Different pharmacological responses of atrium and ventricle: Studies with human cardiac tissue

It has been recently reported that 5-hydroxytryptamine (5-HT) increases force of contraction in atrial tissue but not in ventricular tissue. In the present study with trabeculae obtained from non-diseased human hearts, we investigated whether this difference in the contractile response is specific for 5-HT or is also observed for other substances: calcitonin gene-related peptide (CGRP), angiotensin II, adenosine, somatostatin and acetyllcholine. CGRP (10−9 to 10−7 M) and angiotensin II (10−9 to 10−5 M) caused concentration-dependent increases in force of contraction in atrial trabeculae (up to36 ± 8%and42 ± 8% of the response to 10−5 M noradrenaline, respectively). Similar to 5-HT, no effects were observed with CGRP and angiotensin II in ventricular trabeculae. Adenosine (10−8 to 10−5 M) and somatostatin (10−8 to 10−6 M) caused concentration-dependent negative inotropic effects on baseline atrial contractility (−54 ± 17%and−51 ± 25%, respectively, but no response was found on baseline ventricular contractility. Adenosine, but not somatostatin, reduced force of contraction after pre-stimulation with 10−5 M noradrenaline in atrial tissue and, to a lesser extent, in ventricular tissue. Acethlcholine exhibited a biphasic concentration-response curve in the atrial tissue, consisting of an initial negative inotropic response (10−9 to 10−7 M, from 120 ± 41mg at baseline to48 ± 16mg at 10 −7 M, fol lowed by a positive inotropic response (10−6 to 10−3 M, from 48 ± 16 mg at 10−7 M to77 ± 55mg). On the baseline ventricular for foce of contraction, acetylcholine (10−9 to 10−4 M) induced only a positive inotropic effect, starting at 10−9 M (from 252 ± 65mg at baseline to353 ± 71mg at 10−4M). After pre-stimulation with 10−5 M noradrenaline, acethylcholine reduced force of contraction in both tissue at 10−3 M(atrium: −14 ± 4%,ventricle: −61 ± 5%). The data indicate that, in atrial tissue, force of contraction can be affected by either postive or negative inotropic agents. However, in ventricular tissue only positive inotropic effects could be detected. Since atrial and ventricular tissues display different responses to the above biogenic substances, a different mechnism of regulation of contractility seems feasible

Characterization of the positive and negative inotropic effects of acetylcholine in the human myocardium

In the human isolated myocardium, acetylcholine (10−9 to 10−3 M) elicited a biphasic inotropic effect (a decrease in the lower and an increase in the higher concentration range) in atrial and a positive inotropic effect in ventricular trabeculae. However, under conditions of raised contractility achieved by exposure to noradrenaline (10−5 M), only negative inotropic effects were observed in both atria and ventricles. Atropine (10−6 M), but not propranolol (10−6 M), antagonized both positive and negative inotropic effects of acetylcholine, thus showing that the responses were mediated by muscarinic acetylcholine receptors. The use of subtype selective muscarinic receptor antagonists (10−7 to 10−5 M), pirenzepine (M1 > M3 > M2), AF-DX 116 (11-({2-[(diethylamino)-methyl]-1-piperidyl}acetyl)-5,11-dihydro-6H-pyridol[2,3-b][1,4]benzodiazepine-6-one base; M2 > M1 > M and HHSiD (p-fluorohexahydro-siladifenidol hydrochloride; M3 ≥ M1 ⪢ M2) revealed that the negative inotropic effect of acetylcholine in atrial as well as the positive inotropic effect in ventricular trabeculae were best antagonized by AF-DX 116 and not by pirenzepine, suggesting the involvement of the muscarinic M2 receptor subtype, possibly linked to different second messenger systems. On the other hand, the positive inotropic effect of acetylcholine (10−6 to 10−3 M) in the atrial tissue, observed only in preparation with depressed contractility, was not effectively antagonized by either AF-DX 116 or HHSiD, but was significantly reduced by pirenzepine. Furthermore, the selective muscarinic M1 receptor agonist McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethyl ammonium chloride; 10−9 to 10−3 M), which failed to significantly change the baseline contractility in either atrial or ventricular trabeculae, produced a positive inotropic effect in atrial preparations when contractility had been depressed by prior treatment with acetylcholine (10−9 to 10−7 M). This effect of McN-A-343 was effectively antagonized by pirenzepine (10−5 M). These data show that, besides the muscarinic M2 receptor mediating both negative (atria) and positive (ventricle) inotropic effects, muscarinic M1 receptors, capable of reversing depressed atrial contractility, are present in the human heart

Validation of a Single-Nucleotide Polymorphism-Based Non-Invasive Prenatal Test in Twin Gestations : Determination of Zygosity, Individual Fetal Sex, and Fetal Aneuploidy

We analyzed maternal plasma cell-free DNA samples from twin pregnancies in a prospective blinded study to validate a single-nucleotide polymorphism (SNP)-based non-invasive prenatal test (NIPT) for zygosity, fetal sex, and aneuploidy. Zygosity was evaluated by looking for either one or two fetal genome complements, fetal sex was evaluated by evaluating Y-chromosome loci, and aneuploidy was assessed through SNP ratios. Zygosity was correctly predicted in 100% of cases (93/93; 95% confidence interval (CI) 96.1%-100%). Individual fetal sex for both twins was also called with 100% accuracy (102/102; 95% weighted CI 95.2%-100%). All cases with copy number truth were also correctly identified. The dizygotic aneuploidy sensitivity was 100% (10/10; 95% CI 69.2%-100%), and overall specificity was 100% (96/96; 95% weighted CI, 94.8%-100%). The mean fetal fraction (FF) of monozygotic twins (n = 43) was 13.0% (standard deviation (SD), 4.5%); for dizygotic twins (n = 79), the mean lower FF was 6.5% (SD, 3.1%) and the mean higher FF was 8.1% (SD, 3.5%). We conclude SNP-based NIPT for zygosity is of value when chorionicity is uncertain or anomalies are identified. Zygosity, fetal sex, and aneuploidy are complementary evaluations that can be carried out on the same specimen as early as 9 weeks' gestation

5-Hydroxytryptamine-induced contractions of the human isolated saphenous vein: involvement of 5-HT2 and 5HT1D-like receptors and a comparison with grafted veins

The receptors mediating the contractile effect of 5-hydroxytryptamine (5-HT) on the human isolated saphenous vein, obtained from 42 patients undergoing coronary bypass surgery, have been further characterized using a number of 5-HT-related drugs. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT) approximately 5-HT greater than methysergide approximately sumatriptan approximately alpha-methyl-5-HT approximately 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesuccinate (RU 24969) approximately 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) greater than 2-methyl-5-HT greater than 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT). Flesinoxan was inactive as an agonist. Ketanserin (1 mumol/l) hardly affected sumatriptan-induced contractions but it caused a rightward shift of the upper part of the concentration-response curve of 5-HT and 5-CT. The same concentration of ketanserin caused a parallel rightward shift of the concentration-response curves of alpha-methyl-5-HT and DO