Apical sparing in tako-tsubo cardiomyopathy.

BACKGROUND: Tako-tsubo cardiomyopathy (TTC) is an acute reversible cause of segmental myocardial dysfunction that is poorly understood. We have noted a variant of this condition where a tiny segment at the apex retains some contractile function. This paper delineates the frequency of this variant relative to the classical form and the clinical differences between patients suffering from the two forms. METHODS: All cases of TTC (n = 35) were identified from our infarct angiography database and separated on the basis of apical sparing (n = 14) or no apical sparing (n = 21). RESULTS: Compared with the classical form, those with apical sparing were significantly younger (63 +/- 12 vs 72 +/- 13 years) and were more likely premenopausal (5/14 vs 0/21) and had higher ejection fractions (35 +/- 6% vs 32 +/- 4%). There was a trend towards higher recurrence (4/21 vs 0/14). There were no differences in time or season of presentation, precipitant stressor, premorbid drug therapy, haemodynamics at catheterization or acute outcomes. CONCLUSION: The apical sparing variant of TTC is common, accounting for 40% of cases. While the patients are younger and more likely premenopausal, there are no other distinguishing features between the classical and the variant form.

The contribution of cardiovascular mortality to long term outcomes in a relatively young demographic following acute pulmonary embolism: a validation study.

BACKGROUND: Long-term studies following acute pulmonary embolism (PE) remain limited in the current era. A recent study from our collaborative group, in a contemporary adult population, showed substantially increased cardiovascular mortality following PE. We sought to evaluate the contribution of cardiovascular mortality to long-term outcomes in a different demographic that comprised of a significantly younger PE cohort. METHODS AND RESULTS: Demographic and clinical characteristics were retrospectively collected for this cohort, and similar methods and outcome measures were applied as detailed in the original study. We compared a population from a different metropolitan area (LH: Liverpool Hospital) to that from the original study (CRGH: Concord Hospital) over a similar time period. A total of 815 patients comprised this cohort with mean 5.3±3.8year follow-up. There were similar demographics between the two cohorts, though the mean age was significantly younger in LH group (60 vs 68years, p<0.001). Prior history of cardiovascular disease in the LH group was half of that present in the CRGH cohort. The overall mortality was 7.4% per patient-year. Patients with underlying cardiovascular disease when presenting with an acute PE had a 2.3-fold increased risk of death during follow-up compared to those without. Multivariate analysis showed that older age, male gender, malignancy, diabetes, cardiovascular disease and chronic pulmonary disease were independent predictors of post-discharge mortality. CONCLUSIONS: Despite our cohort being significantly younger with a lower incidence of pre-existing cardiovascular disease, cardiovascular disease was still a significant contributor to long-term outcomes and an important predictor of mortality following acute PE.

[125I]-Bolton-Hunter scyliorhinin II: a novel, selective radioligand for the tachykinin NK3 receptor in rat brain.

The cyclic tachykinin scyliorhinin II (SCYII) has high affinity for the [neurokinin B (NKB)-preferring] NK3 receptor. SCYII was iodinated using [125I]-Bolton-Hunter reagent and the product BHSCYII purified using reverse phase HPLC. In rat brain membranes, binding of BHSCYII and of the relatively unselective radioligand [125I]-Bolton-Hunter eledoisin (BHELE) was saturable, reversible and to an NK3 site. In competition studies, the rank order of potency in inhibiting binding of BHSCYII and BHELE was: SCYII greater than or equal to [MePhe7]-NKB approximately senktide greater than NKB greater than or equal to kassinin greater than or equal to eledoisin greater than [Pro7]-NKB greater than neurokinin A greater than neuropeptide K greater than or equal to substance P greater than [Sar9, Met(O2)11]-substance P. In "cold" saturation experiments, binding of BHELE occurred to a single class of high affinity sites (KD, 18.6 +/- 0.91 nM). Binding of BHSCYII was of greater affinity than for BHELE and could be resolved into a high (KD, 1.33 +/- 0.98 nM; 27% of sites) and low affinity (KD, 9.84 +/- 2.75; 73% of sites) component. The total number of binding sites was similar for both radioligands (BHSCYII, 8.27 +/- 0.98; BHELE, 7.94 +/- 0.32 fmol/mg wet weight). In vitro autoradiography in slide-mounted sections of rat brain showed identical binding patterns for both radioligands (100 pM), with dense binding localized predominantly to the cortex, Ammon's horn field 1, premammillary nuclei and interpeduncular nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of the tachykinin NK2 receptor subtype in the rabbit pulmonary artery.

Contractile responses to neurokinin A (NKA), neuropeptide gamma(NP gamma), and the NK2 receptor-selective analogs [Lys5,MeLeu9,Nle10]NKA(4-10) and MDL 28,564 were determined in the endothelium-denuded rabbit pulmonary artery. Responses to NKA, NP gamma, and [Lys5,MeLeu9,Nle10]NKA(4-10) were antagonized by the NK2 receptor antagonist MDL 29,913, with pA2 values of 6.67, 6.46, and 7.32, respectively. Autoradiographic studies failed to demonstrate any specific binding sites for [125I]-iodohistidyl NKA (INKA) over the pulmonary artery. These data suggest the presence in rabbit pulmonary artery of an unusual "nonclassical" NK2 receptor subtype, which appears to lack affinity for INKA.

The autoradiographic distribution of substance P binding sites in guinea-pig vas deferens is altered by capsaicin pretreatment.

The distribution of binding sites for [125I]Bolton-Hunter substance P (BHSP) was investigated in vasa deferentia from normal, capsaicin-pretreated and vehicle-pretreated guinea-pigs, using qualitative and quantitative autoradiography. Dense binding of BHSP was seen over the outer longitudinal muscle with less over the inner longitudinal muscle. Very low specific binding occurred to the circular muscle and was absent in the mucosa. Characterization in slide-mounted sections showed that binding was saturable and of high affinity, with equilibrium dissociation constant (KD) 91 +/- 15 pM. BHSP was displaced by substance P greater than neurokinin A greater than neurokinin B, suggesting binding to NK-1 receptors. Capsaicin pretreatment had no effect on the lengthwise distribution of binding sites but significantly altered their relative distribution between the different smooth muscle layers. There was a very marked increase in BHSP binding over the inner longitudinal muscle and the inner part of the circular muscle layer, whereas binding was virtually abolished over the outer longitudinal muscle, compared with vehicle control. Capsaicin-sensitive binding sites over the outer longitudinal muscle may be located presynaptically on capsaicin-susceptible primary afferent sensory neurons. In contrast, the increase in number of binding sites associated with the inner longitudinal muscle may be due to receptor upregulation resulting from loss of sensory innervation, and suggests that these binding sites are postsynaptic.

Binding sites for [125I]-Bolton-Hunter scyliorhinin II in guinea-pig ileum: a radioligand binding, functional and autoradiographic study.

Binding of the tachykinin NK-3 receptor-preferring radioligand [125I]-Bolton-Hunter scyliorhinin II (BHSCYII) was investigated in membranes from guinea-pig ileum muscularis externa with myenteric plexus (MMP). Specific binding for BHSCYII was saturable and reversible. Curvilinear Scatchard plots and biphasic competition data indicate binding to two classes of sites (0.8 nM, 8% of sites; 340 nM, 92% of sites). Competition-binding data was ambiguous with the rank order of potency neuropeptide K (NPK) > substance P (SP) congruent to [Sar9,Met(O2)11]-SP congruent to [pGlu6,Pro9]SP(6-11) (septide) > neuropeptide gamma (NP gamma) > kassinin congruent to physalaemin > neurokinin A (NKA) > SCYII > neurokinin B (NKB). Senktide, eledoisin, [Lys5,MeLeu9,Nle10]-NKA(4-10), CP 96345, RP 67580, MDL 29913, SR 48968 and Gpp[NH]p were ineffective competitors, suggesting a lack of binding to conventional NK-1, NK-2 or NK-3 receptors. Competition curves for 5 agonists could be resolved into two sites, with no competitor showing outstanding affinity. Autoradiographic studies revealed moderate BHSCYII binding to myenteric plexus ganglia, unaffected by co-incubation with CP 96345 or with senktide. These data suggest a component of BHSCYII binding at unusual NPK/SP-preferring sites on ganglia. [Sar9,Met(O2)11]-SP was the most potent contractile agonist of the isolated ileum, followed by SCYII, NP gamma, senktide and NPK, with [Lys5,MeLeu9,Nle10]-NKA(4-10) least potent. Contractions elicited by senktide were entirely neurogenic. Responses to SCYII were partly sensitive to tetrodotoxin, atropine and CP 96345, indicative of action at both neuronal receptors and smooth muscle NK-1 receptors. The NK-2 antagonist SR 48968 did not alter responses to SCYII, [Sar9,Met(O2)11]-SP or senktide.

Characterization and autoradiographic localization of tachykinin receptors in rat gastric fundus.

Tachykinin receptors in rat gastric fundus were characterized using radioligand binding, functional and autoradiographic techniques. In crude homogenates of fundus, the specific binding of 125I-iodohistidyl-neurokinin A (INKA), 125I-Bolton-Hunter eledoisin (BHELE) and 125I-Bolton-Hunter [Sar9,Met(O2)11]-SP (BHSar-SP) was reversible and saturable. INKA and, in particular, BHSar-SP showed high affinity binding (Kds, 2.2 and 0.6 nM, respectively), with lower affinity for BHELE (Kd, 17 nM). The binding capacity was higher for INKA and BHELE than for BHSar-SP. The superior potency of neurokinin (NK)-2-preferring agonists (neuropeptide gamma > or = [Lys5,MeLeu9,Nle10]-NKA(4-10) > or = neuropeptide K > neurokinin A [NKA] > [Sar9,Met(O2)11]-SP >> senktide) and antagonists (SR 48,968 > GR 94,800 > MDL 29,913 > L-659,877 > MEN 10,207) as competitors for INKA and BHELE binding suggests interaction at mainly NK-2 sites. Additional competition studies showed that BHSar-SP was binding to NK-1 sites. Autoradiographic studies revealed very dense INKA and BHELE specific binding over the circular muscle and muscularis mucosae, while BHSar-SP binding was observed only to the circular muscle. The weak specific binding for 125I-Bolton-Hunter scyliorhinin II localized to the muscularis mucosae may indicate NK-3 sites. This was consistent with functional studies showing concentration-dependent contractions of fundus strips by NK-2-preferring tachykinin agonists (potency, pD2s, 7.1 to 8.1) and [Sar9, Met(O2)11]-SP (pD2, 7.1). The NK-2 selective antagonist MDL 29,913 inhibited INKA binding (Kd, 14 nM) with more than tenfold greater affinity than did MEN 10,207. The antagonism by MDL 29,913 was noncompetitive, with a nonparallel rightward shift of the concentration-response curves to the agonists neuropeptide gamma, neuropeptide K, NKA and [Lys5,MeLeu9,Nle10]-NKA(4-10) (dose ratios at 400 nM MDL 29,913 were 230, 62, 40 and 23, respectively). These data indicate that classic NK-2 receptors predominate in the rat fundus and that NK-1 and perhaps NK-3 receptors also exist.

Radioiodinated substance P, neurokinin A, and eledoisin bind predominantly in NK1 receptors in guinea pig lung.

In homogenates of guinea pig lung, binding of 125I-Bolton-Hunter-labeled substance P (BHSP), Bolton-Hunter-labeled eledoisin (BHELE), and [125I]iodohistidyl neurokinin A (INKA) was investigated. Equilibrium dissociation constants (derived from "cold" saturation experiments) for BHSP, INKA, and BHELE were 0.96 +/- 0.15, 1.61 +/- 0.26, and 1.98 +/- 0.12 nM, respectively. Specific binding of all three radioligands was increased 2-3-fold by 10 microM phosphoramidon. The rank order of potency of unlabeled tachykinins in competing against BHSP was substance P (SP) greater than [Sar9,Met(O2)11]-SP greater than SP methyl ester greater than neuropeptide gamma greater than neurokinin A greater than or equal to neurokinin B = kassinin greater than or equal to eledoisin greater than or equal to scyliorhinin II much greater than neuropeptide K, indicating binding to sites with the general characteristics of NK1 receptors. Similar rank potency orders were observed for INKA and BHELE, showing binding to NK1 sites, rather than to NK2 or NK3 sites, which are labeled with high affinity by these radioligands in other tissues. For all radioligands, competition curves for SP and the NK1-selective agonist [Sar9,Met(O2)11]-SP could be resolved into two components, representing high and low affinity binding sites. These were present in the approximate ratios 2:3 (for BHSP), 1:1 (for INKA), and 8:1 (for BHELE). Other agonist competition curves also yielded high and low affinity components. The data suggest that BHSP and INKA bind partly and BHELE predominantly to high affinity NK1 receptors. The nature of the low affinity site(s) could be another tachykinin receptor or a low affinity state of the NK1 receptor. Binding to a "classical" NK2 receptor is unlikely, because selective NK2 receptor antagonists and analogs were very weak competitors. Our data suggest that, in addition to the NK1 receptor, another type of tachykinin receptor may exist in this tissue. The inability to detect NK2 binding sites is strikingly at variance with functional studies.

Radioligand binding, autoradiographic and functional studies demonstrate tachykinin NK-2 receptors in dog urinary bladder.

Tachykinin receptors in the dog bladder were characterized using radioligand binding, functional and autoradiographic techniques. In detrusor muscle homogenates, specific binding of [125l]iodohistidyl neurokinin A (INKA) and [125l]Bolton Hunter eledoisin was reversible, saturable and, to a single class of sites of Kd, 3,6 and 27 nM, respectively. No specific binding of [125l]Bolton Hunter[Sar9, Met (O2)11] substance P occurred. INKA binding was reduced by the peptidase inhibitor bacitracin. The rank potency order of agonists competing for binding of both radioligands indicated interaction at NK-2 sites. NK-2-selective antagonists also competed for INKA binding, with SR 48968, GR 94800, MDL 29913 and the selective agonist [Lys5, MeLeu9, Nle10]-NKA(4-10) showing biphasic binding profiles. Autoradiographic studies revealed specific binding of INKA and [125l]Bolton Hunter eledoisin over detrusor muscle and small arteries. [125l]Bolton Hunter [Sar9, Met (O2)11] SP labeled the intima of arteries and arterioles, but not the detrusor muscle. Tachykinins contracted detrusor muscle strips, with potency order at the carbachol EC15 NKA = kassinin > [Lys5, MeLeu9, Nle10]-NKA(4-10) = neuropeptide gamma = neuropeptide K = NKB > > MDL 28564, with [Sar9, Met(O2)11]-SP ineffective. Shallow concentration-response curves, variable efficacies and inhibition by atropine and mepyramine suggest that other mechanisms may influence contractile responses. Responses to [Lys5, MeLeu9, Nle10]-NKA(4-10) were inhibited competitively by MDL 29913 and MEN 10207 (pA2 values: 6.4 and 5.3, respectively). Antagonism by SR 48968 and GR 94800 was noncompetitive (both pK8 values 8.9). In summary, NK-2-preferring ligands showed superior potency as both binding competitors and contractile agonists, demonstrating that NK-2 receptors mediate detrusor muscle contraction, similar to the human detrusor. Tachykinins may play important roles in the micturition reflex and in regulating detrusor muscle blood flow in the dog.

Tachykinin receptors: a radioligand binding perspective.

The last decade has witnessed major breakthroughs in the study of tachykinin receptors. The currently described NK-1, NK-2, and NK-3 receptors have been sequenced and cloned from various mammalian sources. A far greater variety of tachykinin analogues are now available for use as selective agonists and antagonists. Importantly, potent nonpeptide antagonists highly selective for the NK-1 and NK-2 receptors have been developed recently. These improved tools for tachykinin receptor characterization have enabled us to describe at least three distinct receptor types. Furthermore, novel antagonists have yielded radioligand binding and functional data strongly favoring the existence of putative subtypes of NK-1 and especially NK-2 receptors. Whether these subtypes are species variants or true within-species subtypes awaits further evidence. As yet undiscovered mammalian tachykinins, or bioactive fragments, may have superior potency at a specific receptor class. The common C terminus of tachykinins permits varying degrees of interaction at essentially all tachykinin receptors. Although the exact physiological significance of this inherent capacity for receptor "cross talk" remains unknown, one implication is for multiple endogenous ligands at a single receptor. For example, NP gamma and NPK appear to be the preferred agonists and binding competitors at some NK-2 receptors, previously thought of as exclusively "NKA-preferring." Current evidence suggests that tachykinin coexistence and expression of multiple receptors may also occur with postulated NK-2 and NK-1 receptor subtypes. Other "tachykinin" receptors may recognize preprotachykinins and the N terminus of SP. In light of these recent developments, the convenient working hypothesis of three endogenous ligands (SP, NKA, and NKB) for three basic receptor types (NK-1, NK-2, and NK-3) may be too simplistic and in need of amendment as future developments occur (Burcher et al., 1991b). In retrospect, the 1980s contributed greatly to our understanding of the structure, function, and regulation of tachykinins and their various receptors. The development of improved, receptor subtype-selective antagonists and radioligands, in addition to recent advances in molecular biological techniques, may lead to a more conclusive pharmacological and biochemical characterization of tachykinin receptors. The 1990s may prove to be the decade of application, where a better understanding of the roles played by endogenous tachykinins (at various receptor subtypes) under pathophysiological conditions will no doubt hasten the realization of clinically useful therapeutic agents.