Long-term survivors after surgical management of metastatic spinal cord compression.

PURPOSE: Metastatic spinal cord compression (MSCC) incidences are increasing. Our objective was to identify predictive factors involved in long-term survival after use of a surgical approach. METHODS: We retrospectively analyzed all patients referred to our institution for MSCC who underwent surgery (N = 138). We identified patients with an overall survival (OS) rate greater than 2 years, compared their characteristics to the remaining patients, and performed recursive partitioning analysis (RPA). RESULTS: Median OS was 7.8 months (95 % confidence interval 4.4-11.2). Thirty-nine patients presented with OS ≥2 years. A comparative analysis found significant differences concerning the delay (first symptom-surgery, p < 0.001), number of systemic (p = 0.001) or bone metastases (p = 0.013), Karnofsky performance status (KPS) (p = 0.006), Frankel (p = 0.025), ASA scores (p < 0.001), weight loss (p = 0.003), hyperalgia (p = 0.002), chemotherapy use (p = 0.034), and primary tumor (p < 0.001). RPA classification identified six prognostic classes based on the ASA score, primary type, KPS, and systemic metastases. CONCLUSION: Long-term metastatic cancer survivor patients are an increasing population with specific characteristics.

Pyrazolidine-3,5-dione angiotensin-II receptor antagonists.

The crystal structures of three angiotensin-II receptor antagonists involving different spacer groups (CO, CONH and NHCO) between the aryl rings are presented, namely 2-[4-[(3-butyl-1,4-dioxo-2,3-diazaspiro[4.4]non-2-yl)methyl]benzoyl]benzoic acid, C(26)H(28)N(2)O(5), (I), 2-[4-[(3-butyl-1,4-dioxo-2,3-diazaspiro[4.4]non-2-yl)methyl]benzamido]benzoic acid, C(26)H(29)N(3)O(5), (II), and 2-[4-[(3-butyl-1,4-dioxo-2,3-diazaspiro[4.4]non-2-yl)methyl]anilinocarbonyl]benzoic acid monohydrate, C(26)H(29)N(3)O(5) x H(2)O, (III). The aryl rings of (II) are almost coplanar, in contrast with compounds (I) and (III). The conformation of (II) is induced by an intramolecular N-H.O hydrogen bond between the amide and carboxylic acid groups.

Effects of oxodipine on isolated rabbit aorta and mesenteric resistance vessels.

The inhibitory effects of the dihydropyridine Ca2+ antagonist, oxodipine, on contractions and 45Ca2+ influx stimulated by noradrenaline (NA) and high K+ in rabbit aorta were compared to the same parameters measured in mesenteric resistance arteries. In aortic rings oxodipine, 10(-11)-10(-6) M, inhibited in a concentration-dependent manner the contractions induced by high K+ (IC50 = 9.0 +/- 4.0 x 10(-10) M) or by Ca2+ in high K+ solution (IC50 = 6.2 +/- 2.4 x 10(-9) M), while responses to NA were only slightly affected (IC50 greater than 10(-6) M). In mesenteric resistance vessels oxodipine inhibited the contractions induced by high K+ and NA but was more effective against NA- than high K(+)-induced contractions (IC50 = 5.2 +/- 3.1 x 10(-10) and 1.2 +/- 1.8 x 10(-8) M, respectively). The concentration-inhibition curves for high K(+)-induced contraction and 45Ca2+ influx in aorta were almost superimposable (I50 = 2.2 +/- 2.0 x 10(-9) M), whereas NA-induced contractions were inhibited less than 45Ca2+ influx (I50 = 8.2 +/- 2.6 x 10(-8) M). In mesenteric resistance vessels the curves for contraction and 45Ca2+ influx stimulated by high K+ and NA were also superimposable, but 45Ca2+ influx stimulated by NA was more sensitive to oxodipine than that stimulated by high K+ (I50 = 3.9 +/- 2.0 x 10(-10) and 2.2 +/- 1.2 x 10(-8) M, respectively). It is concluded that the effects of oxodipine can be attributed to its ability to inhibit Ca2+ entry through both potential- and receptor-operated pathways.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential blockade of agonist- and depolarization-induced 45Ca2+ influx in smooth muscle cells.

ATP stimulated 45Ca2+ influx in rat aortic smooth muscle cells in a concentration-dependent manner (EC50 = 3.6 +/- 0.5 X 10(-7) M). ADP and GTP were less effective than ATP in stimulating 45Ca2+ influx; AMP was weakly active and the adenosine agonist 5'-(N-ethyl-carboxamido)-adenosine (NECA) had no effect. ATP gamma S was about equieffective with ATP, whereas alpha,beta-methylene-ATP (APCPP) did not induce 45Ca2+ influx. Stimulation of 45Ca2+ influx by ATP was not abolished by the dihydropyridine Ca2+ channel antagonist darodipine (PY 108-068), which completely blocked depolarization-induced 45Ca2+ influx. Inorganic cations (La3+, Cd2+, Co2+, Ni2+, Mn2+, and Mg2+) were able to inhibit both agonist- and depolarization-induced 45Ca2+ influx. Cd2+, however, was approximately 20 times more selective in blocking K+-stimulated than agonist-stimulated 45Ca2+ influx. These data indicate that ATP-stimulated Ca2+ influx in rat aortic smooth muscle cells is resistant to darodipine but is reduced by La3+, Cd2+, and other inorganic blockers of Ca2+ channels.

Receptor-operated calcium-permeable channels in vascular smooth muscle.

The extracellular Ca2+ dependence of agonist stimulation of vascular smooth muscle (VSM) has been investigated in rat cultured aortic smooth muscle cells (SMCs) and isolated mesenteric resistance vessels (MRVs). Agonists such as [Arg8]vasopressin (AVP), angiotensin II (Ang II), and adenosine-5'-triphosphate (ATP) stimulated 45Ca2+ entry into the SMCs that was (a) independent of the extent to which the membranes were polarized, and (b) was not inhibited by organic Ca2+ channel antagonists. Measuring the intracellular Ca2+ concentration [( Ca2+]i) after stimulation with agonists revealed a rapid increase of [Ca2+]i, which was followed by a sustained rise that was insensitive to Ca2+ antagonists. In Ca2+-free medium, only the initial peak of [Ca2+]i was still observed, but the sustained response to the agonists disappeared completely. This observation indicates that the sustained elevation seen in Ca2+-containing medium was the consequence of agonist-induced Ca2+ entry. In MRVs, a corresponding Ca2+-antagonist-insensitive, agonist (norepinephrine and AVP)-induced tonic tension was also identified. Moreover, agonists were able to induce sustained tension in the MRVs regardless of whether the membrane was normally polarized or was previously depolarized (80 mM K+) upon their administration. The agonist-stimulated 45Ca2+ entry in the SMCs could be blocked by the multivalent cations La3+, Cd2+, Mn2+, Co2+, Ni2+, and Mg2+ (in this order of potency). Depolarization-induced 45Ca2+ influx was inhibited by these cations in the same order of potency, but was significantly more sensitive to Cd2+ and significantly less sensitive to La3+ than that stimulated by agonists. Treatment with 2-nitro-4-carboxyphenyl-N,N-diphenyl-carbamate (NCDC, a proposed inhibitor of phospholipase C) reduced both the agonist-induced 45Ca2+ influx and the sustained elevation of [Ca2+]i in the SMCs. NCDC also abolished both contraction and depolarization induced by agonists in the MRVs. The kinase C stimulator phorbol-12-myristate-13-acetate (PMA) inhibited the agonist-induced 45Ca2+ influx and sustained increase in [Ca2+]i in the SMCs, whereas the kinase C inhibitor staurosporine had no effect. In the MRVs, in contrast, PMA had no influence on agonist-induced contractions. Staurosporine (1 microM), however, completely prevented these contractions, as did NCDC, but, unlike NCDC, it did so without affecting the agonist-induced depolarization. These data support an important role of receptor-operated Ca2+-permeable channels in VSM activation by agonists and suggest that these channels may be controlled by intracellular enzymic pathways and second messenger systems.

The mechanism of action of endothelin-1 as compared with other agonists in vascular smooth muscle.

The effects of endothelin-1 (ET-1) on tension and membrane potential in rat isolated mesenteric resistance vessels (MRVs) and on 45Ca influx, 45Ca efflux, inositol-1,4,5-triphosphate (IP3) production, and cytoplasmic Ca2+ concentration ([Ca2+]1) in cultured aortic smooth muscle cells were compared with those of other agonists. ET-1 induced contractions of the MRVs, which were slow in onset, but reached a similar maximum amplitude (at 10 nM ET-1) as that seen with norepinephrine (NE, 10 microM) or [arg8]vasopressin (AVP, 0.1 microM). The EC50 for ET-1 was 1.3 +/- 0.1 nM. Removal of extracellular Ca2+ reduced ET-1-induced contractions to 11 +/- 3% of those in Ca2+-containing medium. With NE, the same procedure reduced contractions to 47 +/- 7% of those in Ca2+-containing medium, while with AVP, the reduction was similar in magnitude to that induced by ET-1 (11 +/- 5% of those in Ca2+-containing medium). Relaxation of ET-1-induced and NE-induced contractions by diltiazem was not complete (maximal at 58 +/- 6% with 10 microM diltiazem after 6 nM ET-1, and at 70 +/- 3% after 0.1 microM NE), in contrast to that of 80 mM K+-induced contractions, which were potently (IC50 = 0.2 microM) and completely reversed (100% relaxation at 10 microM diltiazem). ET-1 (6 nM) caused a small but significant depolarization of the MRVs (approximately 7 mV), the magnitude of which was only about one-third of that induced by equieffective contractile concentrations of NE and AVP. The voltage-sensitive Ca2+ channel agonist Bay K 8644 (1 microM), in contrast to ET-1, NE, and AVP, produced a small contraction (30 +/- 2% of the maximum response to NE), but no further depolarization when added in the presence of 15 mM K+ (which elicited approximately 12 mV depolarization but no contraction).(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in Ca2+ handling along the arterial tree: an update including studies in human mesenteric resistance vessels.

The effects of noradrenaline (NA) on rat, rabbit, and human mesenteric resistance vessels (MRVs) in Ca2+-free medium have been compared. The maximum tension obtained in the absence of extracellular Ca2+ is least and is lost most rapidly with time in the MRVs from rabbit, followed by those from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), Sprague-Dawley (SD) rats, and from humans. Hence, it seems that the utilization of intracellular Ca2+ during activation of human MRVs by NA may be more substantial than has been found in the animal models. Nonetheless, in studies of the effects of isradipine on NA-induced tension, the human MRVs are similarly sensitive to the effects of this Ca2+ antagonist as WKY rat MRVs have been shown to be. All these resistance vessels, therefore, present quite a contrast to large vessels from rabbit, such as aorta, wherein the utilization of intracellular Ca2+ for NA-induced contraction is far more substantial, and the sensitivity of NA-induced contractions to Ca2+ antagonists is orders of magnitude less than in the MRVs. The basis for high sensitivity of rat and rabbit MRVs to Ca2+ antagonists may lie, at least in part, in the fact that these vessels (from rabbit and rat) depolarize in response to NA from approximately -50 to -30 mV, while aorta (from rabbit) does not, and the affinities of Ca2+ antagonists for voltage-sensitive Ca2+ channels (VSCs) are known to be voltage-dependent. Finally, the effects of the putative K+ channel opener BRL 34915 in rat MRVs appear to involve two sites of action, one with a lower affinity (K1 approximately 0.1 microM), similar to that shown previously in rat aorta, and a second with a higher affinity (K1 approximately 0.01 nM). In summary, these studies provide further evidence that Ca2+ handling processes controlled by both intracellular organelles and by the plasma membrane differ in mesenteric resistance vessels from those in aorta and in other large arteries.

Agonist-induced activation of rat mesenteric resistance vessels: comparison between noradrenaline and vasopressin.

The effects of noradrenaline (NA, 10(-5) M) and [arginine8]vasopressin (AVP, 10(-7) M) on tension in Ca2+-free medium and on membrane potential, and the inhibition of NA- and AVP-induced contractions by isradipine, have been compared in mesenteric resistance vessels (MRVs) from Wistar-Kyoto (WKY) rats. The release of intracellular Ca2+ by AVP contributed significantly less to its tension development than does that by NA. Nonetheless, the concentration-response curves for inhibition by isradipine of NA- and AVP-induced tonic tension were nearly identical. Similarly, these two agonists produced the same degree of membrane depolarization. In addition, both agonists were able to stimulate large contractions in vessels previously depolarized by 80 mM K+. AVP also stimulated 45Ca influx into rat cultured aortic smooth muscle cells. In contrast to the stimulation of 45Ca influx by KCl depolarization, the agonist-stimulated 45Ca influx was insensitive to inhibition by organic Ca2+ antagonists. It is concluded that Ca2+ entry through receptor-operated Ca2+-permeable channels (ROCs) may contribute to agonist-induced activation of rat aortic and MRV smooth muscle.

Effects of atriopeptin III on isolated mesenteric resistance vessels from SHR and WKY.

The effects of atriopeptin III (AP III) were determined on agonist-induced [i.e., 10(-4) M norepinephrine (NE)] and depolarization-induced (80 mM K+) contractions of isolated mesenteric resistance vessels (ID approximately 100 microns) from spontaneously hypertensive rats (SHR) and from normotensive control Wistar-Kyoto (WKY) rats. The vessels from both groups, when activated by 80 mM K+, were unaffected by AP III. However, activation of WKY vessels by 10(-4) M NE (both phasic and tonic contraction) was inhibited quite effectively and potently by AP III, whereas that in SHR vessels was much less inhibited. In the WKY rat vessels, the concentration of AP III that inhibited contraction by 50% for NE-induced phasic tension was 3.1 +/- 1.3 nM, whereas in SHR vessels it was nearly 1 microM. Comparison of AP III inhibition of NE-induced phasic tension to that at 5 min of activation (tonic tension) indicated that the tonic contractions were less sensitive to AP III than the phasic contractions in the vessels from both strains. A similar experiment indicated that AP III was a potent inhibitor of agonist-induced activation in a human renal resistance vessel (ID 125 microns) and that this vessel depended virtually completely on extracellular Ca2+ for NE-induced contraction. These studies contrast with earlier reports (1, 30) that similar peptides inhibited tension only in rat renal resistance vessels and not in resistance vessels from other vascular beds. The decreased sensitivity and efficacy of AP III in inhibiting tension in SHR compared with WKY mesenteric resistance vessels is discussed in the context of the etiology of spontaneous hypertension.

Vasopressin increases 45Ca2+ influx in rat aortic smooth muscle cells.

[Arg8]Vasopressin (AVP)-induced 45Ca2+ influx was examined in vascular smooth muscle cells derived from rat aorta. AVP stimulated the 45Ca2+ influx in a concentration-dependent manner. The effect was abolished in the presence of La3+. The dihydropyridine calcium channel antagonist darodipine did not affect the AVP-induced influx of 45Ca2+. These data suggest that AVP stimulates in these cultured aortic smooth muscle cells a receptor-operated channel (ROC) that is permeable to Ca2+.

Vascular smooth muscle calcium channels.

Vascular smooth muscle Ca channels function in excitation-contraction coupling. A survey of recent literature reveals several types of excitable Ca channels. There are at least two plasmalemmal Ca channels that are primarily activated by depolarization. In addition, there also exists evidence for the presence of Ca channels in conduit arteries that are primarily activated by agonists. Under circumstances of compromised sarcoplasmic reticulum (SR) Ca accumulation, Ca that enters through the nonregulated Ca leak also contributes to tension development. The Ca release from the SR appears to be mediated by large Ca channels that are activated by free Ca, inositol-1,4,5-trisphosphate, and free ATP. The differential sensitivity to procaine suggests the presence of two separate excitable Ca channels in vascular smooth muscle SR in addition to a basal Ca leak. This presentation concludes with a theoretical model describing how vascular smooth muscle Ca metabolism may be altered in hypertension and how a Ca antagonist may lead to reduction of blood pressure.

45Ca fluxes in rat mesenteric resistance vessels.

In order to evaluate previously utilized 45Ca influx measurements in Wistar-Kyoto (WKY) rat mesenteric resistance vessels, 45Ca compartments obtained under steady-state conditions have been determined. Curve fitting of 45Ca efflux curves resulting from a 50 min washout of 45Ca from vessels incubated in 45Ca-labeled physiological saline solution (PSS) for 1.5 h yields a biexponential as the best fit. The rapidly exchanging compartment has a t1/2 of 58 +/- 5 s, while the slowly exchanging compartment has a t1/2 of 10.5 +/- 1.5 min. A two-compartment model is proposed, with the rapidly exchanging compartment hypothesized to be extracellularly bound Ca2+, and the more slowly exchanging compartment to be intracellular Ca2+. This model is supported by the observation that high K+ increases the 45Ca content of the slowly exchanging fraction, while decreasing that of the rapidly exchanging fraction. Two components of 45Ca efflux can be further distinguished by washout in ice-cold Ca2+-free PSS containing 2 mM EGTA. Under these conditions, the rapidly lost fraction has a t1/2 of 70 +/- 7 s, while the more slowly lost fraction has a t1/2 of 28.9 +/- 5 min. High K+ also increases the 45Ca content of this fraction. The curve relating the steady-state uptake of 45Ca into this fraction to time can best be fitted to a single exponential, for which the t1/2 and 45Ca content are not different from those determined from steady-state 45Ca efflux data.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dihydropyridines on tension and calcium-45 influx in isolated mesenteric resistance vessels from spontaneously hypertensive and normotensive rats.

Contractile tension responses to norepinephrine and depolarizing potassium (80 mM K+), as well as calcium-45 influx stimulated by these agents, were studied in isolated mesenteric resistance vessels (each 100 microM internal diameter) from spontaneously hypertensive rats (SHRs) and from normotensive Wistar Kyoto rats (WKYs). Inhibitory effects of 2 dihydropyridine Ca++ antagonists, PN 200-110 (isradipine) and nisoldipine, on these parameters were also determined. Contractile responses to 80 mM K+ were inhibited by both Ca++ antagonists with the same potency and efficacy in SHR compared with WKY vessels (PN 200-110 IC50 = 2.8 +/- 1.3 X 10(-8) M in SHRs and 2.5 +/- 1.5 X 10(-8) M in WKYs; nisoldipine IC50 = 1.1 +/- 0.4 X 10(-8) M in SHRs and 1.2 +/- 0.9 X 10(-8) M in WKYs). However, contractile responses to norepinephrine (10(-4) M) were inhibited less potently by nisoldipine in SHR vessels (IC50 = 2.2 +/- 0.3 X 10(-9) M) compared with WKY vessels (IC50 = 1.6 +/- 0.6 X 10(-10) M). Similarly, PN 200-110 tended to be less (but not significantly less) potent in SHR vessels (IC50 = 3.3 +/- 1.8 X 10(-8) M) than in WKY vessels (IC50 = 3.4 +/- 0.9 X 10(-9) M); its efficacy was significantly depressed in the SHR vessels (by approximately 20%). When norepinephrine-stimulated calcium-45 influx was determined in the presence of these Ca++ antagonists, a similar profile emerged with respect to a comparison of SHR and WKY vessels. These results support a previously hypothesized alteration in receptor-activated Ca++ influx pathways in SHR mesenteric resistance vessels.

Ca2+ regulation of vascular smooth muscle.

Regulation of intracellular free Ca2+ concentrations in vascular smooth muscle is accomplished mainly by Ca2+ channels and ATP-dependent Ca2+ pumps in the plasmalemma and sarcoplasmic reticulum (SR). Ca2+ entry through the plasmalemma is apparently mediated by four different pathways: leak; receptor-operated Ca2+ channels; potential sensitive Ca2+ channels; and stretch-activated channels. The agonist releasable intracellular Ca2+ store appears to be identical with the SR. Evidence for the involvement of Ca2+-induced Ca2+ release and inositol-1,4,5-trisphosphate in the release of SR Ca2+ is discussed. Smooth muscle contractions induced by certain agonists may be further enhanced by inhibition of Ca2+ uptake by the SR and of active Ca2+ extrusion across the plasmalemma. At the moment it is not clear from a consideration of the Ca2+ regulatory mechanisms present in vascular smooth muscle how dietary Ca2+ affects vascular tone. The increased Ca2+ permeation through smooth muscle cell membranes of resistance arteries taken from spontaneously hypertensive rats may be relevant to this problem.

Calcium activation of vascular smooth muscle. State of the art lecture.

Tension development in arterial smooth muscle is regulated by variations of calcium concentration in the submicromolar range. The receptor for Ca2+ is calmodulin, which through stimulation of myosin light chain kinase can activate sequentially two apparently different contractile states. A third possible contractile state may be related to C-kinase activation. These contractile states are thought to have different Ca2+ sensitivities. Ca2+ is supplied from two major sources: the sarcoplasmic reticulum and the extracellular space. The release of sarcoplasmic reticulum Ca2+ is mediated by the intracellular messenger inositol-1,4,5-trisphosphate (IP3) and perhaps by Ca2+ itself. These two messengers have the potential for amplification; for example, IP3 may release some Ca2+ that may subsequently cause Ca2+-induced Ca2+ release. The entry of Ca2+ from the extracellular space into the cytoplasm is mediated by a Ca2+ leak and by excitable Ca2+ channels and is modulated by a Ca2+ buffer barrier consisting of the superficial sarcoplasmic reticulum. Two types of adenosine 5'-triphosphate-driven Ca2+ pumps in the sarcoplasmic reticulum and plasmalemma are responsible for returning the cytoplasmic Ca2+ concentration to resting level after contraction and for maintaining Ca2+ homeostasis during the life of the cells.

Regulation of cytoplasmic Ca2+ in vascular smooth muscle.

The vascular smooth muscle of conduit arteries can be excited by either depolarization or agonists. The former stimulus opens potential sensitive Ca2+ channels in the plasmalemma and releases bound Ca2+ from its outer surface. Ne interacts with alpha-receptors to open receptor operated Ca2+ channels which are distinct from the PSCs and also liberates surface bound Ca2+. In addition, it releases "trigger" Ca2+ from the inner plasmalemmal surface which in turn induces Ca2+ release from the sarcoplasmic reticulum. The elevated cytoplasmic free Ca2+ then combines with calmodulin to stimulate myosin light-chain kinase.

Differences in norepinephrine activation and diltiazem inhibition of calcium channels in isolated rabbit aorta and mesenteric resistance vessels.

The mechanisms of norepinephrine stimulation of calcium ion entry in isolated rabbit aorta and mesenteric resistance vessels were studied through measurements of effects on calcium-45 influx, tension, and membrane potential. The resistance vessels were considerably less sensitive to norepinephrine than the aorta. The aorta exhibited complex dose-response curves for norepinephrine-stimulated calcium influx and contraction, whereas these were simple in the arterioles. Both vessels were depolarized with increasing concentrations of potassium. Norepinephrine did not depolarize the aorta, whereas it did depolarize the mesenteric resistance vessels. This result supports the contention that norepinephrine opens receptor-operated channels to induce calcium entry in the aorta, while it may activate potential sensitive calcium channels in the mesenteric resistance vessels. However, the maximum depolarization with norepinephrine (10(-4) M) in the arterioles was completely blocked by 10(-5) M diltiazem, whereas that induced by 80 mM potassium was unaltered by the diltiazem. Furthermore, 10(-4) M norepinephrine was able to stimulate virtually the same contraction and calcium influx in 80 mM potassium-depolarized arterioles as in normal polarized tissues. These results are consistent with norepinephrine opening of receptor-operated channels to allow calcium entry in the rabbit mesenteric resistance vessels. That the behavior of norepinephrine-activated channels in the aorta is more complex than in the arterioles is further illustrated by a dramatically decreasing sensitivity of norepinephrine-stimulated calcium influx to diltiazem with increasing norepinephrine in the aorta but not in the arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)

Ca2+ sources mobilized by alpha 1-receptor activation in vascular smooth muscle.

We propose the following model of Ca2+ mobilization by noradrenaline in vascular smooth muscle. Upon receptor occupation Ca2+ from a labile small intracellular store on the inner plasmalemma is released. This Ca2+ does not function as activator Ca2+ but triggers Ca2+ release from the sarcoplasmic reticulum (Ca2+-induced Ca2+ release). Simultaneously Ca2+ from an extracellularly bound store (on the external surface of the plasmalemma) is dislodged, which enters the cell through receptor linked channels. These processes are responsible for the early 'phasic' component of the noradrenaline contraction. In addition, Ca2+ from the free extracellular Ca2+ pool enters through receptor operated channels, supporting the maintained tension development.