Differential recruitment of alpha 1- and beta-adrenoceptors in inotropic control of atrial child myocardium by endogenous noradrenaline.

Noradrenaline release, graded by frequency variation of field stimulation (0.1-2 Hz), in atrial myocardial specimens (n=45) from children (n=21) with congenital heart defects, was used to examine the inotropic responses of graded, receptor-selective, endogenous stimulation. Muscle trabeculae subjected to autonomic blockage by timolol, prazosin and atropine showed a slight positive force-frequency relationship (staircase phenomenon). Blockage by atropine/prazosin (i.e. beta-adrenoceptor stimulation) or atropine/timolol (i.e. alpha1-adrenoceptor stimulation) both resulted in positive inotropic effects. A group of specimens opposed by atropine and primarily subjected to frequency variation, secondly was returned to 1 Hz. Stabilization was followed by sequential reversal by beta-blocker (timolol), alpha 1-adrenoceptor stimulation by exogenous noradrenaline, reversal by alpha 1-blocker (prazosin), and finally supramaximal beta-adrenoceptor stimulation (isoprenaline). The maximal levels of inotropic responses mediated by exogenous alpha 1- and beta-adrenoceptor stimulation was estimated. Analysis of the contraction-relaxation cycles revealed that alpha1- and beta-adrenoceptors were recruited differentially. The alpha1-adrenoceptor mediated, endogenous inotropic effect at 1 Hz was close to the level obtained by exogenous noradrenaline stimulation. In contrast, less than 70% of the beta-adrenoceptor mediated, exogenous inotropic effect was expressed by endogenous noradrenaline at the same stimulating frequency, thus indicating that the alpha1-adrenoceptors may be located closer to the adrenergic nerve terminals than the beta-adrenoceptors. There may be a heterogeneous relationship within the same heart as to the relative distance between the nerve terminals and the adrenoceptors. Spatial localization of adrenergic receptors relative to adrenergic nerve terminals adds another aspect to adrenergic regulation. The alpha1-adrenoceptor pathway may play an important role, especially in low-intensity sympathetic inotropic myocardial control, whereas the beta-adrenoceptor pathway adds important effects to the high-intensity sympathetic regulation. Sympathetic activity may thus tonically stimulate the alpha1-adrenoceptor pathway, without necessarily stimulating the beta-adrenoceptor pathway to the same extent.

[Children and adolescents with Down syndrome in Sør-Trøndelag 1978-97]. / Barn og unge med Downs syndrom i Sør-Trøndelag 1978-97.

Ultrasound examination offered to nearly all pregnant women in Norway may lead to the identification of fetuses with Down's syndrome. This may lead to termination of pregnancies and to a reduction in the prevalence of live-borns with Down's syndrome. In a retrospective study of hospital records we have examined the prevalence of Down's syndrome, associated malformations and diseases during the last 20 years. 68 children and adolescents with Down's syndrome were identified. 43 were born 1988-97 (1.16 per 1,000 births) and 25 1978-87 (0.8 per 1,000 births; p = 0.13). Congenital heart defects were diagnosed in 33 children (49%). Five children (7.4%) had died by the end of 1997, four with a cardiovascular defect. Four children had moved out of the region. Among 59 persons alive at the time of study, 11 (19%) were treated for hypothyroidism, 26 (44%) had been hospitalised because of infections, and 14 (20%) suffered from problems with sleep obstruction. 23 (39%) had impairments in hearing and 30 (51%) in vision. Ten children (18%) had a weight-for-height above the 97.5 percentile of standard growth charts for Norwegian children. Serum concentration of zink was below reference values in 15 children. We conclude that the prevalence of livebirths with Down's syndrome was not reduced in 1988-97 compared to 1978-87. Children with Down's syndrome have a wide range of somatic disorders and need close and systematic medical follow-up.

Endogenous muscarinic activity attenuates adrenergic inotropic effects in field stimulated atrial myocardium from children with congenital heart defects.

To analyse the possible influence of endogenous muscarinic activity on the inotropic effects of endogenously released noradrenaline in field stimulated myocardial preparations from atria of children with congenital heart defects, we studied the maximal effect of the muscarinic antagonist atropine (1.5 micromol L(-1)). Maximal force of contraction increased by 12.8 +/- 2.0% (SEM), while the maximal rate of development of the force increased by 16.7 +/- 2.7% (SEM). Time to half maximal developed force was 57 +/- 5 s (SEM). Time to peak force, time to relax to the 20% level and relaxation time all decreased significantly after atropine. Compared with endogenous adrenoceptor stimulation alone, the combined effects of partial muscarinic and adrenergic receptor stimulation thus were moderate reductions of the maximal force of contraction and maximal rate of development of the force and increased time to peak force, time to relax to the 20% level and relaxation time. The main effect of the endogenous muscarinic activity probably was to attenuate the effect of the beta-adrenoceptor stimulation. The endogenous muscarinic activity in field stimulated atrial preparations from children is significant, and has to be taken into account in experimental set-ups.

Comparison between alpha-1 adrenoceptor-mediated and beta adrenoceptor-mediated inotropic components elicited by norepinephrine in failing human ventricular muscle.

The purpose of our study was to investigate the inotropic response to the endogenous agonist norepinephrine mediated through alpha-1 adrenoceptors and to compare this response to that mediated through beta-adrenoceptors in failing human ventricular myocardium. We studied ex vivo the inotropic effect of norepinephrine in isometrically contracting trabecular myocardium from both ventricles of explanted hearts. By studying influence of appropriate adrenoceptor blockers, qualitative characteristics of the inotropic response and sensitivity of the inotropic response to cholinergic stimulation, it was revealed that norepinephrine evoked both alpha-1 and beta adrenoceptor-mediated inotropic effects in failing human ventricle myocardium. Quantitatively the inotropic responses to norepinephrine varied markedly between preparations, but the mean responses elicited through the respective adrenoceptor systems were of comparable magnitude. Concomitant stimulation of alpha-1 and beta adrenoceptors by norepinephrine alone revealed a contribution of an alpha-1 adrenoceptor-mediated component to the final and unopposed inotropic response. Differential sensitivity of the two adrenoceptor systems to norepinephrine depending on etiology of heart failure and possibly also thyroid status was observed. It is concluded that norepinephrine evokes an alpha-1 adrenoceptor-mediated inotropic effect comparable to that evoked through the beta adrenoceptors in failing human ventricular myocardium, and that this alpha-1 adrenoceptor-mediated inotropic effect may be of functional importance.

Endogenous norepinephrine stimulates both alpha 1- and beta-adrenoceptors in myocardium from children with congenital heart defects.

Atrial tissue removed from the cannulation site prior to cardioplegia (n = 15), and ventricular tissue therapeutically excised from the outflow tract of the right ventricle, (RVOT) (n = 2) were examined with respect to adrenoceptor mediated inotropic effect in children with congenital heart defects (CHD). We used sequential reversal by adrenoceptor antagonists of the tyramine enhanced response to endogenous norepinephrine to quantify the role of the beta- and the alpha 1-adrenoceptors, respectively, in the intropic response. Atrial myocardium had an alpha 1-adrenoceptor mediated component of 14% (median) (range 0-44%) and a beta-adrenoceptor mediated component of 86% (median) (range 56-100%). The patients with the highest alpha 1-adrenoceptor mediated inotropic components, had right ventricular pressure loads in the systemic range. In one specimen from RVOT, the ventricular alpha 1-adrenoceptor component was estimated to be 22% of the total inotropic response, compared to 26% in the corresponding right atrium. In a ventricular specimen from another patient, we could not demonstrate any alpha 1-adrenoceptor mediated inotropic component in contrast to 13% in the right atrium. This patient, however, had infusion of the alpha-adrenoceptor antagonist phentolamine after the excision of atrial tissue, but before the excision of muscular tissue from RVOT. In myocardium of children with CHD we found evidence that endogenous norepinephrine stimulated alpha 1-adrenoceptors in addition to beta-adrenoceptors. The relative contributions from the two adrenoceptors to the inotropic response varied considerably, and may be related to the pressure load of the right ventricle. These observations may be relevant with respect both to pathophysiology and to choice of drug therapy.

Computer acquisition, analysis and presentation of results from a Cobas Bio analyser.

Two computer programs for Macintosh computers have been developed in the LabVIEW programming language to perform data acquisition, analyses and presentation of results originating from a Cobas Bio analysing machine. One program is very flexible in its human interface, and is intended for research use. The program allows the results to be combined in a variety of ways, and allows the user to generate graphs to highlight the results. The other program is intended for routinely follow-up of analyses of proteases. It only allows the user to follow strict instructions, and only limited flexibility is built-in.

Functional characterization of an ex vivo preparation of atrial myocardium from children with congenital heart defects: sensitivity to tyramine and adrenoceptor antagonists.

Small pieces of atrial tissue removed from the cannulation site before cardioplegia were used to develop a method for studying adrenergic regulation of the myocardial contractile force in children operated on for congenital heart defects (CHD). We measured the development of the isometric force of contraction dT/dtmax (T'max). Reduction in basal contractility induced by the beta-adrenoceptor antagonist timolol indicated that the myocardium was about half-maximally stimulated by endogenous norepinephrine (NE), probably released from nerve endings by the electrical stimulation. The inotropic effect of endogenous NE could be further increased by tyramine (EC50 approximately 5 microM). A maximal concentration of tyramine increased T'max by a median of 62.5% above the basal level. Sequential blockade of the beta- and alpha 1-adrenoceptors after tyramine stimulation by timolol and prazosin, respectively, indicated that a near-maximal response to combined adrenoceptor stimulation by endogenous NE was mediated by both beta-adrenoceptors (median 77%) and alpha 1-adrenoceptors (median 23%). The basal level of endogenous NE may conceal inotropic effects by exogenous alpha-agonists added to this type of preparation. This preparation is suitable for studying adrenergic regulation by reversing the effects of endogenous NE.