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PubMed2000

Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery.

1. Mechanisms of protease-activated receptor-1 (PAR1)- and PAR2-induced relaxation were investigated in pre-contracted porcine coronary artery ring preparations. 2. Thrombin (0.01 - 0.3 u ml(-1)) and the PAR1-activating peptide SFLLRN (0.1 - 10 microM) caused concentration- and endothelium-dependent relaxation. pEC(50)s (-log u ml(-1) for enzymes, -log M for peptides) and maximum relaxations (R(max), %) for thrombin were 1.8+/-0.1 and 93.5+/-2.8% respectively, and for SFLLRN 6.8+/-0.1 and 90.8+/-1.3%. Similar concentration- and endothelium-dependent relaxations occurred with trypsin (pEC(50) 2.3+/-0.2; R(max) 94.1+/-1.9%) and the PAR2-activating peptide SLIGRL (pEC(50) 6.5+/-0.2; R(max) 92.4+/-1.6%). 3. Relaxations to thrombin, SFLLRN, trypsin and SLIGRL were significantly inhibited (P<0.05) to similar extents by the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 100 microM) and the NO scavenger oxyhaemoglobin (20 microM), both separately and in combination. 4. In the presence of the L-type voltage-operated calcium channel (L-VOCC) inhibitor nifedipine (0.3 microM), K(+) (67 mM) abolished the L-NOARG-resistant relaxations to thrombin, SFLLRN, trypsin and SLIGRL. However, nifedipine alone significantly (P<0.05) reduced the pEC(50) (1.5+/-0.1) and R(max) (77.5+/-7.0%) for thrombin but had no effect on relaxations to SFLLRN, trypsin or SLIGRL. Furthermore, L-NOARG-resistant relaxations to thrombin were abolished by nifedipine, whereas relaxations to SFLLRN, trypsin or SLIGRL were not further inhibited by combined treatment with nifedipine and L-NOARG, than they were with L-NOARG treatment alone. 5. Similar selective inhibition of the L-NOARG-resistant relaxation to thrombin, but not SFLLRN, occurred with verapamil (1 microM) and diltiazem (3 microM). 6. Our results suggest heterogeneous mechanisms in the NO-independent relaxation to thrombin and peptide activators of PAR1 in the porcine coronary artery.

Animals↗
PubMed2003

Contribution of Na+ -Ca2+ exchanger to pinacidil-induced relaxation in the rat mesenteric artery.

1 Pinacidil relaxes blood vessels through opening the K(ATP) channels with a resultant membrane hyperpolarization and inhibition of Ca(2+) influx. The aim of this study was to examine the mechanisms thereby pinacidil induces K(+) channel-independent relaxation in isolated endothelium-denuded rat mesenteric artery. 2 Pinacidil-induced relaxation was inhibited by glibenclamide (1-10 micro M) in phenylephrine-preconstricted rings, but was unaffected by glibenclamide after inhibition of K(+) channels and VGCCs. Pinacidil-induced K(+) channel-independent relaxation remained unchanged after treatment with cyclopiazonic acid (10 micro M), thapsigargin (1 micro M), ouabain (100 micro M), propranolol (10 micro M), Rp-cAMPS triethylamine (30 micro M), L-NNA (100 micro M), or ODQ (10 micro M). 3 Pinacidil induced more relaxant effect in the presence of nifedipine than in the presence of 60 mM K(+) plus nifedipine. Pretreatment with Na(+)-Ca(2+) exchanger inhibitors, nickel (30-300 micro M) or benzamil (20 micro M) attenuated pinacidil-induced relaxation in normal or in nifedipine-containing solution. Pinacidil (1 micro M) produced less relaxant effect with decreasing extracellular Na(+) concentration. Na(+)-free condition abolished the inhibitory effect of benzamil. Both nickel and benzamil inhibited pinacidil-induced relaxation in the presence of glibenclamide (10 micro M). Nickel (300 micro M) did not affect the relaxant response to sodium nitroprusside. 4 Pinacidil relaxed the rings preconstricted by active phorbol and U46619 with similar potency. 5 The present results indicate that stimulation of the forward mode Na(+)-Ca(2+) exchange pathway is in part responsible for pinacidil-induced K(+) channel-independent vasorelaxation. Pinacidil also induces K(+) channel-dependent but VGCCs-independent relaxation. The PKC-mediated cellular pathway may be a target site for pinacidil only in higher concentrations.

Animals↗
PubMed2003

Chronic treatment of male rats with daidzein and 17 beta-oestradiol induces the contribution of EDHF to endothelium-dependent relaxation.

1. We investigated the effect of chronic (7 days) treatment of male rats with the isoflavone daidzein (0.2 mg kg(-1) sc per day) or 17beta-oestradiol (0.1 mg kg(-1) sc per day) on the contribution of nitric oxide (NO), prostaglandins and endothelium-derived hyperpolarising factor (EDHF) to endothelium-dependent relaxation of isolated aortic rings. 2. The sensitivity and maximum relaxation to acetylcholine (ACh) were significantly greater in aortic rings from rats treated with daidzein or 17beta-oestradiol, in comparison to vehicle-treated rats. Inhibition of nitric oxide synthase with N-nitro-l-arginine (l-NOARG) abolished ACh-induced relaxation in the aortae from vehicle-treated rats, but only attenuated relaxation in aortae from daidzein or 17beta-oestradiol-treated rats. The presence of haemoglobin in addition to l-NOARG did not cause any further inhibition of relaxation. 3. The cyclooxygenase inhibitor indomethacin had no effect on endothelium-dependent relaxation in aortae from any treatment group. Charybdotoxin (ChTX), which blocks large-conductance calcium-activated potassium channels (BK(Ca)) and intermediate-conductance calcium-activated potassium channels (IK(Ca)), plus apamin, which blocks small-conductance calcium-activated potassium channels (SK(Ca)), but not iberiotoxin, which only blocks BK(Ca), attenuated endothelium-dependent relaxation of aortae from daidzein or 17beta-oestradiol-treated rats. Blockade of K(Ca) channels had no effect on the responses to ACh in aortae from vehicle-treated rats. In aortae from daidzein- or 17beta-oestradiol-treated rats, endothelium-dependent relaxation was also attenuated by inhibition of cytochrome P450 (CYP450) epoxygenase with 6-(2-propargylloxyphenyl)hexanoic acid (PPOH) or inhibition of K(IR) channels and Na(+)/K(+)-ATPase with barium and oubain, respectively. 4. This study demonstrates that endothelium-dependent relaxation of male rat aorta is normally entirely mediated by NO, whereas treatment with daidzein or 17beta-oestradiol stimulates a contribution from a non-NO, nonprostaglandin factor acting through the opening of SK(Ca) and IK(Ca) channels, and involving activation of Na/K-ATPase, K(IR) and CYP450 epoxygenase. This pattern of sensitivity to the tested inhibitors is consistent with the contribution of EDHF to relaxation. Thus, EDHF contributes to the enhanced endothelium-dependent relaxation that is observed after chronic treatment with the phytoestrogen daidzein or with 17beta-oestradiol.

Animals↗
PubMed1995

Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats.

1. Impaired endothelium-dependent relaxation has been previously demonstrated in blood vessels of hypertensive rats and in humans with essential hypertension. Arteries from spontaneously hypertensive rats have been shown to produce, in response to high concentrations of acetylcholine, a vasoconstrictor substance called endothelium-derived contracting factor, the production of which can be inhibited by indomethacin or other cyclo-oxygenase inhibitors, suggesting that it is a prostanoid. The mechanisms involved in endothelium-dependent relaxation of human arteries are unclear, and the potential generation of endothelium-derived contracting factor by endothelium in human hypertension has not been established. 2. We investigated the effects of acetylcholine on precontracted small arteries dissected from gluteal subcutaneous fat biopsies from normotensive subjects and subjects with borderline and mild essential hypertension. Vessels from normotensive subjects and those from borderline hypertensive patients, precontracted by noradrenaline, were relaxed completely by acetylcholine, whereas those from patients with mild essential hypertension relaxed slightly but significantly less, indicating that generation of endothelium-derived relaxing factor (endothelium-derived nitric oxide) was only minimally reduced or that production of minor amounts of endothelium-derived contracting factor occurred in small arteries from these hypertensive subjects. This impairment of endothelium-dependent relaxation was not corrected by indomethacin, which indicated that the contribution of endothelium-derived contracting factor, if any, was minimal in this subset of essential hypertensive patients. In contrast, mesenteric small arteries of adult spontaneously hypertensive rats presented strong contractions in response to the higher concentrations of acetylcholine, which were abolished by exposure to indomethacin. 3. The relaxation induced by acetylcholine in arteries from both hypertensive and normotensive humans was partially blunted (by 30%) by pretreatment with 0.1 mmol/l NG-nitro-L-arginine methyl ester or NG-nitro-monomethyl-L-arginine (inhibitors of nitric oxide synthase) and by 10 mumol/l Methylene Blue (a blocker of soluble guanylate cyclase), indicating the role of endothelium-derived nitric oxide and the generation of its intracellular second messenger cyclic guanosine monophosphate in acetylcholine-induced relaxation. The remaining relaxation elicited by acetylcholine could be blocked with 30 mmol/l KCl or with 10 mumol/l ouabain (inhibitor of Na+, K(+)-ATPase), and, when combined with NG-nitro-L-arginine methyl ester, these interventions abolished acetylcholine-induced relaxation. Tolbutamide at 2 mmol/l or 10 mumol/l glyburide (blockers of ATP-sensitive potassium channels) partially inhibited NG-nitro-L-arginine methyl ester-resistant endothelium-dependent relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1991

Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease.

BACKGROUND: Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS: We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS: Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g, P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference, increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation, 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3 +/- 2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P less than 0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant). CONCLUSIONS: Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.

Acetylcholine↗
PubMed2005

Intraband relaxation in CdSe nanocrystals and the strong influence of the surface ligands.

The intraband relaxation between the 1Pe and 1Se state of CdSe colloidal quantum dots is studied by pump-probe time-resolved spectroscopy. Infrared pump-probe measurements with approximately 6-ps pulses show identical relaxation whether the electron has been placed in the 1Se state by above band-gap photoexcitation or by electrochemical charging. This indicates that the intraband relaxation of the electrons is not affected by the photogenerated holes which have been trapped. However, the surface ligands are found to strongly affect the rate of relaxation in colloid solutions. Faster relaxation (<8 ps) is obtained with phosphonic acid and oleic acid ligands. Alkylamines lead to longer relaxation times of approximately 10 ps and the slowest relaxation is observed for dodecanethiol ligands with relaxation times approximately 30 ps. It is concluded that, in the absence of holes or when the holes are trapped, the intraband relaxation is dominated by the surface and faster relaxation correlates with larger interfacial polarity. Energy transfer to the ligand vibrations may be sufficiently effective to account for the intraband relaxation rate.

Journal Article↗
PubMed1975

Protein-water interaction studied by solvent 1H, 2H, and 17O magnetic relaxation.

Previous studies of the magnetic field dependence of the magnetic relaxation rate of solvent protons in protein solutions have indicated that this dependence (called relaxation dispersion) is related to the rotational Brownian motion of the solute proteins. In particular, the dispersion of the longitudinal (spin-lattice) relaxation rate 1/T1 shows a monotonic decrease with increasing field, with an inflection point corresponding to a proton Larmor frequency which is inversely proportional to the orientational relaxation time of the protein. We have now compared the relaxation dispersion of solvent 1H, 2H, and 17O In aqueous solutions of lysozyme (molecular weight 14,700) and 1H and 2H in solutions of hemocyanin (molecular weight 14,7 00) and 1H and 2H in solutions of hemocyanin (molecular weight 9 x 10(6)). The main experimental observation is that the dispersion of the relaxation rates of the three solvent nuclei in lysozyme solutions, normalized to their respective rates in pure water, is essentially the same. This is also true for 1H and 2H relaxation in hemocyanin solutions. These results confirm that entire solvent water molecules, rather than exchanging protons, are involved in the interaction. We have been unable to deduce the correct mechanism to explain the data, but we can eliminate several interaction mechanisms from consideration. For example, all observations combined cannot be explained by a simple two-site model of exchange, in which water molecules are either in sites on the protein with a relaxation rate characteristic of these sites, or else in the bulk solvent (the observed relaxation rate being the weighted average of the two). Also eliminated is the class of models in which the protein molecules induce a preferential partial alignment of neighboring solvent molecules, for example by electrostatic interaction of the electric dipole moments of the water with the electric fields produced by surface charges of the protein molecules. In addition, the idea that relaxation of solvent nuclei is due, in the main, to interactions with protein protons is precluded. Rather, it appears that the protein molecules influence the dynamics of the motion of solvent water molecules in their neighborhood in a manner that imposes on all the solvent molecules a correlation time for their orientational relaxation which equals that of the solute proteins.

Animals↗
PubMed1982

Role of endothelial cells in relaxation of isolated arteries by bradykinin.

Bradykinin elicits relaxation of isolated transverse rings of canine coronary, celiac, superior mesenteric, renal, splenic, pulmonary, gastric, and femoral arteries. After endothelial cells of the vessel wall are removed by rubbing of the intimal surface, canine arteries fail to relax upon addition of bradykinin. The endothelium-dependent relaxation of canine arteries remains intact after treatment with cyclooxygenase inhibitors (indomethacin and flurbiprofen), and this argues against mediation by prostaglandins. When they are stimulated with bradykinin, endothelial cells of canine arteries appear to release a substance mediating vascular smooth muscle relaxation. In contrast, preparations of arteries of cats (superior mesenteric) and rabbits (superior mesenteric and celiac) may be rubbed on the intimal surface without a consistent loss of sensitivity to the relaxing effects of bradykinin. In addition, relaxation of the cat and rabbit arteries is completely blocked by cyclooxygenase inhibitors. Preliminary studies indicate that bradykinin relaxes human arteries in an endothelium-dependent manner and that this effect is not mediated by prostaglandins. We have previously reported that arteries of all species tested require the presence of endothelial cells for relaxation in response to acetylcholine and we have also demonstrated, using the rabbit aorta, that this effect is mediated by the release of an uncharacterized substance from these cells that relaxes vascular smooth muscle. We conclude that bradykinin relaxes canine and human arteries via a similar mechanism but that it relaxes cat and rabbit arteries by stimulating release of prostaglandins from as yet undefined cell types.

Animals↗
PubMed1954

Relaxation in extracted muscle fibers.

1. Ethylenediamine tetraacetic acid (EDTA) in low concentrations imitates all the known effects of the relaxation factor ("Marsh factor"). In extracted muscle fibers which have contracted in a solution containing adenosinetriphosphate (ATP), the addition of EBTA causes relaxation, the subsequent addition of CaCl(2), contraction. 2. In fibers which have been briefly immersed in 5 MM EDTA, ATP causes rapid relaxation if Mg is also present. These fibers have essentially the same properties as briefly extracted fibers. Brief immersion into a solution containing CaCl(2) restores at once the original condition. It is concluded that EDTA produces its action by firmly combining with bound Ca, thereby inactivating it. 3. In relaxed muscle fibers not only Ca, but also lowering the concentration of Mg below a critical level, causes contraction. In such fibers Mg in the lowest effective concentrations increases contraction, but the effect reverses above a certain concentration. 4. At 0 degrees Mg in the presence of ATP has a relaxing effect without the relaxation factor. 5. The results indicate that Mg has two distinct effects in the presence of ATP. It causes contraction at low concentrations, but above a critical concentration its relaxing action prevails. The last of these effects is blocked by bound Ca. If the latter is inactivated by EDTA, Mg in sufficiently high concentrations causes relaxation. The action of the relaxation factor can similarly be explained by assuming that it acts as a complexing agent which inactivates bound Ca. 6. Previous evidence that the relaxed state depends on the formation of an enzymatically inactive ATP-protein complex was confirmed. It was found that PP in low concentrations strongly increases the relaxing effect of ATP in briefly extracted fibers.

Adenosine Triphosphate↗
PubMed2001

Angiotensin converting enzyme protects acetylcholine-induced relaxation from its attenuation by formyl-methionyl-leucyl-phenylalanine in rat aorta.

OBJECTIVE: A chemotactic tripeptide formyl-methionyl-leucyl-phenylalanine (fMLP) attenuated acetylcholine (ACh)-induced relaxation. Because angiotensin converting enzyme (ACE), which inactivates fMLP, is rich in vascular endothelial cells, we examined whether endothelial cell ACE inhibits the attenuating effect of fMLP on ACh-induced relaxation. DESIGN AND METHODS: ACh-induced relaxation was evaluated in aortic rings from 9-week-old Sprague-Dawley rats. We examined the effects of ACE, the ACE inhibitor captopril and/or fMLP on ACh-induced relaxation in aortas from rats with or without dexamethasone treatment, which enhances ACE activity. RESULTS: Pre-treatment with ACE did not alter ACh-induced relaxation in control aortas but abolished the inhibitory effect of fMLP on ACh-induced relaxation [maximal relaxation (Emax): 95.4 +/- 1.2 versus 75.5 +/- 1.9%, P < 0.05]. Conversely, captopril enhanced the attenuation of ACh-induced relaxation by fMLP (Emax: 62.5 +/- 3.3 versus 74.0 +/- 2.2%, P < 0.05), although captopril did not affect ACh-induced relaxation in control aortas. In addition, fMLP did not attenuate ACh-induced relaxation in aortas from dexamethasone-treated rats (Emax: 89.7 +/- 3.7 versus 85.2 +/- 3.8%, NS), which enhanced ACE activity of aortas (3.37 +/- 0.25 versus 2.70 +/- 0.20 IU/mg protein, P < 0.05). CONCLUSION: Endothelial-cell ACE attenuates the effect of fMLP on ACh-induced relaxation, possibly by its cleavage.

Acetylcholine↗
PubMed1987

Effects of nonsteroidal phospholipase inhibitors and glucocorticoids on endothelium-dependent relaxations of rabbit aorta induced by different agents.

The present study investigates the effect of described nonsteroidal phospholipase inhibitors [mepacrine, papaverine, trifluoperazine (TFP), p-bromophenacyl bromide (pBPB), compound CB 874] and of glucocorticoids on endothelium-dependent and -independent relaxations of rabbit aorta. Endothelium-dependent relaxations were elicited by acetylcholine, Ca2+ ionophore A23187, melittin, and thimerosal. These four agents also stimulated vascular prostacyclin formation. Prostacyclin does not relax rabbit aorta; it was measured as an indicator of phospholipid hydrolysis. All putative nonsteroidal phospholipase inhibitors blocked acetylcholine-induced relaxations. Since papaverine did not inhibit prostacyclin production, it cannot be considered a phospholipase inhibitor in this tissue. Relaxations in response to A23187 were blocked only by pBPB and CB 874, which can interact with phospholipases directly. Melittin-induced relaxations were suppressed by mepacrine, TFP, pBPB, and CB 874. Relaxations elicited by thimerosal were not affected by mepacrine, but were abolished by the other three inhibitors. All inhibitors were ineffective against endothelium-independent relaxations induced by glyceryl trinitrate. Effective blockade of endothelial relaxations correlated with inhibition of prostacyclin formation. In the presence of glucocorticoids, no inhibition of endothelium-mediated relaxations and no inhibition of prostacyclin formation occurred, indicating unimpaired phospholipase activity. These findings suggest that cleavage of phospholipids may be important in the triggering of the production of endothelium-derived relaxing factor.

Acetophenones↗
PubMed1996

Impaired endothelium-dependent relaxation in rabbit pulmonary artery after subarachnoid hemorrhage.

We investigated the changes in endothelial function of pulmonary as well as basilar artery after experimental subarachnoid hemorrhage (SAH) induced by cisternal blood injection in rabbits. The animals were killed on day 2 and day 7, and the mechanical responses were determined on transverse strips of the main pulmonary artery and rings harvested from the basilar artery. To examine the role of the vagal nerve, we cut the left vagal nerve immediately before injecting cisternal blood. Relaxation response of pulmonary and basilar arteries to acetylcholine (ACh) and A23187 were abolished after endothelial removal and reality inhibited by either NG-nitro-L-arginine (NOARG) or methylene blue (MB). Indomethacin failed to modify these relaxation responses. Relaxation response of the main pulmonary artery strips to ACh was significantly (p < 0.05 and p < 0.01) attenuated on day 2 in 6 of 12 rabbits. In the remaining 6 rabbits, relaxation was not affected. No change in relaxation responses to A23187 and sodium nitroprusside (SNP) was observed in any of the 12 cases. In the vagotomized rabbits no decreased response to ACh was observed. On day 7, relaxation response to ACh returned to normal. ACh also produced decreased relaxation in basilar artery rings on day 2 with no change in A23187- and SNP-induced relaxation. Contractile responses of pulmonary and basilar arteries to norepinephrine (NE), endothelin-1 (ET-1), 5-hydroxytryptamine (5-HT), and U46619 were not affected after SAH. These results suggest that less functional muscarinic receptors that produce/release less endothelium-derived relaxation factor [EDRF/nitric oxide (NO)] are involved in causing the reduced relaxation of pulmonary and basilar arteries after SAH and the vagal nerve may play a role in regulating the receptor-mediated, endothelium-dependent relaxation in the main pulmonary artery after experimental SAH.

Acetylcholine↗
PubMed2006

Stress relaxation at the bone-pedicle screw interface in human bone.

STUDY DESIGN: A biomechanical study using human lumbar vertebra. OBJECTIVES: To assess the effects of stress relaxation on the pullout behavior of the pedicle screw in human bone. SUMMARY OF BACKGROUND DATA: The standard pullout test is widely used to assess screw-holding power; however, the effects of incremental deformation on the pullout behavior of pedicle screws are not known in human bone. A recent study in bovine bone suggests that stress relaxation during incremental pullout significantly reduces failure loads seen in pullout testing. METHODS: Fourteen human lumbar vertebrae were instrumented with pedicle screws and tested with one of two pullout protocols: standard pullout model, a continuous withdrawal, and stress relaxation pullout model, an incremental withdrawal allowing stress relaxation. Peak loads and stiffness were calculated and relaxation data were assessed using the stretched exponential function. RESULTS: Pullout strength and stiffness were significantly lower in the stress relaxation model group (P < 0.05). The characteristic relaxation time decreased and relaxation ratio increased with the increasing deformation level. The pullout and stress relaxation parameters were found to correlate with the bone quality. CONCLUSIONS: The stress relaxation process significantly affects the mechanical and viscoelastic properties of the bone-screw interface in human cadaveric bone. Stress relaxation pullout model might be a better representative of in vivo conditions by introducing the time and incremental deformation into the in vitro biomechanical testing.

Biomechanical Phenomena↗
PubMed1989

Effects of antihypertensive agents on endothelium-dependent and endothelium-independent relaxations.

1. Antihypertensive agents normalize blood pressure and restore depressed endothelium-dependent relaxations in experimental models of hypertension, but little is known regarding whether antihypertensive agents themselves can directly modulate responses to agonists of endothelium-dependent or independent relaxations, or contractions. 2. Normal rats were treated with either tap water, captopril, hydralazine or enalapril in their drinking water for 2 weeks, following which endothelium-dependent and endothelium-independent relaxations were tested with acetylcholine and sodium nitroprusside, respectively, in aortic rings suspended in organ chambers. 3. All antihypertensive agents caused slight but similar potentiation of sodium nitroprusside-induced relaxations. However, their effects on acetylcholine-induced relaxations were quite different: captopril had a marked potentiating effect, hydrazaline a slight potentiating effect, and enalapril had no significant effect on these relaxations. 4. The relaxations induced by acetylcholine and potentiated by captopril were not altered when indomethacin was included in the tissue bath. However, pyrogallol, an inhibitor of endothelium-derived relaxing factor (EDRF), markedly inhibited these relaxations suggesting that captopril's effect may involve EDRF. 5. SQ 14,534, a stereoisomer of captopril which is 100 fold less potent in inhibiting angiotensin converting enzyme, also significantly enhanced acetylcholine induced relaxations. Thus the effects of both captopril and SQ 14,534 upon EDRF appear independent of the effects of these compounds on the angiotensin converting enzyme. 6. We conclude that certain antihypertensive agents may modulate endothelium-dependent relaxations in response to agonists, and that these properties may be of therapeutic importance in cardiovascular diseases.

Acetylcholine↗
PubMed1991

Endothelium-dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors.

1. The effects of selective inhibitors of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) phosphodiesterases (PDEs) were investigated on PDEs isolated from the rat aorta and on relaxation of noradrenaline (1 microM) precontracted rat aortic rings, with and without functional endothelium. 2. Four PDE forms were isolated by DEAE-sephacel chromatography from endothelium-denuded rat aorta: a calmodulin-activated PDE (PDE I) which hydrolyzed preferentially cyclic GMP, two cyclic AMP PDEs (PDE III and PDE IV) and one cyclic GMP-specific PDE (PDE V). The latter was selectively and potently inhibited by zaprinast. The two cyclic AMP PDEs were discriminated by specific inhibitors: one was inhibited by cyclic GMP (PDE III) and by new cardiotonic agents (milrinone, CI 930, LY 195115 and SK&F 94120); the other was inhibited by denbufylline and rolipram (PDE IV). None of these drugs significantly inhibited PDE I. 3. The PDE III inhibitors caused endothelium-independent relaxations of rat aortic rings with the following EC50 values (microM concentration producing 50% relaxation): LY 195115: 3.4, milrinone: 5.7, CI 930; 7.8, SK&F 94120: 14.7. Neither NG-monomethyl-L-arginine (L-NMMA, 300 microM), an inhibitor of the L-arginine-NO pathway, nor L-arginine (1 mM) modified the effect of PDE III inhibitors. However, methylene blue (10 microM) an inhibitor of soluble guanylate cyclase abolished relaxation induced by PDE III inhibitors except in the case of compound CI 930. 4. The specific PDE IV and PDE V inhibitors both produced endothelium-dependent relaxations which were inhibited by L-NMMA and by methylene blue (10 microM). In the presence of L-NMMA, relaxation was restored by subsequent addition of L-arginine. 5. The relaxant effects of denbufylline and rolipram were studied in the presence of drugs stimulating either adenylate cyclase (forskolin and isoprenaline) or soluble guanylate cyclase (sodium nitroprusside, SNP), or inhibiting PDE III (milrinone). In endothelium-denuded rings, a relaxing effect of both denbufylline and rolipram was found in the presence of milrinone (EC5o values 1.7 and 12 microM, respectively) or SNP (EC50 values 12.3 and 124 microM, respectively), but not in the presence of forskolin or isoprenaline. However in the presence of functional endothelium, relaxations produced by PDE IV inhibitors were significantly potentiated by forskolin, isoprenaline, milrinone and SNP (respective EC50 values for denbufylline: 2, 2, 0.4 and 0.7 microM and for rolipram: 7, 13, 7 and 1.2 microM). 6. These results indicate that the relaxant effects of inhibitors of the cyclic AMP-specific PDE IV are markedly enhanced by cyclic GMP elevating agents and by the PDE III inhibitor milrinone. They support the hypothesis that cyclic GMP enhances cyclic AMP-mediated relaxation, possibly through the inhibition of the cyclic GMP-inhibited PDE III.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMedDate not supplied

Endothelium-dependent and -independent coronary relaxation induced by urocortin.

Urocortin, a newly identified polypeptide, possesses cardiac effects. However, the underlying mechanism of its coronary action is still unclear. In the present study we investigated the possible role of endothelial nitric oxide and Ba2+-sensitive K+ channels in the endothelium-dependent relaxant response to urocortin in the isolated rat left anterior descending coronary arteries. Changes of vessel tone were measured in microvessel myographs. Urocortin produced both endothelium-dependent and -independent relaxation with IC50 of 2.52 nM and 16.5 nM, respectively. Denuation of endothelium decreased the relaxing potency of urocortin. In the endothelium-intact rings pretreated with 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME) or 10 microM 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ), the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. The relaxant response to urocortin was markedly reduced in endothelium-intact rings preconstricted by 35 mM K+. Pretreatment with 100 microM BaCl2 significantly reduced urocortin-induced relaxation without an effect on the maximum relaxation. Combined treatment with BaCl2 plus L-NAME did not produce additive inhibition. In contrast, BaCl2 did not alter urocortin-induced relaxation in the endothelium-denuded rings. In the endothelium-denuded rings, BaCl2 at 100 microM also inhibited nitric oxide donor-induced relaxation. In conclusion, our results suggest that urocortin-induced endothelium-dependent relaxation of rat coronary arteries is primarily mediated by endothelial nitric oxide and subsequent activation of Ba2+-sensitive K+ channels. The urocortin-induced endothelium-dependent relaxation appears to be cyclic GMP-dependent.

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

The possible role of nitric oxide in relaxations and excitatory neuroeffector transmission in the cat airway.

1. To study the possible role of nitric oxide (NO free radical; NO) or NO-containing compounds in the non-adrenergic, non-cholinergic (NANC) relaxations, we observed the effects of carboxy-2-phenyl-4, 4, 5, 5-tetramethyl-imidazoline-1-oxyl-3-oxide (C-PTIO; a newly synthesized NO scavenger) on NANC relaxations in the cat airway. In addition, we also observed the effects of C-PTIO on excitatory junction potentials (EJPs), since NO has a prejunctional action on transmitter release. 2. Nitrosocystine (Cys-NO) (10(-7)-10(-3) M) dose-dependently relaxed the bronchial tissue in the presence of 5-HT, atropine and guanethidine and C-PTIO (10(-4) M) shifted the concentration-response curve of the Cys-NO to the right. 3. Electrical field stimulation (EFS) evoked biphasic NANC relaxations in the small bronchi of the cat. In general, C-PTIO suppressed non-selectively both the first and second components of the NANC relaxations to a similar extent. However, in some bronchial preparations C-PTIO (10(-4) M) selectively suppressed the first component of the NANC relaxation to approximately 50% of the initial value, enhancing the amplitude of the second component of the NANC relaxations. 4. After pretreatment of the bronchial tissues with alpha-chymotrypsin (1 unit ml-1) for 30 min in order to inhibit any response to peptides, EFS evoked monophasic NANC relaxation. C-PTIO (10(-5) - 10(-4) M) dose-dependently suppressed, and at a concentration of 10(-4) M almost halved, the amplitude of NANC relaxation. Additional application of L-NAME further reduced the C-PTIO-resistant NANC relaxation to 20-30% of the initial value. 5. C-PTIO (10(-4) M) enhanced the EJP amplitude evoked by single EFS in the trachea but not in the bronchi. However, C-PTIO enhanced the summation of the EJPs to repeated stimulation to a similar extent in the tracheal and bronchial tissues. Simultaneous application of C-PTIO and L-NAME did not further enhance the summation. 6. These results indicate that NO. and NO-containing compounds are involved in the L-NAME-sensitive NANC relaxation in the cat airway, and that only NO. has a prejunctional action which inhibits excitatory neuroeffector transmission.

Animals↗
PubMed2004

MR imaging relaxation times of abdominal and pelvic tissues measured in vivo at 3.0 T: preliminary results.

PURPOSE: To measure T1 and T2 relaxation times of normal human abdominal and pelvic tissues and lumbar vertebral bone marrow at 3.0 T. MATERIALS AND METHODS: Relaxation time was measured in six healthy volunteers with an inversion-recovery method and different inversion times and a multiple spin-echo (SE) technique with different echo times to measure T1 and T2, respectively. Six images were acquired during one breath hold with a half-Fourier acquisition single-shot fast SE sequence. Signal intensities in regions of interest were fit to theoretical curves. Measurements were performed at 1.5 and 3.0 T. Relaxation times at 1.5 T were compared with those reported in the literature by using a one-sample t test. Differences in mean relaxation time between 1.5 and 3.0 T were analyzed with a two-sample paired t test. RESULTS: Relaxation times (mean +/- SD) at 3.0 T are reported for kidney cortex (T1, 1,142 msec +/- 154; T2, 76 msec +/- 7), kidney medulla (T1, 1,545 msec +/- 142; T2, 81 msec +/- 8), liver (T1, 809 msec +/- 71; T2, 34 msec +/- 4), spleen (T1, 1,328 msec +/- 31; T2, 61 msec +/- 9), pancreas (T1, 725 msec +/- 71; T2, 43 msec +/- 7), paravertebral muscle (T1, 898 msec +/- 33; T2, 29 msec +/- 4), bone marrow in L4 vertebra (T1, 586 msec +/- 73; T2, 49 msec +/- 4), subcutaneous fat (T1, 382 msec +/- 13; T2, 68 msec +/- 4), prostate (T1, 1,597 msec +/- 42; T2, 74 msec +/- 9), myometrium (T1, 1,514 msec +/- 156; T2, 79 msec +/- 10), endometrium (T1, 1,453 msec +/- 123; T2, 59 msec +/- 1), and cervix (T1, 1,616 msec +/- 61; T2, 83 msec +/- 7). On average, T1 relaxation times were 21% longer (P <.05) for kidney cortex, liver, and spleen and T2 relaxation times were 8% shorter (P <.05) for liver, spleen, and fat at 3.0 T; however, the fractional change in T1 and T2 relaxation times varied greatly with the organ. At 1.5 T, no significant differences (P >.05) in T1 relaxation time between the results of this study and the results of other studies for liver, kidney, spleen, and muscle tissue were found. CONCLUSION: T1 relaxation times are generally higher and T2 relaxation times are generally lower at 3.0 T than at 1.5 T, but the magnitude of change varies greatly in different tissues.

Abdomen↗