Interactions of angiotensin and cocaine on the output of noradrenaline from isolated rabbit hearts

Summary The output of noradrenaline from isolated rabbit hearts during sympathetic nerve stimulation is increased by angiotensin (1.3 ng/ml) to 176% of the preceding control stimulation period. During inhibition of noradrenaline re-uptake by cocaine (5 or 15 g/ml), the augmentation caused by the peptide is unchanged (181 and 171%, respectively). The result favours the assumption that angiotensin enhances the output of noradrenaline by an increase of the amount of transmitter liberated from the nerve terminals rather than by interfering with transmitter inactivation.     

Influence of drugs with affinity for α-adrenoceptors on noradrenaline release by potassium,tyramine and dimethylphenylpiperazinium

The influence of oxymetazoline and phentolamine on the overflow of noradrenaline evoked by potassium, tyramine and dimethylphenylpiperazinium (DMPP) was investigated in isolated perfused rabbit hearts.Oxymetazoline decreased, and phentolamine increased, the outflow of noradrenaline evoked by potassium. In hearts previously perfused with (?)-³H-noradrenaline, oxymetazoline reduced, and phentolamine enhanced, potassium-induced overflow of both ³H-noradrenaline and total tritium. These actions closely resemble previously described effects on noradrenaline overflow evoked by electrical stimulation of sympathetic nerves. At concentrations which modified the response to potassium, oxymetazoline and phentolamine did not influence the overflow evoked by tyramine. Both drugs diminished DMPP-induced overflow.It is concluded that oxymetazoline depresse noradrenaline release evoked by potassium or orthodromic action potentials through activation of neuronal α-adrenoceptors, followed by inhibition of electro-secretory coupling. Phentolamine blocks the analogous inhibitory effect of liberated noradrenaline and thus enhances release. The action of tyramine does not involve electro-secretory coupling and therefore is not changed. The influence of oxymetazoline and phentolamine on noradrenaline release by DMPP is not related to α-adrenoceptors.     

The effect of methacholine on noradrenaline release from the rabbit heart perfused with indometacin

Summary The experiments were undertaken in order to study the effect of inhibition of prostaglandin synthesis on the muscarinic inhibition of noradrenaline release evoked by sympathetic nerve stimulation. The right sympathetic nerves of the perfused rabbit heart were stimulated electrically. The noradrenaline output was enhanced after perfusion of the hearts with indometacin 3×10^–5 M indicating blockade of the prostaglandin-mediated negative feedback control. Both in the presence and in the absence of indometacin methacholine 4×10^–5 M decreased the noradrenaline output by a similar percentage. It is concluded that the muscarinic inhibition of noradrenaline release does not require the functional integrity of the prostaglandin-mediated feedback system.     

Differential effects of hypothermia on neuronal efflux,release and uptake of noradrenaline

Summary Isolated rabbit hearts were perfused at 34° (control), 24° or 12°C. The neuronal efflux of noradrenaline after perfusion with the amine for 1 h was depressed at 24° C (Q ₁₀ about 5) in the presence or absence of desipramine; at 12°C the efflux was below the limit of estimation. Moderate reduction of the temperature (24° C) decreased the removal of perfused noradrenaline to about 60% of the control value and caused a 1.7-fold increase of the output of noradrenaline evoked by sympathetic nerve stimulation. It is concluded that the extremely temperature-dependent efflux of noradrenaline across the axonal membrane is not part of the release of noradrenaline evoked by nerve stimulation.     

The effects of acute administration of propranolol and practolol on the uptake,content, release,and turnover of noradrenaline in the rat heart in vivo

Summary The effect of the acute administration of (±)-, (+)-, and (–)-propranolol and practolol, respectively, on the cardiac turnover of noradrenaline was studied in male Wistar rats kept under controlled conditions of environmental lighting. Propranolol caused no or only minor effects on the turnover in concentrations of 0.001–0.1 mmoles/kg, whereas higher doses (0.2–0.4 mmoles/kg) decreased the noradrenaline turnover in rat hearts concomitantly with toxic signs from the CNS. The endogenous noradrenaline content was not changed by any concentration of propranolol. Practolol (0.1–0.4 mmoles/kg) did not influence the cardiac noradrenaline turnover, but, like an indirectly acting sympathomimetic drug, released noradrenaline.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

ACTH increases noradrenaline release in the rabbit heart

Summary The effects of ACTH on the release of noradrenaline and the increase of heart rate produced by sympathetic nerve stimulation (1 Hz) were studied in isolated perfused rabbit hearts. ACTH-(1–24) 0.1–100 nmol/l increased the stimulation-evoked overflow of noradrenaline concentration-dependently, reversibly and up to two-fold. The basal outflow of noradrenaline, the basal heart rate and the stimulation-evoked increase in heart rate were not changed. Human ACTH-(1–39) also increased the evoked overflow of noradrenaline. The effect of ACTH-(1–24) 0.3 nmol/l persisted after blockade of -adrenoceptors with propranolol and blockade of neuronal catecholamine uptake by cocaine. ACTH-(1–24) 3 nmol/l did not change the removal of noradrenaline from the perfusion fluid, when hearts were perfused with medium containing 59 nmol/l noradrenaline. The results show that ACTH increases the action potential-evoked release of noradrenaline from cardiac postganglionic sympathetic neurones, probably by activating specific presynaptic ACTH receptors. The high potency of ACTH suggests that these presynaptic receptors may be activated in vivo by circulating ACTH under certain pathophysiological conditions.Send offprint requests to B. Szabo at the above address     

Central action of phentolamine administered intraventricularly in the rat

Phentolamine injected intraventricularly in unanaesthetized rats decreased their locomotor activity and antagonized the excitatory effect of intraventricularly injected noradrenaline, or amphetamine injected s.c. Phentolamine did not influence the level of noradrenaline and 5-hydroxytryptamine in the rat brain. The mechanism of observed action of phentolamine is discussed.     

Effects of 4-aminopyridine on mechanical activity and noradrenaline release in the rat portal vein in vitro.

4-Aminopyridine (4-AP) increased the spontaneous mechanical activity of the isolated rat portal vein. Since denervation and adrenergic receptor blockade failed to prevent this effect of 4-AP it is suggested that the drug enhances the electrical excitability of the muscle membrane. 4-AP significantly increased the response of the muscle to electrical nerve stimulation in most experiments but had little effect on the response to applied noradrenaline (NA). Both spontaneous and evoked release of 3H-activity, following preincubation in 3H-noradrenaline, were increased in the presence of 4-AP (10(-3) M). The present results with 4-AP can be explained by its known ability to block the transient potassium conductance which accompanies the action potential in excitable tissues.     

Time-dependent changes in neuronal net uptake of noradrenaline after pretreatment with pargyline and/or reserpine

Summary Isolated rabbit hearts were perfused with 20 to 200 ng/ml of (–)-noradrenaline and arterio-venous differences were determined at various times to measure the rate of net removal of the amine from the perfusion fluid. Animals were untreated or pretreated with reserpine and/or pargyline to block vesicular retention and/or intraneuronal monoamine oxidase (MAO).The arterio-venous difference (in percent of the arterial concentration) remained rather constant during prolonged perfusions of untreated hearts with (–)-noradrenaline, the magnitude of the difference being inversely related to the arterial concentration. After block of MAO the rate of net removal declined exponentially with time; the rate of decline increased with increasing arterial concentration of the amine and also after the additional pretreatment with reserpine. The time-dependent decline in the rate of net removal was shown to be due to an increased efflux of the amine from the nerve endings. The net removal of noradrenaline-H³ at the 5th min of perfusion of pargyline-pretreated hearts was mainly due to neuronal net uptake, since a) O-methylation accounted for only 5% of the removal, and b) cocaine (10–30 (g/ml) virtually abolished net removal.Initial rates of removal were not affected by the various pretreatments.In untreated hearts retention of exogenous (–)-noradrenaline increased linearly with the duration of the perfusion but the increase was exponential after block of MAO. Apparently, the storage capacity becomes exhausted during prolonged perfusions of pargyline-pretreated hearts.The ratio noradrenaline retained by the heart/noradrenaline removed by the heart was quite small in untreated (0.16), very small in reserpine-pretreated (0.03) and nearly unity in pargyline-pretreated hearts.It is concluded that any impairment of the intraneuronal mechanisms of inactivation (vesicular storage and MAO) leads to an increase in the axoplasmic concentration of free noradrenaline which causes an increased efflux of the amine, while the influx remains unchanged. The axoplasmic concentration of free noradrenaline seems to rise more after block of MAO than after pretreatment with reserpine and is most pronounced after both. Changes in the sensitivity of the pacemaker to (–)-noradrenaline were found to be correlated with changes in the rate of removal of the amine from the perfusion fluid.Part of this study was supported by the Deutsche Forschungsgemeinschaft.