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PubMed1998

Femtomolar bradykinin-induced relaxation of isolated bovine coronary arteries, mediated by endothelium-derived nitric oxide.

We reported previously that bradykinin induces endothelium-dependent relaxation at nanomolar (nM) concentrations in isolated bovine coronary arteries with an intact endothelium. Recently we have found that in the presence of 10 microM indomethacin, femtomolar (fM) concentrations of bradykinin induce endothelium-dependent relaxation in some bovine coronary arteries (approximately 10% of the coronary arteries examined). The present study was designed to characterize the relaxation induced by fM bradykinin. Relaxation was completely abolished by repeated application of fM bradykinin, by 100 microM N(omega)-nitro-L-arginine methyl ester and by 10 microM methylene blue. Relaxation induced by nM bradykinin was partly affected by these treatments. Relaxation induced by both concentrations of bradykinin was inhibited by a B2-kinin receptor antagonist, [Thi5,8, D-Phe7]-bradykinin, in a concentration-dependent manner, but not by a B1-kinin receptor antagonist, des-Arg9, [Leu8]-bradykinin. In the presence of 10 microM captopril, an angiotensin-converting enzyme (ACE) inhibitor, all coronary arteries examined in this experiment showed endothelium-dependent relaxation to fM bradykinin. These results show that some bovine coronary arteries relax in response to fM bradykinin, and this response is mediated predominantly by the release of nitric oxide via stimulation of endothelial B2-kinin receptors. The relaxation may be dependent on ACE activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Garlic and its active metabolite allicin produce endothelium- and nitric oxide-dependent relaxation in rat pulmonary arteries.

1. The aims of the present study were to investigate the effects of fresh garlic and one of its active metabolites, allicin, on rat isolated pulmonary arteries (RPA). 2. In endothelium-intact and phenylephrine-precontracted RPA, the addition of a water or a 5% ethanol extract of fresh garlic (1-500 microg/mL) resulted in a dose-dependent relaxation reaching a maximum (mean +/- SEM) of -91 +/- 3 and -93 +/- 2%, respectively, with an ED(50) of 113 +/- 12 and 106 +/- 10 microg/mL, respectively. The vasorelaxation was readily reversible upon washing and no tachyphylaxis was noted. 3. An extract of the external garlic storage leaf produced a significantly greater relaxation than the inner stem. Microfiltration of extracts with a 10,000 molecular sieve did not attenuate relaxation. Inactivation of alliinase and allicin formation, with either boiling of the garlic clove for 30 min or 100% ethanol treatment, completely abolished relaxation. In contrast, similar treatment of crushed garlic with formed allicin retained the relaxation response. 4. Pure allicin produced a similar relaxation as garlic extract, with an EC(50) of approximately 0.8 microg/mL. Disruption of endothelium or N(G)-nitro-L-arginine methyl ester pretreatment attenuated the relaxation, whereas indomethacin had no effect. 5. Prior garlic (500 microg/mL) treatment enhanced acetylcholine relaxation by shifting the response curve to the left, but had no effect on nitric oxide (NO) donor-induced responses. 6. These results demonstrate that garlic and the active metabolite allicin are capable of eliciting a NO-dependent relaxation in RPA and that this response is likely to be mediated via garlic activation of NO formation rather than its stabilization.

Animals↗
PubMed2002

Effect of palmitoleic acid on bradykinin-induced endothelium-dependent relaxation in isolated pig ciliary artery.

BACKGROUND: Endothelial-dependent relaxation has been reported to be impaired in some normal tension glaucoma patients. The present study investigates whether the gap junction uncoupling agent palmitoleic acid (PA) affects bradykinin-induced endothelium-dependent relaxation in isolated pig ciliary artery. MATERIAL AND METHODS: In a myograph system (isometric force measurement), vessels precontracted with the thromboxane A2 agonist U 46619 ( approximately 0.1 micrometer) were relaxed by increasing concentrations (cumulative) of bradykinin (0.003 - 3 micrometer). Experiments were repeated in the presence of 100 micrometer L-NAME (inhibitor of nitric oxide formation) and/or 100 micrometer PA. Some experiments were conducted in vessels with a non-functional endothelium (intentionally and mechanically damaged). All experiments were conducted in the presence of 10 microM indomethacin (cyclooxygenase inhibitor). RESULTS: In a concentration-dependent manner, bradykinin evoked a relaxation (101 +/- 2 %) that was abolished in vessels with a non-functional endothelium (maximal relaxation: 7 +/- 1 %, p < 0.001). In the presence of L-NAME, relaxations induced by bradykinin were almost completely inhibited (maximal relaxation: 25 +/- 5 %, p < 0.001). Relaxations evoked by bradykinin were not significantly affected by PA (either in the presence or in the absence of L-NAME). CONCLUSIONS: The bradykinin-induced relaxation, known to be associated in porcine ciliary arteries with an electrical coupling between endothelial and smooth muscle cells, appears to be unaffected by the gap junction uncoupling agent palmitoleic acid. Further investigations are needed to understand the physiology of the endothelium-dependent ocular blood flow modulation that is considered to be dysregulated in some glaucoma patients.

Animals↗
PubMed1988

Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts.

Both the internal mammary artery and the saphenous vein are used to construct coronary-artery bypass grafts. We hypothesized that the release or production of endothelium-derived relaxing factor, which regulates blood flow and inhibits platelet function, may differ in venous and arterial grafts. We therefore studied endothelium-dependent relaxation in internal mammary arteries, internal mammary veins, and saphenous veins obtained from 58 patients undergoing coronary bypass surgery. Vascular rings with and without endothelium were suspended in organ chambers, and isometric tension was recorded. Acetylcholine (10(-8) to 10(-4) M), thrombin (1 U per milliliter), and adenosine diphosphate (10(-7) to 10(-4) M) evoked potent endothelium-dependent relaxation in the mammary artery but weak response in the saphenous vein (P less than 0.005; n = 6 to 27). In the mammary artery, relaxation was greatest in response to acetylcholine (86 +/- 4 percent reduction in norepinephrine-induced tension), followed by thrombin (44 +/- 7 percent) and adenosine diphosphate (39 +/- 8 percent). In the saphenous and mammary veins, relaxation was less than 25 percent. Relaxation was unaffected by indomethacin but was inhibited by methylene blue and hemoglobin (P less than 0.005 and 0.01, respectively), which suggests that endothelium-derived relaxing factor was the mediator. Endothelium-independent relaxation in response to sodium nitroprusside was similar in arteries and veins. We conclude that endothelium-dependent relaxation is greater in the mammary artery than in the saphenous vein. The possibility that this contributes to the higher patency rate among arterial grafts than among venous grafts will require further study.

Acetylcholine↗
PubMed2005

Primary and secondary relaxations in bis-5-hydroxypentylphthalate.

Broadband dielectric spectroscopy was used to study the relaxation dynamics in bis-5-hydroxypentylphthalate (BHPP) under both isobaric and isothermal conditions. The relaxation dynamics exhibit complex behavior, arising from hydrogen bonding in the BHPP. At ambient pressure above the glass transition temperature T(g), the dielectric spectrum shows a broad structural relaxation peak with a prominent excess wing toward higher frequencies. As temperature is decreased below T(g), the excess wing transforms into two distinct peaks, both having Arrhenius behavior with activation energies equal to 58.8 and 32.6 kJmol for slower (beta) and faster (gamma) processes, respectively. Furthermore, the relaxation times for the beta process increase with increasing pressure, whereas the faster gamma relaxation is practically insensitive to pressure changes. Analysis of the properties of these secondary relaxations suggests that the beta peak can be identified as an intermolecular Johari-Goldstein (JG) process. However, its separation in frequency from the alpha relaxation, and both its activation energy and activation volume, differ substantially from values calculated from the breadth of the structural relaxation peak. Thus, the dynamics of BHPP appear to be an exception to the usual correlation between the respective properties of the structural and the JG secondary relaxations.

Journal Article↗
PubMed2006

Pressure effects on the alpha and alpha' relaxations in polymethylphenylsiloxane.

In some polymers, in addition to the usual structural alpha relaxation, a slower alpha' relaxation is observed with a non-Arrhenius temperature dependence. In order to understand better the molecular origin of this alpha' relaxation in poly(methylphenylsiloxane) (PMPS) we have studied, for the first time, the pressure dependence of its relaxation time, together with the usual temperature dependence, by means of dynamic light scattering (DLS). For the same material the alpha relaxation was also studied by means of DLS and dielectric spectroscopy (DS) in broad temperature and pressure ranges. We find that the temperature dependence of both alpha and alpha' relaxation times, at all pressures studied, can be described by a double Vogel-Fulcher-Tammann (VFT) law. The pressure dependence of the characteristic temperatures Tg (glass transition temperature) and T0 (Vogel temperature) as well as the activation volumes for both alpha and alpha' processes are very similar, indicating, that both relaxation processes originate from similar local molecular dynamics. Additionally, for both alpha and alpha' relaxations the combined temperature and pressure dependences of the relaxation times can be described using a parameter Gamma=rhon/T with the same value of the exponent n.

Computer Simulation↗
PubMed1998

Relaxing effects of cyclic GMP and cyclic AMP-enhancing agents on the long-lasting contraction to endothelin-1 in the porcine coronary artery.

In the coronary circulation, endothelin-1 (ET-1) evokes spasms which are difficult to treat when the endothelial integrity is compromised. This study compares several classes of relaxing agents on already established contractions to ET-1 in an in vitro model using ring segments of the porcine left descending coronary artery (pLAD). All segments were precontracted with 10 nmol/L ET-1. The calcium channel blocker isradipine was 300 times more potent than verapamil, but was only a partial relaxant; the maximal relaxation obtained was 52 +/- 2% (n = 6). Atrial natriuretic peptide (ANP) was an equally potent relaxant of the ET-1 contraction; however, it too was an incomplete relaxant, maximal relaxation being < 60%. A 50% relaxation of the ET-1 contraction was obtained with 0.28 +/- 0.24 mumol/L ANP, n = 4 (IC50). Comparison of cyclic nucleotide analogues revealed a 30 times higher potency for 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP)(IC50 44 +/- 11 mumol/L, n = 6) than for 8-bromo-cyclic adenosine monophosphate (8-Bi-cAMP) (IC50 1600 mumol/L, n = 6). The cyclic nucleotide phosphodiesterase (PDE) inhibitor milrinone, a PDE 3-inhibitor with an IC50 2.4 +/- 1.8 mumol/L, (n = 6) was 10 times more potent than rolipram (PDE 4-inhibitor), zaprinast (PDE 5-inhibitor) and vinpocentine (PDE 1-inhibitor). Withdrawal of these analogues and inhibitors from segments continuously exposed to 10 nmol/l ET-1 revealed that vinpocentine and 8-Br-cGMP were irreversible relaxants, in contrast to milrinone and 8-Br-cAMP. In conclusion, this study has demonstrated that cGMP-enhancing agents, such as the naturally occurring ANP, the calcium channel blocker isradipine, and the synthetic inhibitor of PDE 3, were the most effective relaxants of ET-1 evoked contractions in pLAD in vitro.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1974

Differences in the charge distribution of glycerol-extracted muscle fibers in rigor, relaxation, and contraction.

Glycerol-extracted rabbit psoas muscle fibers were impaled with KCl-filled glass microelectrodes. For fibers at rest-length, the potentials were significantly more negative in solutions producing relaxation than in solutions producing either rigor or contraction; further the potentials in the latter two cases were not significantly different. For stretched fibers, with no overlap between thick and thin filaments, the potentials did not differ in the rigor, the relaxation, or the contraction solutions. The potentials measured from fibers in rigor did not vary significantly with the sarcomere length. For relaxed fibers, however, the potential magnitude decreased with increasing sarcomere length. The difference between the potentials measured for rigor and relaxed fibers exhibited a nonlinear relationship with sarcomere length. The potentials from calcium-insensitive fibers were less negative in both the rigor and the relaxation solutions than those from normal fibers. When calcium-insensitive fibers had been incubated in Hasselbach and Schneider's solution plus MgCl(2) or Guba-Straub's solution plus MgATP the potentials recorded upon impalement were similar in the rigor and the relaxation solution to those obtained from normal fibers in the relaxed state. It is concluded that the increase in the negative potential as the glycerinated fiber goes from rigor to relaxation may be due to an alteration in the conformation of the contractile proteins in the relaxed state.

Animals↗
PubMed1996

Triexponential decomposition of 1H spin-lattice relaxation decay curves of paramagnetically doped red cell suspensions at 7 T.

The spin-lattice relaxation behaviour of protons in paramagnetically doped red cell suspensions at two haematocrit levels has been studied using high-field (7 T) inversion recovery data. The resulting relaxation decay curves were found to be best characterized by triexponential functions. The two-site exchange model, generally applied to biexponential relaxation data in calculating red cell water exchange parameters, was applied to the two fastest-relaxing fractions of the triexponential fits. The intracellular to extracellular water exchange rates so obtained were in good agreement with literature values. Additional exchange parameters including intracellular and extracellular water volume fractions and extracellular relaxation rates were also calculated directly from the relaxation data and found to be consistent with sample haematocrits and with independent relaxation rate measurements of the resuspension medium. The small-amplitude, slowly relaxing third component recovered from the triexponential fits of the relaxation data is attributed to intracellular haemoglobin protons.

Adult↗
PubMed1986

Measurement of relaxation in isolated rat ventricular myocardium during hypoxia and reoxygenation.

The effects of hypoxia and subsequent reoxygenation were examined in isolated left ventricular papillary muscles from the rat at 28 degrees C and 33 degrees C. Studies of relaxation were carried out in isometric and physiologically sequenced contractions. In studies of isometric contractions, the following variables were determined: active tension (AT), maximum rate of tension increase (+dT/dt), time to peak tension (TPT), time for tension to fall from peak to 50% of peak tension (RT1/2), maximum rate of tension decline (-dT/dt), isometric peak (-dT/dt/T), and isometric maximum (-dT/dt per T). Variables measured in physiologically sequenced contractions were the slopes of the relation between -dT/dtmax and end systolic length (SIM) and maximum rate of isotonic muscle lengthening (+dL/dtmax) and end systolic length (SIT). Tau, the exponential time constant for isometric relaxation, was also examined. Pronounced changes in active tension and +dT/dt were seen during hypoxia at both temperatures, whereas changes in measured relaxation variables were less prominent and inconsistent. At neither 28 degrees C nor 33 degrees C did TPT or RT1/2 indicate impaired relaxation during hypoxia. Isometric peak -dT/dt declined with hypoxia at both temperatures but the normalised indices, isometric peak -dT/dt/T, peak (-dT/dt per T), and tau showed consistent impairment of relaxation only at 33 degrees C. In physiologically sequenced contractions, SIM suggested impaired relaxation during hypoxia at 28 degrees C but not at 33 degrees C. SIT showed impaired relaxation at both 28 degrees C and 33 degrees C. These findings are consistent with data suggesting impairment of the cardiac relaxing system during hypoxia. Nevertheless, relaxation appears less affected than contraction, and impairment is best seen late in the cardiac cycle.

Animals↗
PubMed1991

Age related attenuation of the endothelium dependent relaxation to noradrenaline in isolated pig coronary arteries.

STUDY OBJECTIVE: The aim was to investigate the relationship between vascular aging and endothelial regulation of the vascular tone by various agonists in isolated pig coronary arteries. EXPERIMENTAL MATERIALS AND DESIGN: Coronary artery rings from young (4-6 month old) and aged (3-4 years old) Yorkshire pigs were studied under isometric tension by organ chamber experiments. Cumulative concentration-response curves were obtained for vasorelaxing agents including noradrenaline (with beta blocker), substance P, bradykinin, and glyceryl trinitrate in rings precontracted with prostaglandin F2 alpha (PGF2 alpha). The degree of atherosclerosis of the coronary arteries was examined by light microscopy after the pharmacological experiments. MEASUREMENTS AND MAIN RESULTS: In the presence of propranolol (3 x 10(-6)M), noradrenaline (10(-8)-10(-5)M) caused endothelium dependent relaxation. The maximum relaxation was significantly greater in the young [45.4(SEM 2.5)% of the magnitude of precontraction induced by PGF2 alpha] than in the aged group [26.9(3.0)%] (p less than 0.001). However, magnitudes of relaxation to substance P, bradykinin, and glyceryl trinitrate were not significantly different between the young and the aged groups. The alpha 2 antagonist yohimbine (3 x 10(-6)M) inhibited the endothelium dependent relaxation to noradrenaline, but the alpha 1 antagonist prazosin (10(-6)M) failed to inhibit the response. Gossypol (3 x 10(-5)M) and methylene blue (10(-5)M), both inhibitors of endothelium dependent relaxation, abolished alpha 2 adrenoceptor mediated relaxation, but a cyclo-oxygenase inhibitor indomethacin (10(-5)M) did not affect the response. Histologically almost all young pig coronary arteries were free of atherosclerotic changes, whereas aged arteries had fatty streaks with slightly narrowed lumen in 22 of 38 rings (58%). The remaining aged pig coronary rings were free from atherosclerosis. Comparison of the endothelium dependent relaxation to noradrenaline between the rings with fatty streaks and those without lesions in the aged pigs suggested that the attenuated response was due both to vascular aging and to fatty streak development. CONCLUSIONS: The endothelium dependent relaxation to noradrenaline via the alpha 2 adrenoceptor was attenuated by vascular aging and also by fatty streak formation in isolated pig coronary arteries. Thus vascular aging may affect the sympathetic regulation of the coronary arterial tone by the attenuation of endothelium dependent relaxation to catecholamines via alpha 2 adrenoceptors.

Aging↗
PubMed1992

Effects of regional ischaemia, with or without reperfusion, on endothelium dependent coronary relaxation in the dog.

OBJECTIVE: The aim was to establish whether the duration of coronary ischaemia and coronary ischaemia with reperfusion selectively reduced the magnitude of relaxation mediated by endothelium dependent relaxing factor (EDRF) in response to thrombin, compared with relaxation produced by acetylcholine and calcimycin. METHODS: Adult male dogs, anaesthetised with sodium pentobarbitone (30 mg.kg-1 intravenously) were used. Coronary artery occlusions were maintained for either 15 or 45 min; in half the dogs from each timepoint, occlusion was followed by 60 min reperfusion. At the end of each in situ period, coronary arteries were removed from both ischaemic and non-ischaemic regions, cut into rings, and hung in isolated organ baths. Dose-response relationships to the EDRF dependent vasodilators thrombin, acetylcholine, and calcimycin, and to the EDRF independent vasodilator isoprenaline, were then established. RESULTS: Thrombin (0.003-0.3 units.ml-1) caused dose dependent relaxation in all tissues. Relaxant responses (E(max)) in the non-ischaemic vessels from both 15 and 45 min treatment groups were used as control data for the responses in ischaemic vessels. Maximum responses were not different in the non-ischaemic groups from either 15 or 45 min studies, at 82.7 (SEM 3.7)% after 15 min, and 82.1(2.4)% after 45 min. There was a small but significant reduction in E(max) after 15 min and 45 min ischaemia, to 74.4(3.2)% and 74.4(3.0)% respectively. Sixty minutes reperfusion provoked a further reduction in E(max) to 64.9(3.8)% after 45 min ischaemia, but not after 15 min ischaemia [70.3(4.2)%]. Neither 15 nor 45 min interventions altered E(max) of relaxation to acetylcholine or calcimycin (greater than 88.0% in each group). Similarly there were no significant differences between groups to the relaxation stimulated by isoprenaline (E(max) greater than 90.0%). CONCLUSIONS: The data suggest that loss of EDRF dependent relaxation to thrombin is more sensitive to ischaemia than the relaxation produced by either acetylcholine or calcimycin, and appears to be manifested early in the onset of ischaemic injury.

Acetylcholine↗
PubMed1998

Predominant role for nitric oxide in the relaxation induced by vasoactive intestinal polypeptide in human uterine artery.

It has been previously shown that vasoactive intestinal polypeptide (VIP) induces endothelium-dependent relaxation of the human uterine artery. However, the nature of the mediator of the VIP-induced endothelium-dependent relaxation of the human uterine artery has not yet been determined. Therefore these experiments were undertaken to examine the effects of VIP on human uterine arteries and to establish the role of various endothelial factors on the relaxation induced by VIP. The experiments were performed on isolated human uterine arterial rings. VIP (0.3-100 nM) induced a concentration-dependent relaxation of human uterine arteries with intact endothelium (pEC50 = 8.06+/-0.14, n = 28). After the removal of the endothelium this relaxation was abolished (n = 6). Indomethacin (10 microM), a cyclooxygenase inhibitor, and diethylcarbamazine (100 microM), a lipoxygenase blocker, had no effects on VIP-induced relaxation. In contrast, methylene blue (10 microM), a blocker of guanylate cyclase, NG-monomethyl-L-arginine (10 microM), an inhibitor of nitric oxide (NO) synthase, and 4-aminopyridine (1 mM), a non-selective blocker of K+ channels, antagonized the effect of VIP with suppression of maximal VIP-induced relaxation. Non-competitive antagonism with methylene blue revealed that the pKa value for VIP-receptor complex was 8.10+/-0.10 (n = 6) and the receptor reserve expressed as KA/EC50 was 0.89+/-0.11, where pKa = log10KA, and KA is the dissociation constant of VIP-receptor complex. Therefore, on the basis of the results presented, we can conclude that VIP induces endothelium-dependent relaxation in human uterine arteries, acting as a partial agonist on this blood vessel. It appears that endothelium-dependent relaxation induced by VIP in human uterine artery can be entirely explained by the release of NO from endothelial cells.

4-Aminopyridine↗
PubMed1993

Cocaine significantly impairs myocardial relaxation.

OBJECTIVES: To determine the immediate effects of intravenous "recreational" doses of cocaine on myocardial ventricular relaxation and contraction and on coronary blood flow. To determine the cardiac effects of cocaine after the administration of propranolol, as propranolol has been used to limit the cardiovascular effects of cocaine. DESIGN: Prospective study. SUBJECTS: Twenty mongrel dogs. INTERVENTIONS: We continuously recorded central aortic pressure, left atrial and ventricular pressures, coronary artery blood flow, and electrocardiograms in each dog. We determined from the left ventricular pressure waveforms the maximum rate of pressure increase [(dP/dt)max] and the time constant of isovolumic ventricular relaxation as our indices of ventricular contraction and relaxation. MEASUREMENTS AND MAIN RESULTS: In our initial series of experiments, we obtained pressure, coronary artery blood flow, and electrocardiographic recordings in ten anesthetized dogs before and for 40 mins after the intravenous administration of cocaine, in doses of 2.5 and then 5 mg/kg. In our second series of experiments in ten additional dogs, we injected 0.5 mg/kg of propranolol intravenously 30 mins before the injection of cocaine (2.5 mg/kg), and obtained hemodynamic and electrocardiographic recordings before and for 40 mins after the injection of propranolol and cocaine. Cocaine, 2.5 mg/kg, abruptly increased the time constant of isovolumic ventricular relaxation from 22.9 +/- 1.2 to 29 +/- 2.2 msecs at 1 min (p < .05) and to 35.3 +/- 2 msec at 40 mins (p < .01) but did not significantly change the mean arterial pressure, left atrial pressure, heart rate, coronary blood flow, or the maximum rate of left ventricular pressure increase [(dP/dt)max]. Cocaine also progressively displaced the electrocardiographic ST segments by 3.2 +/- 0.6 mm (p < .01) over 40 mins. Cocaine, 5 mg/kg, rapidly increased the time constant of isovolumic ventricular relaxation from 28.5 +/- 2.5 to 41 +/- 3 msecs in 1 min (p < .05) and to 48.7 +/- 4 msecs at 40 mins (p < .01) and reduced (dP/dt)max from 2905 +/- 370 to 1422 +/- 121 mm Hg/sec at 1 min (p < .01); (dP/dt)max returned to 2351 +/- 415 mm Hg/sec during the next 39 mins. Cocaine did not significantly change either the mean arterial or left atrial pressures. However, this dose of cocaine did decrease, over 40 mins, the heart rate from 184 +/- 11 to 139 +/- 11 beats/min (p < .01) and reduced coronary blood flow by 20% (p < .01). Cocaine also displaced the electrocardiographic ST segments by 3.3 mm over 40 mins (p < .05). Cocaine and propranolol abruptly increased the time constant of isovolumic ventricular relaxation from 26.4 +/- 1.3 to 43.2 +/- 2.1 msecs (p < .01) at 1 min and to 46.8 +/- 1.5 msecs at 3 mins (p < .01). The time constant of isovolumic ventricular relaxation remained abnormally increased at 43.0 +/- 1.4 msecs at 40 mins. Cocaine and propranolol reduced (dP/dt)max from 2760 +/- 458 mm Hg/sec to a minimum value of 1400 +/- 119 mm Hg/sec at 2 mins (p < .01). However, (dP/dt)max then returned to 2201 +/- 359 mm Hg/sec during the next 38 mins. Cocaine and propranolol did not significantly change the mean arterial and left atrial pressures, or heart rate, but did reduce coronary blood flow, over 40 mins, by 25% (p < .001). Cocaine also maximally displaced the electrocardiographic ST segments by 1 +/- 0.2 mm (p < .01). CONCLUSIONS: Cocaine substantially impairs myocardial ventricular relaxation for periods of at least 40 mins. Propranolol significantly intensifies cocaine's depressant effect on ventricular relaxation.

Animals↗
PubMed1999

NMRD investigation of DyDTPA- and GdDTPA-labeled starch particles. Selection of a suitable suspension medium and influence of the starch matrix on relaxivity.

RATIONALE AND OBJECTIVES: The primary aim was to investigate the influence of the starch matrix on the T1 relaxivities of starch particles labeled with gadolinium and dysprosium diethylenetriamine pentaacetic acid (GdDTPA-SP and DyDTPA-SP). Achieving this required the selection of a medium that was suitable for suspending the particles and that had field-independent T1 relaxation rates, thereby eliminating errors in relaxivity determinations resulting from a field-dependent background. METHODS: GdDTPA-SP with low and high gadolinium content, DyDTPA-SP, and empty DTPA-SP were suspended in an aqueous medium containing 5% (w/w) of a polyethylene glycol-based block copolymer. 1/T1 NMRD profiles were obtained in the temperature range of 5 degrees to 35 degrees C. RESULTS: Using the block copolymer, particles did not settle, and samples could be prepared at a low temperature to avoid particle degradation, the intrinsic T1 relaxation rate of the suspension medium was field-independent and identical to that of water from 25 degrees to 35 degrees C. The T1 relaxivities of DyDTPA-SP were higher than those of dysprosium diethylenetriamine pentaacetate-bis(methylamide) (DyDTPA-BMA) and decreased with increasing magnetic field strength. The T1 relaxivity of GdDTPA-SP was higher than that of GdDTPA at all fields, and decreased with decreasing temperature and increasing gadolinium content. CONCLUSIONS: The GdDTPA-SP results showed that the particulate starch matrix served a dual role, with opposing influences on relaxivity. It provided a means for increasing the rotational correlation time (tau R), which resulted in higher relaxivities. However, it also retarded radial diffusion of water molecules within the particle interior, which significantly counteracted the enhancing effect of tau R. For DyDTPA-SP, the starch matrix provided an additional diamagnetic contribution, resulting in relaxivities higher than those of DyDTPA-BMA. The block copolymer was suitable as a suspension medium for DyDTPA-SP and GdDTPA-SP and should also be applicable for other particulates.

Contrast Media↗
PubMed2001

Relaxant effects of 17-beta-estradiol in cerebral arteries through Ca(2+) entry inhibition.

Estrogens account for gender differences in the incidence and outcome of stroke, but it remains unclear to what extent neuroprotective effects of estrogens are because of parenchymal or vascular actions. Because reproductive steroids have vasoactive properties, the authors assessed the effects and mechanisms of action of 17-beta-estradiol in rabbit isolated basilar artery. Cumulative doses of 17-beta-estradiol (0.3 micromol/L to 0.1 mmol/L) induced concentration-dependent relaxation that was larger in basilar than carotid artery, in male than female basilar artery, and in KCl-precontracted than UTP-precontracted male basilar artery. Endothelium removal did not modify relaxation induced by 17-beta-estradiol in basilar artery, whereas relaxation induced by acetylcholine (1 nmol/L to 0.1 mmol/L) was almost abolished. Neither the estrogen receptor antagonist ICI 182,780 (1 micromol/L), nor the protein synthesis inhibitor cycloheximide (1 micromol/L) affected 17-beta-estradiol-induced relaxations. Relaxations induced by the K(+) channel openers NS1619 and pinacidil in the same concentration range were greater and lower, respectively, when compared with relaxation to 17-beta-estradiol, which was not significantly modified by incubation with the K(+) channel blockers charybdotoxin (1 nmol/L and 0.1 micromol/L) or glibenclamide (10 nmol/L and 1 micromol/L). Preincubation with 17-beta-estradiol (3 to 100 micromol/L) produced concentration-dependent inhibition of CaCl(2)-induced contraction, with less potency than the Ca(2+) entry blocker nicardipine (0.01 to 10 nmol/L). The authors conclude that 17-beta-estradiol induces endothelium-independent relaxation of cerebral arteries with tissue and gender selectivity. The relaxant effect is because of inhibition of extracellular Ca(2+) influx to vascular smooth muscle, but activation of estrogen receptors, protein synthesis, or K(+) efflux are not involved. Relatively high pharmacologic concentrations of 17-beta-estradiol causing relaxation preclude acute vascular effects of physiologic circulating levels on the cerebral circulation.

Animals↗
PubMed1989

Impaired relaxation of the hypertrophied myocardium is potentiated by angiotensin II.

Relaxation delay is an important feature of hypertensive heart disease which impairs diastolic coronary flow and ventricular filling and therefore contributes to heart failure. We investigated the hypothesis that impaired relaxation is a property of the myocardium, rather than the consequence of ischaemia or interstitial fibrosis. A new videomicroscope system was used to define the contraction-relaxation cycle of isolated cardiac myocytes from spontaneously hypertensive rats (SHR) and normotensive control (Wistar-Kyoto, WKY) rats. The SHR cells showed a marked relaxation delay. Angiotensin II (Ang II) increased the contraction maximum by about 35% in WKY rats and induced a relaxation delay. In SHR Ang II greatly potentiated this relaxation delay. Our results demonstrate that impairment of relaxation is a property of the single cardiomyocyte. Angiotensin II induces a relaxation delay that is independent of blood pressure. The combination of hypertrophy and high levels of Ang II potentiates relaxation impairment and may therefore contribute to hypertensive left ventricular failure.

Angiotensin II↗
PubMed1999

EDHF-mediated relaxation is impaired in fructose-fed rats.

Insulin resistance (IR) is associated with endothelial dysfunction. A defect in endothelium-dependent relaxation via outward potassium conductance has been observed in mesenteric arteries from IR rats. The purpose of this study was to assess whether this defect in endothelium-dependent relaxation was due to impaired endothelium-derived hyperpolarizing factor (EDHF) and to determine which specific potassium channel(s) are involved in relaxation. This was accomplished by using specific potassium channel inhibitors in the presence of nitric oxide synthase and cyclooxygenase inhibition. In addition, we sought to assess the function of smooth muscle cell adenosine triphosphate (ATP)-dependent potassium (K(ATP)) channels. Sprague-Dawley rats were randomized to control or IR. To determine EDHF-mediated relaxation, acetylcholine (ACh)-induced (10(-9)-10(-5) M) relaxation was measured (in vitro) in mesenteric arteries in the presence of indomethacin (10(-5) M) and N-nitro-L-arginine (L-NNA) (10(-4) M). Subsequently the combination of charybdotoxin (CTX) (0.1 microM) and apamin (0.5 microM) or glibenclamide (Glib) (10 microM) was added to the bath to inhibit KCa or K(ATP), respectively. In separate experiments, relaxation to pinacidil (10(-13)-10(-5) M), a K(ATP) activator, was assessed in vessels with intact endothelium, endothelium denuded, or with L-NNA. Maximal relaxation to ACh in the presence of L-NNA and indomethacin was 68+/-6% for control and 12+/-3% for IR (p<0.01). The addition of CTX + apamin almost abolished EDHF-mediated relaxation in control (Emax, 8+/-5% vs. 68+/-6%; p<0.01), whereas Glib had little affect. Neither CTX + apamin nor Glib had any affect on IR. Additionally, IR arteries were less sensitive to pinacidil than were controls (EC50, 1.5+/-0.9 microM vs. 5x10(-4)+/-3x10(-4) microM, respectively; p<0.01). Endothelial removal or L-NNA pretreatment of control arteries decreased the response to pinacidil similar to IR, whereas IR vessels were unaffected. EDHF-mediated relaxation is impaired in IR arteries. In addition, the K(Ca) channel appears to be imperative for activity of EDHF in rat small mesenteric arteries. Moreover, activation of K(ATP) channels by pinacidil is impaired in IR, and this appears to be a result of endothelial dysfunction.

Animals↗