The highly specific beta-adrenoceptor radioligand, (+/-)-[125I]iodocyanopindolol, has been used to subclassify beta-adrenoceptors in membranes from human right atrial appendage obtained during open heart surgery. Binding of (+/-)-[125I]iodocyanopindolol was saturable (Bmax = 86.4 +/- 7.4 fmol (+/-)-[125I]iodocyanopindolol bound/mg protein, n = 4), of high affinity (KD = 53 +/- 6 pM, n = 4), rapid, reversible, and stereospecific. The relative potencies of isoprenaline, adrenaline, and noradrenaline for inhibition of (+/-)-[125I]iodocyanopindolol binding and activation of adenylate cyclase were 1:10:10, indicating a population composed mainly of beta 1-adrenoceptors. Inhibition of (+/-)-[125I]iodocyanopindolol binding by beta 1- (practolol, metoprolol, betaxolol) and beta 2- (IPS 339, ICI 118,551, zinterol, procaterol) selective drugs, however, resulted in biphasic displacement curves with slope factors (nH, pseudo Hill coefficients) significantly less than 1.0. Nonlinear regression analysis of these curves revealed a beta 1: beta 2 ratio of 80:20 in human right atrial appendage. Nonselective beta-adrenergic drugs (propranolol, isoprenaline, and adrenaline), on the contrary, inhibited binding with monophasic displacement curves and nH = 1.0. Binding of agonists to the beta-adrenoceptors in human right atrial appendage seems to be regulated by guanyl nucleotides. In the absence of GTP, isoprenaline binds to high and low affinity state of the beta-adrenoceptors. GTP (10(-4) M) converts this heterogeneous binding into a homogeneous one of low affinity. It is concluded that, in human right atria, beta 1- and beta 2-adrenoceptors coexist; however, beta 1-adrenoceptors predominate. The physiological function of beta 2-adrenoceptors in human right atrium remains to be elucidated.

On the isolated electrically driven muscle strip of human right atrial appendages the beta-adrenoceptor subtypes mediating the positive inotropic effects of isoprenaline, dobutamine and procaterol were characterized using the beta 1-selective antagonist bisoprolol and the beta 2-selective antagonist ICI 118,551. The three agonists induced concentration-dependent increases in force of contraction with an order of potency: procaterol (pD2-value: 8.03) greater than isoprenaline (pD2-value: 7.73) greater than dobutamine (pD2-value: 5.44). In saturating concentrations all three agonists produced the same maximum of developed tension. ICI 118,551 (10(-9)--10(-7) mol/l) and bisoprolol (10(-9)--10(-7) mol/l) were nearly equipotent in antagonizing the positive inotropic effects of isoprenaline and dobutamine. However, the slopes of the Schild-plots for both antagonists against both agonists were significantly less than 1.0 indicating interaction with beta 1- and beta 2-adrenoceptors. On the other hand, ICI 118,551 (10(-10)--10(-8) mol/l) was approximately 100 times more potent than bisoprolol (10(-8)--10(-6) mol/l) in antagonizing the positive inotropic effect of the highly selective beta 2-agonist procaterol. In addition, the slopes of the Schild-plots for antagonism of ICI 118,551 and bisoprolol against procaterol were not significantly different from unity indicating interaction with a homogeneous class of beta-adrenoceptors. The pA2-value for ICI 118,551 was 9.49, for bisoprolol it amounted to 6.99.(ABSTRACT TRUNCATED AT 250 WORDS)

In isolated electrically driven right auricular strips of human hearts (1 Hz at 37 degrees C) the ability of the endogenous catecholamines noradrenaline, adrenaline, and dopamine to mediate positive inotropic effects by stimulation of myocardial alpha-adrenoceptors was investigated. 1. The concentration-response curve for the positive inotropic effect of noradrenaline was shifted to the right by pindolol, 10(-8)M, whereas the additional blockade by phentolamine, 3 x 10(-6)M, was without further effect; therefore, the positive inotropic effect of noradrenaline is mediated by beta-adrenoceptors only. 2. In contrast, the positive inotropic effects of adrenaline as well as of dopamine are caused by stimulation of both, beta- and alpha-adrenoceptors. 3. These results are discussed with respect to the possible physiological and pathophysiological function of myocardial alpha-adrenoceptors.

No abstract

Superfused strips of the human saphenous vein preincubated with 3H-noradrenaline were used to investigate the influences of serotonin (5-HT) receptor agonists and antagonists on the electrically evoked tritium overflow. 5-HT and the preferential 5-HT1A receptor agonist 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] concentration-dependently inhibited the evoked 3H overflow. The evoked 3H overflow was not affected by 0.1 or 1 mumol/l TVX Q 7821 (2-(4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl)-1,2-benzoisothiazol -3(2H)one-1,1-dioxide), which selectively binds to 5-HT1A sites; TVX Q 7821 10 mumol/l produced an increase in overflow. The inhibitory effect of 5-HT on the impulse-evoked 3H overflow was abolished by the nonselective 5-HT receptor antagonist metitepin, but was not attenuated by propranolol. Metitepin also abolished the inhibitory effect of 8-OH-DPAT on evoked 3H overflow, whereas the 5-HT2 receptor antagonist ketanserin was inactive in this respect. There was also no antagonism of the effect of 8-OH-DPAT by the alpha 2-adrenoceptor antagonist rauwolscine or the dopamine receptor antagonist flupenthixol. These results suggest that both 5-HT and 8-OH-DPAT inhibit noradrenaline release by activating inhibitory 5-HT receptors on the sympathetic nerves of the human saphenous vein. These receptors possess similarities to 5-HT1 recognition sites, but a further subclassification is not yet possible on the basis of the available data.

The beta-sympathomimetic effect of prenalterol was investigated on the electrically driven left atrium as well as on the tracheal chain of the guinea pig. 1. On the atrium driven at 2 Hz prenalterol caused a positive inotropic effect with a pD2-value of 7.0 +/- 0.08 (N = 4). Compared to isoprenaline (1.0) its intrinsic activity amounted to 0.3. 2. On the tracheal chain prenalterol caused very little relaxation. Its intrinsic activity was virtually negligible when compared with those of fenoterol (1.0) or noradrenaline (1.0); it amounted to 0.07 only. 3. On the atrium the positive inotropic effect of prenalterol vanished after 1 hour of incubation. At this time the concentration-response curve for isoprenaline was shifted dose-dependently to the right. The pD2-value for isoprenaline was significantly diminished (P less than 0.001) by prenalterol, 10(-6)M, from 8.36 to 7.14. 4. Likewise, on the trachea prenalterol caused a pronounced, dose-dependent shift of the concentration-response curves for fenoterol as well as for noradrenaline to the right. 5. The results presented here show that on beta-adrenoceptors of the guinea pig prenalterol is acting like a partial agonist in the left atrium, but as full antagonist in the trachea.

A case of successful operative treatment of an intramural fibroma of the left ventricular posterior wall is presented. Symptomatology, diagnosis, and a surgical procedure based on ventricular replacement using a doubled Dacron patch, fixed in "sandwich" technique, are discussed. It is possible to resect and replace large parts of the ventricular wall because of the well-developed compensatory capacity of the remaining unaffected myocardium in children.

An increase of arterial carbon dioxide (CO2) partial pressure induces an increase of cerebral blood flow by dilatation of the resistance vessels. By the Transcranial Doppler sonographic technique (TCD) blood flow velocity as a correlate of flow volume can be measured within the great basal intracranial arteries. We investigated 8 patients with an internal carotid artery occlusion or high-grade stenosis and 5 cerebrovascular diseased patients without extracranial stenosis. 12 healthy volunteers and patients without vascular disease served as the control group. Blood flow velocities in the middle cerebral arteries were evaluated before and after 5 minutes of breathing a 5% CO2 gas mixture. In a prestudy the end tidal pCO2 was monitored during this procedure. As a result of the close parallelity of pCO2 increase in the prestudy group we planned to standardize the CO2 reactivity tests without consideration of the individual pCO2 values. The CO2 inhalation provoked a flow velocity increase of at least 20% in the control subjects (47.1 +/- 17.3%). The vascular diseased without extracranial stenosis responded with 34.8 +/- 17.4% (minimum: 23.5%, n. s.). The CO2 reactivity in cases of occlusion or greater than 50% stenosis was significantly decreased (p less than 0.001) both when considering only the affected sides (12.4 +/- 7.5%, maximum: 20%) and when including the non affected sides (22.6 +/- 15.0%). It is concluded that the CO2 reactivity test is a simple and valid method to evaluate the cerebrovascular reserve capacity in any case of uncertainty about the benefits of surgical treatment of a carotid stenosis. In future this technique might become one fundamental argument beside others in selecting adequate treatment.