To find out whether indirect negative inotropic effects of carbachol (i.e. decreases in force of contraction that had been stimulated by cyclic AMP-increasing agents) might differ dependent on the agonist employed to increase contractile force in isolated human right atrium; we studied effects of carbachol on atria prestimulated with noradrenaline, terbutaline, histamine and serotonin. All four agonists increased right atrial adenylyl cyclase activity and contractile force, whereby increases for terbutaline, histamine and serotonin, but not for noradrenaline, were significantly larger in right atria from (beta1-adrenoceptor antagonist-treated vs. non-beta(1)-adrenoceptor antagonist-treated patients. Carbachol (10(-8)-10(-3) M) concentration-dependently decreased agonist-stimulated contractile force: maximum, decrease was not significantly different within the four agonists. pD(2) values for carbachol, however, were higher in atria from non-beta(1)-adrenoceptor antagonist-treated vs. beta(1)-adrenoceptor antagonist-treated patients.We conclude that, in isolated human right atria, carbachol-induced indirect negative inotropic effect is not dependent from the agonist employed to increase (via cyclic AMP accumulation) contractile force. However, in atria from beta(1)-adrenoceptor antagonist-treated patients, carbachol-induced indirect negative inotropic effect is attenuated. (C) 2002 Elsevier Science B.V. All rights reserved.

OBJECTIVES The purpose of this study was to elucidate whether the neuronal noradrenaline reuptake transporter (uptake(1)) undergoes age-dependent regulation in the human heart.BACKGROUND Aging is associated with various alterations in cardiovascular function.METHODS We determined uptake(1) density (by [H-3]-nisoxetine binding to membranes) and activity (by accumulation of [H-3]-noradrenaline into tissue slices) in the right atria (RA) of 42 patients (age range 3 months to 76 years) undergoing open-heart surgery without apparent heart failure. Moreover, the effects of 1 mumo/l desipramine on the noradrenaline-induced positive inotropic effect were assessed in the isolated, electrically driven RA trabeculae of these patients.RESULTS There was a significant negative correlation between RA uptake, density and age; moreover, RA uptake(1) activity was significantly reduced in elderly patients. Desipramine (1 mumol/l) significantly shifted noradrenaline concentration-response curves to the left; this shift was significantly more pronounced in younger patients than in older patients.CONCLUSIONS With increasing age, human myocardial uptake, activity decreases, possibly because of age-dependent downregulation of uptake(1) density. (J Am Coll Cardiol 2002: 40:1459-65) (C) 2002 by the American College of Cardiology Foundation.

In rats, injection of the alkaloid monocrotaline (MCT) causes right ventricular hypertrophy and cardiac failure. In order to study whether, in MCT-treated rats, changes in the cardiac beta -adrenoceptor-G-protein(s)-adenylyl cyclase system might be comparable to those found in human primary pulmonary hypertension, we assessed in right and left ventricles from MCT-treated rats the components of the beta -adrenoceptor system: the receptor number and subtype distribution (by (-)-[I-125]iodocyanopindolol binding), the G-proteins (by quantitative Western blotting), and the activity of adenylyl cyclase. A single injection of 60 mg/kg i.p. MCT caused in rats right ventricular hypertrophy (RVH); part of the rats developed cardiac failure (RVF). In these rats the cardiac beta -adrenoceptor-G-protein(s)-adenylyl cyclase system was markedly changed: beta -adrenoceptors were desensitized due to a decrease in receptor number, an uncoupling of the receptor from the G(s)-adenylyl; cyclase system, a decrease in G(s) and a decrease in the activity of the catalytic unit of adenylyl cyclase. In general, these changes were more pronounced in right ventricles v left ventricles, and in rats with RVF v rats with RVH. On the other hand, cardiac muscarinic receptors and G(i) appeared not to be altered. We conclude that in MCT-treated rats changes in the cardiac beta -adrenoceptor-G-protein(s)-adenylyl cyclase system occur that resemble those observed in human primary pulmonary hypertension. Thus, MCT-treated rat appears to be a suitable animal model to study in more detail the pathophysiology of the development of right heart failure, and to identify new therapeutic possibilities. (C) 2000 Academic Press.

In human right atrium, endothelin A (ET(A)) receptors couple to both inositol phosphate formation and inhibition of adenylylcyclase, whereas in human left ventricle, ET(A) receptors couple only to inositol phosphate formation. To find out whether this might be of functional relevance, we studied, in right atria obtained from 32 patients undergoing coronary bypass grafting without apparent heart failure, and in right atria and left ventricles from eight patients with end-stage heart failure (NYHA IV) undergoing heart transplantation, the effects of endothelin-1 (ET-1) on basal force of contraction or on force of contraction increased by 1 microM forskolin. ET-1 (0.1 microM) exerted a positive inotropic effect in atrial and ventricular tissue; this could be antagonized by the ET(A)-receptor antagonist BQ 123, but not by the ET(B)-receptor antagonist BQ 788. In atrial, but not in ventricular tissue, this positive inotropic effect was preceded by a transient negative inotropic effect. This negative inotropic effect was inhibited by BQ 123, but not by BQ 788. It was significantly prolonged in forskolin-prestimulated atria, and was significantly larger in atria from failing hearts. We conclude that, because ET-1 inhibits adenylylcyclase and causes negative inotropic effects in atria but not in ventricles, adenylylcyclase inhibition might be responsible for the transient negative inotropic effect of ET-1.

The aim of this study was to characterize the receptor subtype involved in cardiac effects of prostanoids. For this purpose we determined in neonatal and adult rat cardiomyocytes effects of prostanoids on inositol phosphate (InsP)‐formation (assessed as accumulation of total [3H]‐InsP's in myo‐[3H]‐inositol pre‐labelled cells) and on rate of protein synthesis (assessed as [3H]‐phenylalanine incorporation), and on contractile force in left ventricular strips of the rat heart. For comparison, effects of prostanoids on InsP‐formation and contractile force were determined in rat thoracic aorta, a classical TP‐receptor containing tissue. Prostanoid increased InsP‐formation and rate of protein synthesis in neonatal as well as adult rat cardiomyocytes; the order of potency was in neonatal (PGF2α>PGD2PGE2U 46619>PGE1) and adult (PGF2α>PGD2PGE2>U 46619) rat cardiomyocytes well comparable. Moreover, in electrically driven left ventricular strips PGF2α caused positive inotropic effects (pD2 7.5) whereas U 46619 (up to 1 μM) was uneffective. In contrast, in rat thoracic aorta U 46619 was about 100 times more potent than PGF2α in increasing InsP‐formation and contractile force. The TP‐receptor antagonist SQ 29548 only weakly antagonized prostanoid‐induced increases in rate of protein synthesis (pKB about 6) in rat cardiomyocytes but was very potent (pKB about 8–9) in antagonizing prostanoid‐induced increases in InsP‐formation and contractile force in rat aorta. We conclude that, in cardiomyocytes of neonatal and adult rats, the prostanoid‐receptor mediating increases in InsP‐formation and rate of protein synthesis is a FP‐receptor. Moreover, stimulation of these cardiac FP‐receptors can mediate increases in contractile force. British Journal of Pharmacology (2000) 129, 1723–1731; doi:10.1038/sj.bjp.0703243

In the human heart, as in the heart of several other species, muscarinic receptors are predominantly of the M2-subtype that couple via a pertussis toxin-sensitive Gi-protein to inhibit adenylyl cyclase. However, it is not clear whether an additional muscarinic receptor subtype exists in the human heart. In human right atrium, stimulation of muscarinic M2 receptors causes direct negative inotropic and chronotropic effects; in human ventricular myocardium, however, the negative inotropic effect can be only achieved when basal force of contraction has been pre-stimulated by cyclic AMP-elevating agents such as β-adrenoceptor agonists, forskolin or phosphodiesterase inhibitors (indirect effect); this has been shown in various in vitro and in vivo studies. Evidence has accumulated that in chronic heart failure vagal activity is decreased. Cardiac muscarinic M2 receptor density and functional responsiveness (inhibition of adenylyl cyclase activity and negative inotropic effects), however, are not considerably changed when compared with non-failing hearts although cardiac Gi-activity is increased.

On isolated, electrically driven human right atrial strips, carbachol (10−8–10−3 M) concentration-dependently decreased force of contraction prestimulated with 1 μM forskolin; maximal negative inotropic effects of carbachol (10−6–3×10−6 M), however, were in atria from patients aged <25 years (mean age: 16.8±2.0 years, n=9) significantly larger than in patients aged 50–69 years (mean age: 62.5±0.7 years, n=33) and were further decreased in patients aged >70 years (mean age: 73.8±0.6 years, n=11). We conclude that, in human right atrium, the recently described age-dependent decrease in muscarinic M2 receptor density is accompanied by a decrease in negative inotropic effects.

We could not find a consensual increase in prostacyclin formation in the anterior part of the fellow eye following alcali burn.

Background Consensual ocular response has been known to occur following intracranial stimulation of the trigeminal nerve, intracameral injection of prostaglandins and other substances, after paracentesis and contusio bulbi.Material and method We have examinated the prostacyclinformation in both eyes after experimental alcali burn (0,25 mol/l NaOH) on 30 rabbits with ELISA over a follow up period of 14 days.Results After the alcali burn the aqueous prostacyclinlevel on the right eye is increased from 327 pg/ml aqueous to 27098 pg/ml aqueous, but on the left it stays normally. In conjunctiva and anterior uvea we measured normal amounts of prostacyclin.Conclusions We could not find a consensual increase in prostacyclinformation in the anterior part of the fellow eye following alcali burn.