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On guinea-pig ileum and rabbit mesenteric artery contracted by high potassium (100 mM) histamine produced relaxations which were inhibited by the H2-receptor antagonist metiamide. These results are thus indicative for the role of H2-receptors in mediating relaxation and for H1-receptors in mediating contraction on smooth muscle. Time course studies for the relaxing and cyclic AMP responses to histamine showed that the cyclic AMP increase preceded the H2-receptor mediated relaxation. The cyclic AMP increase in response to histamine was prevented by metiamide, but remained unaffected by mepyramine on both the guinea-pig ileum and the rabbit mesenteric artery. In addition, dose-response curves obtained on the mesenteric artery demonstrated that the H2-receptor mediated depressor responses coincided with cyclic AMP increases. Thus, these results gave clear-cut evidence that cyclic AMP is an intracellular metabolic event only implicit in the H2-receptor mediated relaxation, but not in the H1-receptor mediated contraction on smooth muscle preparations.

Bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulphide (FLA-63) inhibits in vitro purified bovine adrenal medullary dopamine beta-hydroxylase (BDH) concentration-dependently; 50% inhibition is produced by 2 x 10(-6)M FLA-63. Spectrophotometric experiments show that FLA-63 is reduced by ascorbate very likely to the corresponding dithiocarbamate-derivative, which acts as a Cu++-chelator. Cu++-ions are able to completely abolish the inhibition of the DBH caused by FLA-63 in concentrations up to 2.5 x 10(-6)M. It is concluded that FLA-63 inhibits the DBH mainly in its reduced form via the formation of a chelate-complex with copper ions derived from the DBH.

Several neuroleptic drugs enhance the release and the turnover of noradrenaline in the central nervous system and in peripheral organs. The present study demonstrates the effect of long term treatment (18 days) with atypical neuroleptic drugs (clozapine, thioridazine, and sulpiride) on beta-adrenoceptor density in the cerebral cortex and in the myocardium of rats. 1. Clozapine and thioridazine significantly reduced the number of 3H-dihydroalprenolol (DHA)-binding sites by 24 and 21%, respectively, in a crude cortical membrane fraction, and by 28 and 24% in myocardial membranes. 2. Sulpiride failed to alter the maximal number of binding sites in the cortex and in the myocardium. 3. The affinity of 3H-DHA to its binding sites remained unchanged by treatment with neuroleptic drugs. 4. Desipramine, which is known to reduce cerebral beta-adrenoceptors during chronic administration, was tested as reference compound. It proved to be more effective in this regard than clozapine and thioridazine in the cortex, but failed to reduce 3H-DHA binding in the myocardium. 5. Acute treatment with desipramine, clozapine, and thioridazine had no effect on 3H-DHA binding in the cerebral cortex. The decrease in beta-adrenoceptor density after long term treatment with neuroleptics may be ascribed to an increased concentration of noradrenaline at the receptor site due to antagonism at presynaptic alpha 2-adrenoceptors and inhibition of noradrenaline reuptake.

In isolated guinea-pig left atria driven by rates of 0.5, 1,2, 3 and 4 Hz digoxin was infused continuously until cardiac arrest occurred. The experiments were performed in Tyrode solution with normal and twice the calcium content. Calculated was the toxic concentration of digoxin as that concentration which caused arrest of the preparation. In normal Ca2+-content (1.8 mM) an increase of the driving frequency decreased significantly the toxic concentration of digoxin, i.e. elevated the toxicity of this cardiac glycoside. The elevation of the Ca2+-content of the Tyrode caused a further diminution of the toxic concentrations of digoxin in dependence of the driving rate, thus demonstrating a synergism of Ca2+ and digoxin with regard to its toxicity.

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.

Thyroid hormones are known to influence the noradrenergic neurotransmission in several peripheral organs. In order to find out whether similar changes exist in the central nervous system, we investigated adrenoceptor-mediated responses in the rat brain cortex during propylthiouracil-induced hypothyroidism. In contrast to unchanged basal cAMP levels, the cAMP accumulation following (-)noradrenaline incubation (3 X 10(-6)--3 X 10(-5) M) was significantly reduced in brain slices from hypothyroid animals. The difference between controls and propylthiouracil-fed rats became more pronounced when (-) isoprenaline (3 X 10(-6)--3 X 10(-5) M) was used for selective stimulation of beta-adrenoceptors. Since the cAMP increase mediated via alpha-adrenoceptors was not affected, it may be concluded that thyroid hormone deficiency only impairs the beta-adrenergic transmission. Phosphodiesterase activity remained unaltered suggesting that thyroid hormones influence the beta-adrenoceptors or the adenylate cyclase coupled to it. The sensitivity of presynaptic alpha-adrenoceptors modulating the release of noradrenaline was evaluated using occipital cortical slices preincubated in 3H-noradrenaline. Clonidine inhibited whereas phentolamine enhanced the 3H-overflow induced by electrical stimulation in a dose-dependent manner. No differences could be detected between control- and propylthiouracil-treated animals. Thus presynaptic alpha-adrenoceptors are not affected by hypothyroidism.

A sensitive radioenzymatic procedure for the simultaneous determination of dihydroxymandelic acid, dihydroxyphenylglycol, and dihydroxyphenylacetic acid has been developed. The catechols were methylated by catechol-O-methyltransferase using S-adenosyl[methyl-3H]methionine as methyl donor. The assay involved extraction into organic solvent, thin-layer chromatography and periodate oxidation. The applicability of the procedure was tested by measuring the amounts of deaminated metabolites of noradrenaline, adrenaline and dopamine in heart perfusion samples and plasma of rabbits.

Isolated left guinea-pig atria were used to examine the influence of D 600 and papaverine on baseline contractile function and inotropic response to isoprenaline, under variable conditions of temperature (27 degrees to 42 degrees C) and rate of beat (0.125 to 4 Hz). The inotropic stimuli, caused by increasing the frequency of stimulation and decreasing the temperature, could not overcome the depressive action of D 600 on basal systolic tension. In addition the inotropic effects evoked by papaverine at low rates of beat and high temperatures were converted into cardiodepressive effects at high stimulation rates and low temperatures. The inotropic response to isoprenaline appeared to be by far more resistant to the depressive actions of D 600 and papaverine than the baseline contractile function. Only at a stimulation frequency of 2 Hz, high concentrations of D 600 (3 X 10(-7)M) and papaverine(3 X 10(-5)M) reduced the response caused by isoprenaline. At a stimulation frequency of 0.5 Hz, however, D 600 left the inotropic responses to isoprenaline unchanged, whereas papaverine potentiated these responses. It appears from the present results that the frequency of stimulation and the temperature greatly modify the cardiodepressive actions evoked by D 600 and papaverine.

Experiments were carried out on the isolated rabbit papillary muscle driven at 0.5 Hz in order to further elucidate the mechanism of the positive inotropic effect evoked by dopamine. The dose-response curve for dopamine was not affected by the antagonists pimozide (10(-6) M), yohimbine (10(-5) M) pindolol (3 x 10(-8) M) and phentolamine (10(-6) M) when these agents were given separately. Only the simultaneous administration of yohimbine plus pindolol and phentolamine plus pindolol, respectively, shifted the entire curve to the right. This shift was not further influenced by pimozide. Dopamine (10(-4) M) increased the cyclic AMP content of the papillary muscle by about 50%; this increase was not affected by pimozide, but was markedly elevated by yohimbine and completely depressed by pindolol. From the present results it is concluded, that dopamine produces its positive inotropic effect through stimulation of myocardial alpha-as well as beta-adrenoceptors to about the same degree; stimulation of specific dopaminergic receptors, however, is not involved. The stimulation of beta-adrenoceptors is accompanied by an increase of the cyclic AMP level, while that of alpha-adrenoceptors is not.

The influence of thyroid hormones on the concentration and properties of alpha 1-adrenoceptors in a crude membrane fraction obtained from the rat cerebral cortex was investigated using the [3H]-WB 4101 binding assay. Animals were made hypothyroid by feeding 6-propyl-2-thiouracil for 8 weeks. Hyperthyroidism was induced by triiodothyronine injections (50 microgram/100 g body weight) for 9 days. 1. The binding of [3H]-WB 4101 was saturable and of high affinity in controls as well as in hyper- and hypothyroid animals. The maximal number of binding sites (Bmax), which amounted to 95 fmol/mg protein in control animals, was increased by 27% in cortical membranes from hyperthyroid rats and reduced by 23% in the hypothyroid group. 2. The reduction in [3H]-WB 4101 binding due to 6-propyl-2-thiouracil feeding was reversible by triiodothyronine treatment. 3. Dissociation constants (KD) calculated from saturation experiments (0.25 nM) or kinetic data (0.21 nM) remained unchanged in altered thyroid states. 4. Inhibition of [3H]-WB 4101 binding by adrenergic agonists and antagonists revealed no differences between euthyroid and hypothyroid animals. The higher affinity of prazosin to the binding sites compared with yohimbine indicated that [3H]-WB 4101 predominantly labeled alpha 1-adrenoceptors. It is concluded that thyroid hormones regulate the number of alpha 1-adrenoceptors in membranes of the rat cerebral cortex, leaving their affinities unchanged.

In isolated, electrically driven right auricular strips of the human heart the inotropic effect of phenylephrine was studied. 1. First, the influence of the driving rate on the tension developed (i.e., the frequency-force relationship) was determined by stimulation of the preparations at 0.1, 0.5, 1, 2 and 3 HZ. The force of contraction was lowest at a stimulation rate of 0.1 HZ (36.9 g/g dry weight). The maximally developed force of contraction observed at frequencies of 0.5, 1 and 2 HZ amounted to about 200 g/g dry weight. The values did not significantly differ from each other. 2. The negative log of the EC50 (-log EC50) for the positive inotropic effect of phenylephrine determined at a frequency of 0.5 and 1.0 HZ amounted to 5.28 +/- 0.08 and 5.34 +/- 0.11, respectively. The alpha-adrenolytic drug phentolamine (3 x 10(-6) M) diminished significantly the -log EC50 to 5.01 +/- 0.04 and 4.89 +/- 0.10, respectively. 3. At a frequency of 1 HZ a shift of the concentration-response curve to the right was observed after treatment with the beta-adrenolytic drug pindolol (3 x 10(-8) M); the -log EC50 of phenylephrine decreased significantly to 4.08 +/- 0.07. 4. From these results it is concluded that alpha-adrenoceptors are present in human atria; they mediate positive inotropic effects and are stimulated by phenylephrine.

The effects of dopamine on the force of contraction and on cylic adenosine monophosphate (AMP) levels were investigated in isolated electrically driven left atria (32 degrees C, 1 Hz) and papillary muscles (37 degrees C, 0.5 Hz) of the rabbit. In both preparations only the combined application of phentolamine (10(-6) M) and pindolol (3 X 10(-8) M) shifted the entire dose-response curves for the positive inotropic effect of dopamine to the right, while either antagonist used separately had no effect. Similar results were obtained when the indirect action of dopamine via the release of endogenous noradrenaline was inhibited by cocaine (3 X 10(-5) M) or by pretreatment of the rabbits with reserpine (6 mg/kg, s.c., 16 hr). Increases in cyclic AMP induced by dopamine (10(-4) M in atria and 3 X 10(-4) M in papillary muscles) were prevented by cocaine or by pretreatment with reserpine, indicating that these increases are mainly evoked by released endogenous noradrenaline. It is concluded that both alpha- and beta- adrenoceptors may play roles in the direct positive inotropic action of dopamine in the rabbit heart. The failure of the direct action of dopamine to increase cyclic AMP may be due to a cyclic-AMP-decreasing effect of alpha-adrenoceptor stimulation, which may counteract cyclic AMP increases induced by dopamine via beta-adrenoceptor stimulation.

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 radioenzymatic assay for determination of normetanephrine in blood plasma is described. It was based on N-methylation of normetanephrine by phenylethanolamine-N-methyltransferase using S-adenosyl[methyl-3]methionine as the methyl donor. 2981 +/- 85 cpm (mean +/- s mean, n = 32) were obtained from 1 ng normetanephrine. Blank values corresponded to 27 +/- 3 pg (n = 7). Normetanephrine levels measured in the blood plasma of 12 persons ranged from 1.3 to 9.6 ng/ml.

Right and left guinea-pig atria responded to decreasing temperatures (42-27 degrees C) with elevation for force of contraction and concomitant increases in cAMP. When atria were rapidly cooled from 42 to 27 degrees C the increase in cAMP occurred prior to the onset of the inotropic responses. Papaverine (3 X 10(-5) M) potentiated the effects of temperature on cAMP and force of contraction on left atria driven at 0.5 Hz. On right atria beating spontaneously at frequencies above 2 Hz papaverine only potentiated the effect of decreasing temperatures on the response of cAMP but not on that of force of contraction. Time course studies of the effects of isoprenaline (3 X 10(-8) M) on right atria at 27 degrees C showed large inotropic responses to isoprenaline which were accompanied by increases in cAMP. At 42 degrees C the responses of force of contraction and cAMP to isoprenaline occurred faster and were only short-lasting. As with the time courses for isoprenaline, dose-response curves for the effect of isoprenaline and papaverine on cAMP content and force of contraction also appeared to be shifted towards higher levels at hypothemia. However, pD2 values reflected increases in affinity for inotropic, but not for the cAMP responses to isoprenaline and papaverine at hypothermia. These results show that cyclic AMP is involved in the inotropic responses to hypothermia, but not in the supersensitivity of heart to isoprenaline and papaverine as observed at low temperatures.

In the isolated papillary muscle of the rabbit the time course of the effects of selective beta- and alpha-adrenoceptor stimulation by isoprenaline and methoxamine, respectively, on the contractile force and on the level of 3',5'-cyclic AMP (cAMP) was determined. 1. Isoprenaline (3 times 10(-7) M) increased significantly the content of cAMP at 15 sec and elevated it to the maximal level-about twice the control value-at 30 sec after its administration, while the developed tension of the papillary muscle was also increased significantly at 15 sec and reached gradually its maximum at 90 sec. 2. Compared with isoprenaline methoxamine (10(-4) M) increased the developed tension very slowly: the maximal response was reached after 20 min. The level of cAMP, on the other hand, was changed neither before nor during the induction of the positive inotropic effect of methoxamine. 3. The phosphodiesterase inhibitor papaverine (10(-5) M) inhibited the PDE activity of the papillary muscle by about 40% after an incubation of 1 hr, and increased the level of cAMP significantly. The effects of isoprenaline on the contractile forced and on the level of cAMP were considerably enhanced by papaverine: the content of cAMP was increased by isoprenaline (3 times 10(-7) M) to about 3 times the control value and also its positive inotropic effect was significantly greater than in controls without papaverine. On the other hand, the positive inotropic effect of methoxamine (10(-4) M) was not affected by papaverine (10(-5) M). Furthermore, in the papillary muscle treated with papaverine the level of cAMP was significantly reduced by methoxamine: the papaverine-induced increase of cAMP was abolished by methoxamine. 4. The present results are compatible with the hypothesis that cAMP is involved as a mediator in the positive inotropic effect induced by beta-adrenoceptor stimulation, and indicate further that the stimulation of alpha-adrenoceptors evokes its positive inotropic effec through a mechanism other than that elicited by beta-adrenoceptor stimulation, i.e., independent of cAMP.

The influence of thyroid hormone deficiency on beta-adrenoceptors in the rat cerebral cortex was investigated using the 3H-dihydroalprenolol binding assay. The maximal number of binding sites (Bmax) and the dissociation constants (KD) were determined in the brain tissue from euthyroid animals and from rats made hypothyroid by feeding 6-propyl-2-thiouracil. Hypothyroidism resulted in a 37% decrease in beta-adrenoceptor density (Bmax). The dissociation constants (KD) of both groups were not significantly different.

In guinea-pig aorta phenylephrine and noradrenaline induced concentration-dependent contractions when beta-adrenoceptors were blocked. The contractile response to phenylephrine was amplified by previous application of subthreshold concentrations of 5-hydroxytryptamine, ouabain, B-HT 920, Bay K 8644, phorbol-12-myristate-13-acetate and arachidonic acid. Bay K 8644 also enhanced the contractile response to noradrenaline. The amplification was not substantially altered by removing the endothelium of the aorta. The increase in cytosolic calcium availability induced by the vasoconstrictor agents investigated may be responsible for the enhancement of the alpha 1-adrenoceptor-mediated contractions.

In rabbit left atrium and ileum as well as in guinea-pig tracheal chain preparations dose-response curves for isoprenaline, adrenaline, noradrenaline and fenoterol have been determined. In order to assess the coexistence of beta 1- and beta 2-adrenoceptor subtypes in these tissues the antagonism of the relative selective adrenolytic drugs metoprolol (beta 1-) and H35/25 (beta 2-) against these sympathomimetic agents was tested. The determination of the pD2-values for the agonists showed a relative high affinity of fenoterol and adrenaline to tracheal beta-adrenoceptors whilst noradrenaline was most affine to atrial beta-adrenoceptors. In all three organs isoprenaline showed the highest affinity. On rabbit atrium driven by 1 Hz both beta-adrenolytic drugs competitively inhibited the effects of all sympathomimetic agents. The pA2-values characterizing the antagonism between metoprolol and isoprenaline, adrenaline or noradrenaline were comparable. Those determined for the interaction of H35/25 with these agonists also were in the same range but lower than those for metoprolol. Both adrenolytic drugs showed higher pA2-values to fenoterol. Furthermore for classification of beta-adrenoceptor binding sites the method of Paton and Rang (1965) was applied. The dose-ratio of isoprenaline after combination of metoprolol and H35/25 was multiplicative thus confirming the existence of different binding sites in the atrium. On rabbit ileum pA2-values for both antagonists could only be determined when isoprenaline was the agonist. The effect of the endogenous catecholamines, adrenaline and noradrenaline, was only blocked by metoprolol. On the other hand, fenoterol could not be blocked by either antagonist alone, but only by the combination of both adrenolytic drugs indicating a comparable affinity of fenoterol to both binding sites.--The Schild-plot for the antagonism of propranolol versus noradrenaline or fenoterol supports the view of the existence of different types of adrenoceptors stimulated by either agonist. On the guinea-pig tracheal chain both adrenolytic drugs inhibited competitively the effects of the sympathomimetic agonists. The pA2-values for H35/25 where the highest when compared with those of atrium or ileum. Using the combination of metoprolol and H35/25 the resulting dose-ratio for adrenaline was multiplicative demonstrating again the presence of two binding sites. The present results indicate the coexistence of beta 1- and beta 2-adrenoceptor subtypes on the organs investigated. This conclusion has been reached by the use of at least two methods in parallel, namely the determination of the pA2-values for selective antagonists to selective agonists and that for a nonselective antagonist to selective agonists and furthermore, the calculation of the dose-ratio of agonists after the combined administration of two selective antagonists.

On guinea-pig heart we investigated whether cyclic AMP serves as a messenger for H1 - and/or H2-mediated responses to histamine. (1) On papillary muscle histamine elicited positive inotropic responses which were antagonized by burimamide but not by promethazine. The stimulation of H2-receptors was not only associated with an increase in contractility but also with an increase in cAMP. As shown by the time course of effects for 10(-5) M histamine, the maximal increase in cAMP preceded the maximum in contractility. The mechanical and biochemical responses to histamine were potentiated by the phosphodiesterase inhibitor papaverine, but antagonized by burimamide. (2) On the left guinea-pig atrium containing H1-receptors the inotropic response to histamine (10(-5) M) was not accompanied by increases in cAMP at stimulation frequencies of 0.5 and 2 Hz, respectively. In addition, in the presence of papaverine (3 X 10 (-5) M) no change in the cyclic AMP level occurred after application of histamine. Papaverine by itself, however, concomitantly increased contractility and cyclic AMP at a stimulation frequency of 0.5 Hz. In contrast, at 2 Hz papaverine increased only cAMP leaving the contractility unchanged. At this frequency the well-known Ca2+-antagonistic effect comes into prominence, thus masking the positive inotropic effect attributable to the inhibition of the phosphodiesterase. (3) On the right guinea-pig atrium the mediation of the positive chronotropic response to histamine by H2-receptors which is partly involved in the inotropic effect via the frequency-force relationship does not lead to a concomitant increase in cAMP. Also, in the presence of papaverine, histamine had no influence on the cAMP. However, papaverine potentiated the cardioacceleration produced by histamine. Although it is very likely that the cAMP in the sinus node rises, we were not able to detect an increase in cAMP in the whole atrial tissue. From the present results the conclusion can be drawn that the mediation of the inotropic effect due to stimulation of H2-receptors by histamine is associated with an increase of cyclic AMP, whereas that of H1-receptors is not. The view that cAMP may be the second messenger in the chronotropic action of histamine needs further elucidation by experiments on sino-atrial cells.

On the isolated rabbit papillary muscle experiments were carried out to determine whether the positive inotropic effects mediated by alpha- and by beta- adrenoceptors are brought about by different mechanisms or not.--For this reason the influence of temperature and the effect of the calcium antagonist D600 on the responses to phenylephrine and to isoprenaline were compared. 1. The maximal inotropic effects of phenylephrine, isoprenaline and calcium were not affected by raising the temperature of the organ bath from 37 degrees to 42 degrees C, wheras the basal developed tension of the muscle was significantly decreased. 2. The dose-response curve for phenylephrine was markedly shifted to the right by raising the temperature (pD2=0.89), while that for isoprenaline was also shifted to the right, but to a lesser extent (pD2=0.23). 3. In the presence of 1.5 times 10-8 M pindolol the shift of the dose-response curve for phenylephrine induced by elevation of temperature was more prominent (pD2=1,91), whereas phentolamine (3 times 10-6 M) inhibited the temperature-induced shift. 4. The positive inotropic effect of phenylephrine--mediated by alpha-adrenoceptors under blockade of beta-adrenoceptors by 1.5 times 10-8 M pindolol--was markedly depressed by D600 (10-7 and 3 times 10-7 M): the dose-response curve was shifted to the right ant the maximal response was depressed. On the other hand, the positive inotropic effect of isoprenaline--mediated by beta-adrenoceptors--was affected to a lesser extent by D600 and the maximal response was not changed. It indicates that the stimulation of alpha- adrenoceptors in the rabbit papillary muscle induces a positive inotropic response through a biochemical process different from that caused via beta- adrenoceptors, i. e., stimulation of alpha- adrenoceptors may increase the intracellular calcium level mainly by changing the transmembrane calcium flux.

On guinea-pig atria part of the inotropic response to histamine is attributable to a concomitant increase of the frequency [7]. Since the chronotropic effect of histamine is mediated by a stimulation of H2-receptors a direct interaction of histamine with H1-receptors a direct interaction of histamine with H1-receptors mediating the inotropic response on heart may be overlooked. For this reason the ability of the H1-antagonist promethazine and the H2-antagonist burimamide to inhibit the positive chronotropic, inotropic and coronary vascular responses to histamine was determined in spontaneously beating and electrically driven perfused guinea-pig hearts. (1) Burimamide produced a competitive blockade of the positive chrono- and inotropic responses to histamine. (2) On the other hand, promethazine in concentrations that had no effect on cardiac function by itself, proved to be ineffective against the positive chrono- and inotropic responses produced by histamine on spontaneously beating and electrically driven heart preparations. (3) The predominant coronary vasodilation observed after infusion with histamine was competitively antagonized by promethazine and burimamide. This blockade was not attributable to an interaction with myocardial H2-receptors mediating increases in heart rate and contractility and was, therefore, direct in nature. (4) Based upon the present study and former investigations [7] the following distribution of different histamine receptors in the guinea-pig heart does exist: H1-receptors are present in the atrial muscle and the coronary vascular bed. H2-receptors are located in the sinus node, the ventricular myocardium and the coronary vessels.

The influence of removing the endothelial cells on the alpha-receptor-mediated contractile response in segments of rat aorta was investigated using agonists with a range of affinity for alpha 1- and alpha 2-receptors. The preferential alpha 1-agonists were methoxamine, cirazoline, ST 587, and Sgd 101/75 and the preferential alpha 2-agonists were B-HT 920, clonidine, and guanfacine. When the endothelium was intact, the intrinsic activity (compared to noradrenaline) varied widely (0.0-0.7) for both groups of agonists. After removal of the endothelium the intrinsic activity was increased in each case to that of noradrenaline, or close to it. Furthermore, an increase in potency was obtained for each agonist, although to different degrees. No correlation, however, was found between the selectivity of the agonists and the degree of enhancement caused by the removal of the endothelium, in terms of either the intrinsic activity or the potency. Moreover, the use of the selective alpha 2-receptor antagonist rauwolscine on intact tissues did not mimic the effect of removing the endothelium. Therefore, the alpha-receptors of the endothelium could not be classified as either of the alpha 1- or alpha 2-subtype.