Effect of chronic hypoxia on alpha-1 adrenoceptor-mediated inositol 1,4,5-trisphosphate signaling in ovine uterine artery.
The present study examined the effect of chronic hypoxia on coupling efficiency of alpha-1 adrenoceptors to inositol 1,4,5-trisphosphate (InsP3) signaling in ovine uterine artery. Chronic hypoxia did not change the time course of InsP3 formation, but significantly decreased the potency (pD2: 6.17 +/- 0.09 --> 5.26 +/- 0.12) and the maximal response (220.7 +/- 21.7 --> 147.7 +/- 15.3 pmol/mg protein) of norepinephrine-induced InsP3 synthesis. The coupling efficiency of alpha-1 adrenoceptors to InsP3 synthesis (picomoles InsP3 per femtomoles receptor) was decreased 45% by chronic hypoxia. In addition, simultaneous measurement of norepinephrine-induced contractions and InsP3 synthesis indicated that for a given amount of InsP3 generated, the contractile force of the uterine artery was significantly less in chronically hypoxic than in control tissues (0. 27 +/- 0.01 versus 0.35 +/- 0.02 g tension/pmol InsP3). InsP3 receptors were characterized using radioligand binding techniques. Although the density of InsP3 receptors was not changed by chronic hypoxia (Bmax: 325 +/- 35 --> 378 +/- 18 fmol/mg protein), the dissociation constant (Kd) of InsP3 to its receptors was significantly increased (Kd: 5.20 +/- 0.40 --> 7.81 +/- 0.34 nM). Analysis of InsP3 receptor occupancy-tension development relationship indicated no difference in intrinsic ability of the InsP3-receptor complex in eliciting contractions between the control and hypoxic tissues. Our results suggest that chronic hypoxia attenuates coupling efficiency of alpha-1 adrenoceptors to InsP3 synthesis in the uterine artery. In addition, the tissue contractile sensitivity to InsP3 is reduced, which is mediated predominantly by a decrease in InsP3 binding affinity to InsP3 receptors. (+info)
In oculo transplants of myometrium from postpartum guinea pigs fail to support sympathetic reinnervation.
Sympathetic nerves to the enlarged fetus-containing region of the uterus undergo degenerative changes during late pregnancy and show slow regrowth after parturition. It is not known whether this unusual response of sympathetic nerves to smooth muscle hypertrophy is due to the sensitivity of short adrenergic neurons to hormonal changes, or whether the nerves respond to changes in the neurotrophic capacity of the target. We have investigated this question using in oculo transplantation. Small pieces of myometrium from the uterine horn of virgin guinea pigs, or from the region previously occupied by the placenta and fetus in postpartum guinea pigs, were transplanted into the anterior eye chamber. After 3 wk in oculo, the pattern of reinnervation of the transplants was assessed on whole mount stretch preparations stained for tyrosine hydroxylase. The histology of the transplants was examined in toluidine blue-stained semithin sections. Myometrial transplants from virgin donors and uterine artery transplants from both virgin and postpartum donors became organotypically reinnervated by sympathetic fibres from the host iris. In contrast, sympathetic nerves did not reinnervate myometrial transplants from postpartum donors, although they approached the transplants and became distributed in the surrounding connective tissue. All transplanted tissues showed a normal histological appearance. Both the myometrium and uterine artery from postpartum donors retained a hypertrophic appearance after 3 wk in oculo. We interpret these results to indicate that the degeneration of sympathetic nerves in late pregnancy, as well as their slow regrowth to the uterus after delivery, may be due to changes in uterine smooth muscle rather than a particular sensitivity of short adrenergic neurons to hormonal changes. (+info)
Facilitation and depression of ATP and noradrenaline release from sympathetic nerves of rat tail artery.
1. Excitatory junction currents (EJCs) were used to measure ATP release; noradrenaline (NA) oxidation currents and fractional overflow of labelled NA, [3H]NA, were used to monitor the release of endogenous and exogenous NA, respectively, from post-ganglionic sympathetic nerves of rat tail artery. 2. During nerve stimulation with 100 pulses at 5-20 Hz the EJCs initially grew in size (maximally by 23 %, at 2-10 Hz), and then depressed, maximally by 68 % at 20 Hz. 3. The peak amplitude of NA oxidation currents in response to nerve stimulation with 100 pulses at 2-20 Hz grew in size with frequency, while the area was independent of frequency and roughly constant. 4. The size of the NA oxidation currents evoked by nerve stimulation with 4-100 pulses at 20 Hz grew linearly with train length between pulses 4-16. Between pulses 20-100 there was a train length-dependent depression of the signal. 5. Fractional overflow of [3H]NA in response to nerve stimulation with 5-100 pulses at 20 Hz behaved similarly to the EJCs. It initially grew roughly linearly between pulses 5-25, and then showed a dramatic depression similar to that of the EJCs. 6. The alpha2-adrenoceptor antagonists rauwolscine and yohimbine increased the overflow of [3H]NA and the amplitude of NA oxidation currents, but not that of the EJCs. 7. It is concluded that during high-frequency stimulation (i) the release of ATP and NA is first briefly facilitated then markedly depressed, (ii) facilitation and depression of the two transmitters are similar in magnitude and time course, and (iii) alpha2-adrenoceptor antagonists differentially modify EJCs and the NA signals. The results obtained in the absence of drugs are compatible with the hypothesis that ATP and NA are released in parallel, while the effects of alpha2-adrenoceptor antagonists seem to suggest dissociated release. (+info)
Effects of Ca2+ concentration and Ca2+ channel blockers on noradrenaline release and purinergic neuroeffector transmission in rat tail artery.
1. The effects of Ca2+ concentration and Ca2+ channel blockers on noradrenaline (NA) and adenosine 5'-triphosphate (ATP) release from postganglionic sympathetic nerves have been investigated in rat tail arteries in vitro. Intracellularly recorded excitatory junction potentials (e.j.ps) were used as a measure of ATP release and continuous amperometry was used to measure NA release. 2. Varying the extracellular Ca2+ concentration similarly affected the amplitudes of e.j.ps and NA-induced oxidation currents evoked by trains of ten stimuli at 1 Hz. 3. The N-type Ca2+ blocker, omega-conotoxin GVIA (omega-CTX GVIA, 0.1 microM) reduced the amplitudes of both e.j.ps (evoked by trains of ten stimuli at 1 Hz) and NA-induced oxidation currents (evoked by trains of ten stimuli at 1 Hz and 50 stimuli at 10 Hz) by about 90%. 4. The omega-CTX GVIA resistant e.j.ps and NA-induced oxidation currents evoked by trains of 50 stimuli at 10 Hz were abolished by the non-selective Ca2+ channel blocker, Cd2+ (0.1 mM), and were reduced by omega-conotoxin MVIIC (0.5 microM) and omega-agatoxin IVA (40 nM). 5. Nifedipine (10 microm) had no inhibitory effect on omega-CTX GVIA resistant e.j.ps and NA-induced oxidation currents. 6. Thus both varying Ca2+ concentration and applying Ca2+ channel blockers results in similar effects on NA and ATP release from postganglionic sympathetic nerves. These findings are consistent with the hypothesis that NA and ATP are co-released together from the sympathetic nerve terminals. (+info)
Impact of vascular adaptation to chronic aortic regurgitation on left ventricular performance.
BACKGROUND: This investigation was designed to test the hypothesis that vascular adaptation occurs in patients with chronic aortic regurgitation to maintain left ventricular (LV) performance. METHODS AND RESULTS: Forty-five patients with chronic aortic regurgitation (mean age 50+/-14 years) were studied using a micromanometer LV catheter to obtain LV pressures and radionuclide ventriculography to obtain LV volumes during multiple loading conditions and right atrial pacing. These 45 patients were subgrouped according to their LV contractility (Ees) and ejection fraction values. Group I consisted of 24 patients with a normal Ees. Group IIa consisted of 10 patients with impaired Ees values (Ees <1.00 mm Hg/mL) but normal LV ejection fractions; Group IIb consisted of 11 patients with impaired contractility and reduced LV ejection fractions. The left ventricular-arterial coupling ratio, Ees/Ea, where Ea was calculated by dividing the LV end-systolic pressure by LV stroke volume, averaged 1.60+/-0.91 in Group I. It decreased to 0.91+/-0.27 in Group IIa (P<0.05 versus Group I), and it decreased further in Group IIb to 0.43+/-0.24 (P<0.001 versus Groups I and IIa). The LV ejection fractions were inversely related to the Ea values in both the normal and impaired contractility groups (r=-0.48, P<0.05 and r=-0.56, P<0.01, respectively), although the slopes of these relationships differed (P<0.05). The average LV work was maximal in Group IIa when the left ventricular-arterial coupling ratio was near 1.0 because of a significant decrease in total arterial elastance (P<0.01 versus Group I). In contrast, the decrease in the left ventricular-arterial coupling ratio in Group IIb was caused by an increase in total arterial elastance, effectively double loading the LV, contributing to a decrease in LV pump efficiency (P<0.01 versus Group IIa and P<0.001 versus Group I). CONCLUSIONS: Vascular adaptation may be heterogeneous in patients with chronic aortic regurgitation. In some, total arterial elastance decreases to maximize LV work and maintain LV performance, whereas in others, it increases, thereby double loading the LV, contributing to afterload excess and a deterioration in LV performance that is most prominent in those with impaired contractility. (+info)
BDNF is a target-derived survival factor for arterial baroreceptor and chemoafferent primary sensory neurons.
Brain-derived neurotrophic factor (BDNF) supports survival of 50% of visceral afferent neurons in the nodose/petrosal sensory ganglion complex (NPG; Ernfors et al., 1994a; Jones et al., 1994; Conover et al., 1995; Liu et al., 1995; Erickson et al., 1996), including arterial chemoafferents that innervate the carotid body and are required for development of normal breathing (Erickson et al., 1996). However, the relationship between BDNF dependence of visceral afferents and the location and timing of BDNF expression in visceral tissues is unknown. The present study demonstrates that BDNF mRNA and protein are transiently expressed in NPG targets in the fetal cardiac outflow tract, including baroreceptor regions in the aortic arch, carotid sinus, and right subclavian artery, as well as in the carotid body. The period of BDNF expression corresponds to the onset of sensory innervation and to the time at which fetal NPG neurons are BDNF-dependent in vitro. Moreover, baroreceptor innervation is absent in newborn mice lacking BDNF. In addition to vascular targets, vascular afferents themselves express high levels of BDNF, both during and after the time they are BDNF-dependent. However, endogenous BDNF supports survival of fetal NPG neurons in vitro only under depolarizing conditions. Together, these data indicate two roles for BDNF during vascular afferent pathway development; initially, as a target-derived survival factor, and subsequently, as a signaling molecule produced by the afferents themselves. Furthermore, the fact that BDNF is required for survival of functionally distinct populations of vascular afferents demonstrates that trophic requirements of NPG neurons are not modality-specific but may instead be associated with innervation of particular organ systems. (+info)
Alteration of endothelium-dependent hyperpolarizations in porcine coronary arteries with regenerated endothelium.
The present study was designed to test the ability of regenerated endothelium to evoke endothelium-dependent hyperpolarizations. Hyperpolarizations induced by serotonin and bradykinin were compared in isolated porcine coronary arteries with native or regenerated endothelium, 4 weeks after balloon endothelial denudation. The experiments were performed in the presence of inhibitors of nitric oxide synthase (Nomega-nitro-L-arginine) and cyclooxygenase (indomethacin). The transmembrane potential was measured using conventional glass microelectrodes. Smooth muscle cells from coronary arteries with regenerated endothelium were depolarized in comparison with control coronary arteries from the same hearts. Spontaneous membrane potential oscillations of small amplitude or spikes were observed in some of these arteries but never in arteries with native endothelium. In coronary arteries from control pigs, both serotonin and bradykinin induced concentration-dependent hyperpolarizations. In the presence of ketanserin, 10 micromol/L serotonin induced a transient hyperpolarization in control coronary arteries. Four weeks after balloon denudation, the response to serotonin was normal in arteries with native endothelium, but the hyperpolarization was significantly lower in coronary arteries with regenerated endothelium. In control arteries, the endothelium-dependent hyperpolarization obtained with bradykinin (30 nmol/L) was reproducible. Four weeks after balloon denudation, comparable hyperpolarizations were obtained in coronary arteries with native endothelium. By contrast, in arteries with regenerated endothelium, the hyperpolarization to bradykinin became voltage-dependent. In the most depolarized cells, the hyperpolarization to bradykinin was augmented. The changes in resting membrane potential and the alteration in endothelium-dependent hyperpolarizations observed in the coronary arteries with regenerated endothelium may contribute to the reduced response to serotonin and the unchanged relaxation to bradykinin described previously. (+info)
Balloon-artery interactions during stent placement: a finite element analysis approach to pressure, compliance, and stent design as contributors to vascular injury.
Endovascular stents expand the arterial lumen more than balloon angioplasty and reduce rates of restenosis after coronary angioplasty in selected patients. Understanding the factors involved in vascular injury imposed during stent deployment may allow optimization of stent design and stent-placement protocols so as to limit vascular injury and perhaps reduce restenosis. Addressing the hypothesis that a previously undescribed mechanism of vascular injury during stent deployment is balloon-artery interaction, we have used finite element analysis to model how balloon-artery contact stress and area depend on stent-strut geometry, balloon compliance, and inflation pressure. We also examined superficial injury during deployment of stents of varied design in vivo and in a phantom model ex vivo to show that balloon-induced damage can be modulated by altering stent design. Our results show that higher inflation pressures, wider stent-strut openings, and more compliant balloon materials cause markedly larger surface-contact areas and contact stresses between stent struts. Appreciating that the contact stress and contact area are functions of placement pressure, stent geometry, and balloon compliance may help direct development of novel stent designs and stent-deployment protocols so as to minimize vascular injury during stenting and perhaps to optimize long-term outcomes. (+info)