 degrees C was less than that in the control and in the rings incubated with glibenclamide. These results for human umbilical arteries indicate that cooling decreases the relaxation response of smooth muscles and that this is partly due to a decreased response to guanylate cyclase.

Adenosine Triphosphate↗
PubMed1997

Right and left isovolumic ventricular relaxation time intervals compared in patients by means of a single-pulsed Doppler method.

Right and left isovolumic ventricular relaxation time intervals measurements were obtained as follows: from the peak R wave on the electrocardiogram to either the mitral or the tricuspid pulsed Doppler flow trace onset minus the R to end-ejection zero flow crossing of the subaortic (left side) or pulmonary (right side) D flow trace time interval. A ratio was calculated as a percent difference duration between both isovolumic ventricular relaxation time intervals. The aim was to compare isovolumic ventricular relaxation time interval values in 42 healthy controls and to study the changes induced by heart diseases in 27 patients with (1) controlled hypertension without left ventricular hypertrophy, (2) hypertrophic cardiomyopathy, and (3) Cor pulmonale. Mean values of isovolumic ventricular relaxation time intervals significantly differed at paired and unpaired studies, with right isovolumic ventricular relaxation time intervals shorter than those of the left side in all groups (p < 0.001) except for patients with Cor pulmonale. Isovolumic ventricular relaxation time intervals did not correlate with heart rate and moderately correlated with left ventricular mass and age. No significant difference was found between healthy controls and patients with controlled hypertension. Significant changes were found in patients with hypertrophic cardiomyopathy and Cor pulmonale versus healthy controls for both isovolumic ventricular relaxation time intervals. However, significant changes in the ratio were only found in patients with Cor pulmonale (p < 0.005) because of abnormal similar values for both isovolumic ventricular relaxation time intervals. This Doppler method enabled, for the first time, serial comparison of isovolumic ventricular relaxation time intervals with a homologous method. Both isovolumic ventricular relaxation time intervals significantly lengthened with age and with left ventricular indexed mass, but their ratio remained insignificantly changed except for patients with Cor pulmonale. The concomitant right and left isovolumic ventricular relaxation time intervals lengthening in patients with hypertrophic cardiomyopathy and Cor pulmonale suggests interdependence of both ventricles through the septum. This makes recommendable systematic comparison of both sides. The calculation of a ratio, free from the effect of factors intervening on isovolumic ventricular relaxation time intervals, may, in addition, be of diagnostic help.

Adolescent↗
PubMed1988

Hemolysate inhibits cerebral artery relaxation.

In helical strips of dog middle cerebral arteries partially contracted with prostaglandin (PG) F2 alpha, relaxations induced by angiotensin-II, possibly mediated by PGI2, and those induced by PGH2 were reversed to a contraction or markedly reduced by treatment with hemolysate, which, however, attenuated the PGI2-induced relaxation only slightly. The relaxant response of human middle cerebral arterial strips to PGH2 was also suppressed by hemolysate. Dog and monkey middle cerebral arteries responded to transmural electrical stimulation and nicotine with transient relaxations, which were quite susceptible to tetrodotoxin and hexamethonium, respectively; the relaxations were abolished almost completely by hemolysate and methylene blue. On the other hand, the relaxant response of dog cerebral arteries to a low concentration of K+ was not influenced by hemolysate or by methylene blue, but was reversed to a contraction by treatment with ouabain. Relaxations induced by substance-P and nitroglycerin were markedly inhibited by hemolysate; removal of endothelium abolished the relaxation by substance-P, but did not influence the nitroglycerin-induced relaxation. Hemolysate may interfere with the biosynthesis of PGI2 in the vascular wall, thereby reversing the relaxation induced by angiotensin-II and PGH2 to a contraction. Relaxations induced by electrical and chemical stimulation of vasodilator nerves innervating cerebral arteries appear to be elicited by a mechanism dependent on cellular cyclic guanosine monophosphate (GMP), like that underlying the substance-P-induced and nitroglycerin-induced relaxation. These actions of hemolysate may be involved in the genesis of cerebral vasospasm after subarachnoid hemorrhage.

Angiotensin II↗
PubMed2001

Relaxation to authentic nitric oxide and SIN-1 in rat isolated mesenteric arteries: variable role for smooth muscle hyperpolarization.

Authentic nitric oxide (NO; 0.1 - 10 micromoles) caused transient, dose-dependent relaxation of phenylephrine-induced tone without changing membrane potential in mesenteric arteries. Larger doses, above 10 micromoles, did not evoke more relaxation (maximal relaxation to 150 micromoles NO in denuded arteries, 69+/-7%, n=8) but stimulated muscle hyperpolarization (maximum 19+/-3 mV, n=5). The soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM), abolished relaxation to low doses of NO (n=4), but did not modify hyperpolarization with higher doses of NO (n=4). The potassium channel blocker charybdotoxin (ChTX; 50 nM) abolished hyperpolarization to high doses of NO and significantly reduced the maximal relaxation (to 43+/-6%, n=4; P<0.01). ODQ and ChTX together abolished tension and membrane potential change to all doses of NO (n=4). All relaxations to 3-morpholino-sydnonimine (SIN-1; 0.01 - 10 microM) were associated with hyperpolarization. When the endothelium was intact, ChTX inhibited hyperpolarization and relaxation to SIN-1 (n=5), while iberiotoxin (IbTX; 50 nM) or 4-aminopyridine (4-AP; 500 microM) reduced relaxation by 40% and 20%, respectively and by 80% in combination (n=6 in each case). In denuded arteries, relaxation to SIN-1 was unaffected by either ChTX or ODQ alone, but abolished by the inhibitors together (n=6). Alone, 4-AP did not alter relaxation, but in the presence of ODQ it reduced the maximal response by around 45% (n=6; P<0.01). 4-AP, ODQ and IbTX together inhibited relaxation to SIN-1 by 75% (n=6; P<0.01). Therefore, cyclic guanosine 3',5'-monophosphate (cyclic GMP)-independent smooth muscle hyperpolarization, possibly involving direct activation of calcium-activated and voltage-sensitive potassium channels, contributes to relaxation evoked by authentic NO and SIN-1. However, the importance of each pathway depends on the source of NO and with SIN-1 the relative contribution from each pathway is modified by the endothelium.

4-Aminopyridine↗
PubMed2002

Urocortin-induced endothelium-dependent relaxation of rat coronary artery: role of nitric oxide and K+ channels.

1. The mechanisms underlying the vasodilator response to urocortin are incompletely understood. The present study was designed to examine the role of endothelial nitric oxide and Ba(2+)-sensitive K(+) channels in the endothelium-dependent component of urocortin-induced relaxation in the rat left anterior descending coronary artery. 2. Urocortin induced both endothelium-dependent and -independent relaxation with respective pD(2) of 8.64+/-0.03 and 7.90+/-0.10. Removal of endothelium reduced the relaxing potency of urocortin. In rings pretreated with 10(-4) M N(G)-nitro-L-arginine methyl ester, 10(-5) M methylene blue or 10(-5) M ODQ, the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. L-Arginine (5x10(-4) M) antagonized the effect of N(G)-nitro-L-arginine methyl ester. 3. The relaxant response to urocortin was reduced in endothelium-intact rings preconstricted by 3.5x10(-2) M K(+) and abolished when extracellular K(+) was raised to 5x10(-2) M. Pretreatment with 10(-4) M BaCl(2) significantly inhibited urocortin-induced relaxation. Combined treatment with 10(-4) M BaCl(2) plus 10(-4) M N(G)-nitro-L-arginine methyl ester did not cause further inhibition. In urocortin (10(-8) M)-relaxed rings, BaCl(2) induced concentration-dependent reversal in vessel tone. Tertiapin-Q (10(-6) M) also attenuated urocortin-induced relaxation. In contrast, BaCl(2) did not alter urocortin-induced relaxation in endothelium-denuded rings. 4. In endothelium-denuded rings, hydroxylamine- and nitroprusside-induced relaxation was inhibited by 10(-4) M BaCl(2), but not by 10(-6) M tertiapin-Q. 5. The endothelium of the coronary artery was moderately stained with the antiserum against urocortin. 6. Taken together, the present results indicate that the urocortin-induced endothelium-dependent relaxation of rat coronary arteries is likely attributable to endothelial nitric oxide and subsequent activation of Ba(2+)- or tertiapin-Q-sensitive K(+) channels. The urocortin-induced endothelium-dependent relaxation appears to be mediated by cyclic GMP-dependent mechanisms.

Animals↗
PubMed1998

Influence of mode of contraction on the mechanism of acetylcholine-mediated relaxation of coronary arteries from normotensive and spontaneously hypertensive rats.

1. Endothelium-dependent acetylcholine-mediated relaxations of small coronary arteries (approximately 200 microns internal diameter) from 20 weeks old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls were compared under pressurized no-flow conditions after the development of myogenic tone or constriction with the thromboxane A2 mimetic U46619. 2. Relaxations of WKY and SHR arteries following development of myogenic tone did not differ and were not significantly influenced by indomethacin alone (10 mumol/l) or in combination with N omega-nitro-L-arginine (L-NNA, 0.1 mmol/l). Maximum relaxations were significantly attenuated by 30 mmol/l K+ in the SHR, from 85 +/- 7% (n = 11) to 20 +/- 8% (n = 8), P < 0.001, and in the WKY from 86 +/- 5% (n = 9) to 39 +/- 14% (n = 8), P < 0.01. 3. Relaxations following constriction with U46619 were also similar in both rat strains. Maximum relaxations were 50 +/- 11% (n = 8) in SHR and 60 +/- 7% (n = 6) in WKY. Indomethacin did not influence these relaxations. The combination of indomethacin and L-NNA attenuated relaxations in WKY (P < 0.01), but in the SHR the attenuation did not achieve statistical significance (P = 0.07) compared with controls; the maximum responses were reduced to 25 +/- 7% (n = 8) and 14 +/- 11% (n = 6) in the SHR and WKY respectively, but only in the WKY was this reduction significant (P < 0.05). 4. These data demonstrate that, under control conditions, SHR and WKY coronary arteries relax equally effectively, regardless of mode of contraction, and also that the mechanism of acetylcholine-mediated relaxation differs according to the mode of contraction. Acetylcholine relaxes myogenic tone by a K(+)-sensitive mechanism in both WKY and SHR, consistent with a role for endothelium-derived hyperpolarizing factor; NO contributes substantially to the relaxation of U46619-induced tone by acetylcholine in the WKY, but to a diminished extent in the SHR. 5. These data indicate that the choice of vasoconstrictor agent is of critical concern when assessing mechanisms of endothelium-dependent relaxation and abnormalities thereof in hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Primary and secondary relaxations in supercooled eugenol and isoeugenol at ambient and elevated pressures: dependence on chemical microstructure.

Dielectric loss spectra of two glass-forming isomers, eugenol and isoeugenol, measured at ambient and elevated pressures in the normal liquid, supercooled, and glassy states are presented. The isomeric chemical compounds studied differ only by the location of the double bond in the alkyl chain. Above the glass transition temperature T(g), the dielectric loss spectra of both isomers exhibit an excess wing on the high frequency flank of the loss peak of the alpha relaxation and an additional faster gamma process at the megahertz frequency range. By decreasing temperature below T(g) at ambient pressure or by elevating pressure above P(g), the glass transition pressure, at constant temperature, the excess wing of isoeugenol shifts to lower frequencies and is transformed into a secondary beta-loss peak, while in eugenol it becomes a shoulder. These spectral features enable the beta-relaxation time tau(beta) to be determined in the glassy state. These changes indicate that the excess wings in isoeugenol and eugenol are similar and both are secondary beta relaxations that are not resolved in the liquid state. While in both isoeugenol and eugenol the loss peak of the beta relaxation in the glassy state and the corresponding excess wing in the liquid state shifts to lower frequencies on elevating pressure, the locations of their gamma relaxation show little change with increasing pressure. The different pressure sensitivities of the excess wing and gamma relaxation are further demonstrated by the nearly perfect superposition of the alpha-loss peak together with excess wing from the data taken at ambient pressure and at elevated pressure (and higher temperature so as to have the same alpha-peak frequency), but not the gamma-loss peak in both isoeugenol and eugenol. On physical aging isoeugenol, the beta-loss peak shifts to lower frequencies, but not the gamma relaxation. Basing on these experimental facts, the faster gamma relaxation is a local intramolecular process involving a side group and the slower beta relaxation mimics the structural alpha relaxation in behavior, involves the entire molecule and satisfies the criteria for being the Johari-Goldstein beta relaxation. Analysis and interpretation of the spectra utilizing the coupling model further demonstrate that the excess wings seen in the equilibrium liquid states of these two isomers are their genuine Johari-Goldstein beta relaxation.

Journal Article↗
PubMed1994

A non-cyclo-oxygenase, non-nitric oxide relaxing factor is present in resistance arteries of normotensive but not spontaneously hypertensive rats.

The present experiments tested the hypothesis that decreased production of an endothelium-derived relaxing factor in arteries of hypertensive animals contributes to impaired endothelium-dependent relaxation. Acetylcholine-induced relaxation of freshly isolated spontaneously hypertensive rat (SHR) vessels pre-contracted with norepinephrine was impaired compared with Wistar-Kyoto rats (WKY). 10 microM indomethacin partially normalized the SHR response. Inhibition of nitric oxide synthesis with 100 microM nitro-L-arginine methyl ester or 100 microM NG-monomethyl arginine shifted the acetylcholine relaxation curve to the right, but had no effect on the maximal relaxation in WKY and completely inhibited relaxation of SHR. A similar pattern was observed with methylene blue (0.3 microM). Acetylcholine-induced relaxation of WKY vessels pre-contracted with 5 microM norepinephrine and 100 mM K+ was attenuated 60% compared with vessels pre-contracted with norepinephrine alone, and was completely inhibited by nitro-L-arginine methyl ester; relaxation of SHR vessels was decreased by 50%. Six-hour storage at 37 degrees C significantly attenuated acetylcholine-induced relaxation in both strains; treatment with indomethacin improved the response. Moreover, relaxation of WKY vessels was completely inhibited by nitro-L-arginine methyl ester and NG-monomethyl arginine after the storage period. The absence of L-arginine-induced relaxation and lack of effect of supplementation with L-arginine indicated that the constitutively active NO synthetase was not induced and that L-arginine substrate was limiting. The results indicate that mesenteric resistance arteries of the WKY express a relaxing factor generated by a non-cyclo-oxygenase, non-nitric oxide synthetase pathway that is possibly a hyperpolarizing factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1996

Endothelium-dependent relaxation by alpha 2-adrenoceptor agonists in spontaneously hypertensive rat aorta.

Differences in alpha(2)-adrenoceptor-induced relaxation of the aorta between stroke-prone spontaneously hypertensive rats (SHRSP) and control normotensive Wistar Kyoto rats (WKY) were studied. Changes in the tension of ring preparations of the aortas were measured isometrically. Relaxation was observed in the preparations precontracted in the presence of ONO-11113, a thromboxane A(2) analogue. The alpha(2)-agonist clonidine and UK-14304 induced dose-dependent relaxation in both the WKY and SHRSP preparations. The relaxation was impaired in the SHRSP preparation. A modified sandwich experiment showed that the relaxing substance from the SHRSP endothelium was decreased. Acetylcholine (ACh) also induced dose-dependent relaxation, and the relaxation was impaired in the SHRSP preparations. alpha(2)-Agonists induced a greater degree of impairment in the relaxation than did ACh. The relaxation induced by alpha(2)-agonists and by ACh was blocked by N G-nitro-L-arginine (L-NNA). Indomethacin improved the relaxation induced by ACh but not that induced by alpha(2)-agonists in the SHRSP aortas. These results suggest that the impairment of relaxation by alpha(2)-agonists in SHRSP is not caused by the increase in the release of endothelium-derived contracting factor (EDCF) but by the reduction in the release of nitric oxide (NO). Alteration of the alpha(2)-adrenoceptors and/or the intracellular mechanism through which NO is synthesized by stimulation of the alpha(2)-adrenoceptors may be the cause of the reduction in relaxation.

Acetylcholine↗
PubMed2005

How to compare the efficiency of albumin-bound and nonalbumin-bound contrast agents in vivo: the concept of dynamic relaxivity.

RATIONALE AND OBJECTIVES: The objective of this study was to compare, in a rabbit experimental model that mimics a magnetic resonance (MR) angiographic protocol, the efficiency of the following types of compound on the MR signal: (1) a nonalbumin-bound blood pool contrast agent: P792; (2) a weak albumin-bound extracellular contrast agent: Gd-BOPTA; and (3) a strong albumin-bound blood pool contrast agent: MS325. METHODS: The 2 main phases of early distribution after contrast agent injection, ie, the bolus phase (0-15 seconds postinjection) and the postbolus phase (1-5 minutes postinjection) were investigated by measuring Gd blood concentrations in the first 5 minutes postinjection. In the case of MS325 and Gd-BOPTA, the percentage of the free and bound forms were calculated throughout the pharmacokinetic profile. The dynamic relaxivity at 60 MHz in plasma of each contrast agent was determined in the 2 phases after contrast agent injection, ie, the bolus phase and the postbolus phase. RESULTS: Injected under similar conditions, the 3 contrast agents had a comparable profile during the bolus phase (0-15 seconds postinjection). At 1 minute postinjection, only 38% of Gd-BOPTA remained in the blood, whereas 85% of P792 was still present in the blood. MS-325 had an intermediate position with 61% remaining in the blood. During the postbolus phase, the various compounds demonstrated similar behavior: the plasma concentration of P792 was higher than that of MS325 and Gd-BOPTA, ie, Ci/C0 (P792)>Ci/C0 (MS325)>Ci/C0 (Gd-BOPTA). At the peak of the bolus, 75% of MS325 and 93% of Gd-BOPTA was present in free form. This proportion decreased progressively during the postbolus phase, because 5 minutes postinjection, 23% of the free form remained for MS325 and 82% for Gd BOPTA. A significant decrease in dynamic r1 relaxivity was observed at 60 MHz for the products that bind to albumin (Gd-BOPTA and MS325) during the bolus phase. The dynamic relaxivity for MS325 at the bolus phase was 8.6 mMs and 5.2 mMs for Gd-BOPTA. At the postbolus phase, the dynamic relaxivity increased (17.3 mMs for MS325 and 6.7 mMs for Gd-BOPTA). The dynamic relaxivity of P792, which does not bind to albumin, was constantly equal to 26 mMs at each time point of the pharmacokinetic profile (bolus and postbolus phase). CONCLUSIONS: The physicochemical measurements of relaxivity in plasma are made in vitro at a fixed concentration of gadolinium and the value of relaxivity is not necessarily an accurate reflection of the efficiency of the contrast agent in vivo, especially for contrast agents that bind to albumin. Indeed, in vivo, the proportion of free and bound forms of albumin-binding contrast agents varies according to the pharmacokinetic profile, and the relaxivities of albumin-bound and free contrast agents are different. Consequently, the concept of dynamic relaxivity was introduced to compare the efficiency of MS325, Gd-BOPTA, and P792 in vivo. The variation of the dynamic relaxivity of MS325 and Gd-BOPTA between the bolus and postbolus phase is significant (101% for MS325 and 29% for Gd-BOPTA) as a result of the variation in the quantity of bound and free forms during the pharmacokinetic profile. The blood pool agent P792 has different properties, which result from its intravascular retention and its lack of albumin binding. Indeed, contrary to Gd-BOPTA and MS325, the dynamic relaxivity of P792 is higher at the bolus phase (26 mMs) and does not vary during the pharmacokinetic profile. The impact of these different dynamic relaxivities should be integrated in the analysis of the performance of the different classes of contrast agents in clinical MRA protocols.

Animals↗
PubMed1993

Endothelium-dependent noradrenaline-induced relaxation of rat isolated cerebral arteries: pharmacological characterization of receptor subtypes involved.

1. The endothelium-dependence of catecholamine-induced relaxation of rat cerebral arteries was investigated in vitro. 2. In the basilar artery (BA), the maximal relaxant response was most pronounced with noradrenaline (NA), less with isoprenaline (Iso), and only very little with terbutaline. Methoxamine and the alpha 2-adrenoceptor selective agonists BHT 933 and clonidine, had no relaxant effect. 3. In BA, the relaxation by NA or Iso was markedly attenuated by N omega-nitro-L-arginine (L-NOARG) 10(-4) M. Short term perfusion of the vessels by Triton X 100 (1:1,000) suppressed the NA-induced relaxation. 4. The relaxation induced by NA or Iso was markedly reduced in presence of L-NOARG in the posterior, medial and anterior cerebral artery. 5. In BA, NA-induced relaxation was non-competitively inhibited by propranolol, atenolol, and the beta 1- and beta 2-adrenoceptor selective antagonists, CGP 20712 A and ICI 118551. 6. The relaxant NA-effect was not affected by prazosin but was non-competitively blocked by phentolamine. 7. The Iso-induced relaxation was competitively blocked by propranolol, whereas atenolol, CGP 20712 A and ICI 118551 caused a non-competitive inhibition. 8. The experiments indicate that the catecholamine-induced relaxation in rat isolated cerebral arteries depends upon the endothelium. They suggest that the NA-induced relaxation of BA is mediated by different alpha- and beta-adrenoceptors and that the Iso-induced relaxation is mediated by different beta-receptors. The findings would also be compatible with the idea of a receptor type which cannot be characterized by the pharmacological tools that we have used.

Animals↗
PubMed1995

Exposure and characterization of the action of noradrenaline at dopamine receptors mediating endothelium-independent relaxation of rat isolated small mesenteric arteries.

1. Previously, we reported that noradrenaline (NA), in addition to its alpha 1-adrenoceptor-mediated contractile effect, may relax the rat small mesenteric artery (SMA) in order to account for steep Schild plots obtained with compounds classified as alpha 1-adrenoceptor antagonists. In this study, a relaxant action of NA has been exposed in the rat isolated, endothelium-denuded SMA precontracted by the thromboxane A2-mimetic, U46619. 2. NA, but not the selective alpha 2-adrenoceptor agonist, UK14304, produced concentration-dependent contraction of the SMA (pEC50 = 5.7 +/- 0.1). After precontraction with 0.1 microM U46619, 10 nM-30 microM NA produced a further contraction (pEC50 = 6.1 +/- 0.2), while higher concentrations of NA produced small, but significant, relaxant responses. 3. In the presence of 1 microM prazosin, 0.1-30 microM NA produced concentration dependent relaxation (pIC50 = 5.9 +/- 0.1) after precontraction with 0.1 microM U46619. The NA relaxation concentration-effect curve was completely inhibited by 1 microM of the beta 1/beta 2-adrenoceptor antagonist, timolol. However, when the concentration of prazosin was increased by 10 fold (10 microM), NA once again produced concentration-dependent relaxation (pIC50 = 4.5 +/- 0.2). This relaxation concentration-effect curve was not blocked by a 10 fold higher concentration of timolol (10 microM), nor by the presence of idazoxan (10 microM), cyanopindolol (10 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), indomethacin (10 microM) or sulpiride (1 microM). However, haloperidol (10 microM) and (+/-)-SCH-23390 (10 nM) produced significant inhibition of the relaxation, suggesting the involvement of dopamine D1 receptors. 4. Dopamine also produced concentration-dependent relaxation following U46619 precontraction (pIC50 = 5.4 +/- 0.1) which was significantly inhibited by haloperidol and (+)-SCH-23390. Pretreatment with 10 microM phenoxybenzamine for 60 min produced a significant inhibition of the dopamine and NA relaxation curves and application of the operational model of agonism yielded estimates of the affinity (pKA = 5.3 +/- 0.2 and 4.4 +/- 0.2) and efficacy (log gamma = 0.06 +/- 0.11 and 0.01 +/- 0.10) for dopamine and NA, respectively, at D1 receptors. 5. HV723 (0.1 and 1 microM), a ligand that yielded a Schild plot slope parameter of unity as an antagonist of NA in the contractile assay, produced concentration-dependent inhibition of the NA-mediated relaxation (pA2 approximately 8). 6. The results of this study indicate that NA can activate D1 receptors mediating relaxation in the rat SMA at concentrations which were encountered in our previous receptor classification experiments using competitive alpha 1-adrenoceptor antagonists.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Differential effects of tert-butyl-benzohydroquinone, a putative SR Ca2+ pump inhibitor, on isometric relaxation during the staircase in the rabbit and rat ventricle.

1. The effects of 2,5 di-(tert-butyl)-1,4-benzohydroquinone (TBQ), a putative inhibitor of the sarcoplasmic reticulum Ca2+ pump, on mechanical relaxation and contraction-relaxation coupling have been studied at different frequencies (0.5-3 Hz) in isometrically contracting isolated right ventricular preparations of rabbit and rat at 37 degrees C. Two types of mechanical responses have been studied: the twitch tension and the force transient (rewarming spike, RSp) following a rapid cooling contracture (RCC, an index of sarcoplasmic reticulum Ca2+ content) on return to 37 degrees C. 2. The coupling between contraction and relaxation was assessed by two methods: (a) by evaluation of the variation of the slope relating the maximal rate of tension fall to twitch peak tension; (b) by modelling the twitch according to the following equation: TwT (t) = C x (t/A)B x exp(1-(t/AB) where TwT(t) is the time course of isometric tension, t is time, C and A are an inotropic and a chronotropic index respectively and B, a contraction-relaxation coupling index (Nwasokwa, 1993). 3. In the rabbit ventricle, 30 microM TBQ did not prevent the frequency-induced shortening of the twitch time to half-relaxation (t1/2) and of the time constant (tau) describing the final part of the RSp relaxation (tau decreased from 140 ms (0.5 Hz) to 133 ms (3 Hz) in control and from 253 ms (0.5 Hz) to 197 ms (3 Hz) after exposure to TBQ). By contrast, at a given frequency, the prolongation of relaxation induced by TBQ was proportional to its inotropic effect (unchanged slopes and B values) but TBQ did not prevent the acceleration of relaxation observed at high frequencies: B increased from 2.02 (0.5 Hz) to a peak value of 2.18 (1 Hz) in control and from 1.88 (0.5 Hz) to a maximum of 2.48 (2 Hz) after TBQ exposure. TBQ significantly attenuated the decay of RCCs elicited after increasingly longer periods of muscle quiescence as normally observed in control conditions. 4. In the rat ventricle, TBQ depressed relaxation more than expected on the basis of its negative inotropic effects (B decreased from 2.16 to 1.84 at 0.5 Hz and from 2.15 to 1.66 at 3 Hz). TBQ also slowed the rate of RSp relaxation (tau increased from 95 ms to 168 ms at 0.5 Hz, and from 109 ms to 149 ms at 3 Hz) and increased twitch t1/2. By contrast with the results obtained in the rabbit ventricle, B, tau and t1/2 were frequency-insensitive whether or not TBQ was present. 5. TBQ exerts negative inotropic effects consistent with inhibition of the SR Ca2+ pump. In the rabbit ventricle, the TBQ-induced potentiation of relaxation acceleration at high pacing frequencies suggests the involvement of counteracting Ca(2+)-mediated mechanisms probably via Ca(2+)-calmodulin-activated kinases. In the rat ventricle, TBQ did not have any differential effect on relaxation depending on the frequency, probably because the extent of the negative staircase was small in the present experimental conditions.

Action Potentials↗
PubMed1992

Electrical field stimulation causes endothelium-dependent and nitric oxide-mediated relaxation of pulmonary artery.

The objective of this study was to ascertain the mechanism by which electrical field stimulation (EFS) of bovine pulmonary arterial rings causes endothelium-dependent smooth muscle relaxation. Like acetylcholine-elicited relaxation, EFS-elicited relaxation was endothelium-dependent and accompanied by accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) in the vascular smooth muscle. Relaxation in response to EFS was unaltered by tetrodotoxin, guanethidine, atropine, propranolol, chlorpheniramine, cimetidine, indomethacin, aminophylline, alpha, beta-methylene ATP, nifedipine, capsaicin, and certain antioxidants and free radical scavengers. Thus the relaxation was not neurogenically mediated and was not attributed to free radical formation during EFS. Like nitric oxide-elicited relaxation, EFS-elicited relaxation was antagonized by oxyhemoglobin and methylene blue. Relaxation was also antagonized by the three NG-substituted L-arginine analogues: NG-methyl-L-arginine, NG-nitro-L-arginine, and NG-amino-L-arginine. NG-amino-L-arginine also inhibited the tissue cGMP accumulation in response to EFS. The inhibitory effect of the NG-substituted L-arginine analogues was reversed by addition of excess L-arginine but not D-arginine. Relaxation in response to EFS was dependent on the presence of extracellular calcium and intracellular calmodulin, as removal of extracellular calcium or addition of trifluoperazine nearly abolished relaxation. EFS-elicited relaxation was inhibited also by tetraethylammonium chloride and elevated extracellular potassium concentration. These observations indicate that EFS-elicited relaxation of bovine pulmonary artery is mediated by neuronally independent, but endothelium- and calcium-dependent, stimulation of nitric oxide and cGMP formation.

Animals↗