Cardiac Sympathetic Nerve Endings Research Articles

Effects of ouabain on in situ cardiac sympathetic nerve endings

Using dialysis technique, the effects of ouabain on in situ cardiac sympathetic nerve endings were examined in anesthetized cats. Dialysis probes were implanted in the left ventricular myocardium, and the concentration of dialysate norepinephrine (NE) was used as an indicator of NE output at the cardiac sympathetic nerve ending. Locally applied ouabain dose-dependently (1, 10, 100 μM) increased dialysate NE levels. This finding suggested that ouabain causes an increase in NE efflux without any requirement for prior mobilization of NE from vesicular stores. Transection of sympathetic nerves innervating the heart, was without effect on the ouabain (100 μM)-induced increase in NE efflux. Pretreatment with a Ca 2+-channel blocker, ω-conotoxin GVIA (10 μg/kg iv) suppressed the ouabain-induced NE efflux. These data suggested that ouabain opened N-type calcium channels coupled to NE release without centrally mediated neural transmission. Furthermore, ouabain-induced NE efflux was suppressed by pretreatment with desipramine (neuronal NE uptake inhibitor, 100 μM). Our data suggest that the two mechanisms (exocytosis and carrier-mediated outward transport), to the same extent, contributed to the amount of NE efflux evoked by ouabain in in situ cardiac sympathetic nerve endings.

Cardiac sympathetic activity as measured by myocardial 123-I-metaiodobenzylguanidine uptake and heart rate variability in idiopathic dilated cardiomyopathy

In patients with idiopathic dilated cardiomyopathy (IDC) the increased sympathetic activity owing to chronic congestive heart failure leads to an imbalance of cardiac autonomic tone, as reflected by decreased heart rate variability (HRV). Iodine-123-metaiodobenzylguanidine (123-I-MIBG), which has the same affinity for sympathetic nerve endings as norepinephrine, can be used to assess the integrity and function of the cardiac sympathetic nervous system. The aim of the present study was to measure cardiac sympathetic activity by assessing 123-I-MIBG uptake compared with HRV in patients with IDC. In 12 patients with IDC and mild to moderate heart failure, myocardial MIBG uptake was calculated from the myocardial (M) to left ventricular cavity (C) voxel values density ratio and the 123-I activity in a blood sample as a reference (= M/C ratio) using a double radionuclide study with 123-I-MIBG and technetium-99m-MIBI. To investigate the relation between myocardial MIBG uptake and HRV in time domain, the linear regression between the M/C ratio, a new scintigraphic parameter, and the mean RR interval or the HRV triangular index, respectively, was determined. A significant correlation between the M/C ratio and mean RR interval (r = 0.52; p = 0.016) or M/C ratio and HRV triangular index (r = 0.76; p = 0.003), respectively, was found. Thus, the significant correlation between the M/C ratio and HRV indicate that they are both suitable noninvasive methods for evaluating cardiac sympathetic activity in patients with IDC and, furthermore, favor the view that there is evidence of a relation between HRV and the disorder of the cardiac presynaptic sympathetic nerve endings as demonstrated by a reduced M/C ratio.

Activation by Phoneutria nigriventer spider venom of autonomic nerve fibers in the isolated rat heart

In the isolated rat heart, Phoneutria nigriventer spider venom (10–100 μg) produced a dose-dependent and reversible rise in left ventricular developed pressure. A low dose (10 μg) of venom induced a short-lasting, positive inotropic effect ( P<0.05) with no change in heart rate or coronary flow. At a dose of 50 μg, the venom caused significant positive inotropic and chronotropic responses associated with occasional ventricular arrhythmia, whereas coronary flow was not significantly affected within 10 min after venom administration. The highest dose of venom (100 μg) caused bradycardia, transient cardiac arrest, rhythm disturbances and an increase in end diastolic pressure followed by a reduction in coronary flow. Hearts treated with the non-selective β-adrenoceptor antagonist propranolol (3 μM) and the selective β 1-adrenoceptor antagonist CGP-20712A (10 μM) were protected against all the cardiac actions of the venom. The selective β 2-adrenoceptor antagonist butoxamine (10 μM) slightly reduced the cardiac response to 50 μg, but not to 100 μg of venom. Butoxamine also prevented the reduction in coronary flow induced by 100 μg of venom. Hearts from reserpine-treated rats (5 mg kg −1 day −1, i.p., for 2 days) showed a marked decrease in all venom (≤100 μg)-induced cardiac responses. The muscarinic receptor antagonist atropine (1 μM) slightly potentiated the response to 50 μg of venom but had little or no effect on the responses to 100 μg of venom. The cardiac responses to venom (50–100 μg) were unaltered in hearts from rats treated with 8-methyl N-vanillyl-6-nonenamide (capsaicin; 50 mg/kg, s.c.). These findings indicate that P. nigriventer venom releases norepinephrine from cardiac sympathetic nerve endings and this may explain the observed increase in contractile force and heart rate.

Norepinephrine efflux evoked by potassium chloride in cat sympathetic nerves: dual mechanism of action

Using a dialysis technique, prominent efflux of norepinephrine (NE) from cardiac sympathetic nerve endings was observed under local administration of potassium chloride (KCl, 100 mM). KCl induced NE efflux was suppressed by ω-conotoxin GVIA or desipramine but residual efflux of NE was still detectable. In the presence of ω-conotoxin GVIA, KCl induced efflux of NE was augmented by pretreatment with reserpine, indicating that this efflux of NE was derived from axoplasma with neurotransporter. These data suggest that a KCl induced brisk increase in dialysate NE levels might occur as a consequence of exocytotic NE release and carrier mediated outward NE transport from nerve endings.

Effects of ω-conotoxin GVIA on cardiac sympathetic nerve function

Using a cardiac dialysis technique, the effects of ω-conotoxin GVIA ( N-type Ca 2+ channel blocker) on cardiac sympathetic nerve function was examined in anesthetized cats. Dialysis probes were implanted in the left ventricular wall and the concentration of dialysate norepinephrine (NE) served as an indicator of NE output at cardiac sympathetic nerve endings. Administration of ω-conotoxin GVIA (10 μg/kg i.v.) suppressed dialysate NE responses to the nerve stimulation. The ouabain (1 μM) induced NE increment was less markedly suppressed by ω-conotoxin GVIA. Furthermore, ω-conotoxin GVIA neither influenced neuronal NE uptake nor tyramine induced release of NE from stores. These findings suggest that the neuronal effect of ω-conotoxin GVIA is attributable to a reduction of exocytotic NE release without alterations of neuronal NE uptake or storage. Cardiac dialysis with ω-conotoxin GVIA offers a new approach for the discrimination between Ca 2+ dependent exocytotic and non-exocytotic NE release.

Hydroxyl radical production during myocardial ischemia and reperfusion in cats.

We previously showed that generation of reactive oxygen species during myocardial ischemia and reperfusion stimulates cardiac sympathetic afferent nerve endings. We hypothesized that, in this feline model of brief ischemia and reperfusion, HO. is produced during ischemia and the rate and concentration of production of HO.during reperfusion is dependent on the duration of myocardial ischemia. Therefore, we evaluated the time dependency of production of HO. during reperfusion after 2, 5, and 10 min of reversible occlusion of the left anterior descending (LAD) coronary artery to induce ischemia in cats (n = 10). Blood samples collected from the coronary vein at 0.25, 1, 2, and 4 min after 2 min of ischemia revealed net cumulative rate of production of p-, m-, and o-tyrosine of 99 +/- 31, 10 +/- 5.1, and 0.8 +/- 0.2 nmol.min-1.g-1, respectively. After 5 min of ischemia, net cumulative rates of production of p-, m-, and o-tyrosine during reperfusion were 177 +/- 63, 74 +/- 26, and 1.6 +/- 0.8 nmol.min-1.g-1, respectively, whereas after 10 min of ischemia production rates were 153 +/- 42, 78 +/- 29, and 2.1 +/- 0.5 nmol.min-1.g-1, respectively. The highest rate of production of tyrosines was observed immediately after ischemia, perhaps indicating a washout of HO.-derived products that had accumulated in the myocardium during ischemia. To evaluate production of HO. during ischemia, deoxygenated saline (PO2 10 +/- 0.9 mmHg) containing phenylalanine was perfused into the ischemic coronary vascular bed through a cannula placed in the LAD (n = 16). Perfusate was collected from the coronary vein during the 10 min of ischemia. Net production of HO. during ischemia, measured by the production of p-, m-, and o-tyrosine, was 82 +/- 11, 6.6 +/- 0.4, and 1.7 +/- 0.3 nmol.min-1.g-1, respectively. Pretreatment with deferoxamine (10 mg/kg, n = 7) or dimethylthiourea (10 mg/kg, n = 6) decreased net production of HO. during ischemia and reperfusion. These results demonstrate that HO. is produced during brief ischemia and reperfusion, with the greatest amount being produced immediately after ischemia. Additionally, we show that the duration of brief ischemia determines the rate of production of HO. during reperfusion.

Modulation of tyramine induced endogenous norepinephrine release from cardiac sympathetic nerve endings

Modulation of tyramine induced endogenous norepinephrine release from cardiac sympathetic nerve endings

The effect of skin incision followed by alfentanil on catecholamine levels and on the T-wave amplitude of ECG during isoflurane anaesthesia.

Haemodynamic, ECG T-wave amplitude and plasma potassium changes and plasma catecholamine responses to skin incision followed by alfentanil were studied in 24 ASA I patients. Propofol and vecuronium were used without anticholinergics for induction of anaesthesia followed by isoflurane in 02/air. End-tidal isoflurane concentration was kept constant (0.7%) for 30 min before the skin incision. Five min after the skin incision alfentanil 30 mu g kg-1 was given. Blood samples for catecholamines and plasma potassium concentrations were drawn from right ventricle of the heart one minute before and after the skin incision and two minutes after alfentanil. Heart rate, systolic and diastolic arterial pressures increased after the skin incision (P < 0.001), and decreased after alfentanil (P < 0.001). Plasma adrenaline and noradrenaline concentrations increased slightly after the skin incision (P < 0.05 and P < 0.01, respectively). Noradrenaline levels continued to increase after alfentanil (P < 0.001) despite totally abolished haemodynamic responses to the skin incision. ECG T-wave amplitude changes, measured as R/T ratio, did not correlate to the changes in plasma catecholamine levels: both rapid increases and decreases in R/T ratio were seen. No plasma potassium changes were seen during the trial. T-wave changes, occurring in seconds after the skin incision, are probably produced by a direct catecholamine release from cardiac sympathetic nerve endings.

Nicotine-induced exocytotic norepinephrine release in guinea-pig heart, human atrium and bovine adrenal chromaffin cells: Modulation by single components of ischaemia

The influence of single components of myocardial ischaemia, such as anoxia, substrate withdrawal, hyperkalemia and extracellular acidosis, on nicotine-induced norepinephrine (NE) release was investigated in the isolated perfused guinea-pig heart, in incubated human atrial tissue and in cultured bovine adrenal chromaffin cells (BCC). In normoxia, nicotine (1-1000 mumol/l) evoked a concentration-dependent release of NE (determined by high pressure liquid chromatography and electrochemical detection) from guinea-pig heart and human atrium. In contrast to selective anoxia (Po2 < 5 mmHg) or glucose withdrawal, respectively, anoxia in combination with glucose withdrawal (5-40 min) markedly potentiated nicotine-induced NE release both in guinea-pig heart and human atrium. The sensitization of cardiac sympathetic nerve endings to nicotine was characterized by a lower threshold concentration and an approximate two-fold increase of maximum NE release, peaking after 10 min of anoxia and glucose withdrawal. Cyanide intoxication (1 mmol/l) combined with glucose withdrawal resulted in a similar increase of nicotine-induced sympathetic transmitter release both in guinea-pig heart and human atrium. In contrast, the nicotine-induced (10 mumol/l) NE overflow was only slightly potentiated by 10 min of global ischaemia in guinea-pig heart. Both hyperkalemia ([K+] 16 mmol/l) and acidosis (pH 6.8-6.0) distinctly attenuated the stimulatory effect of nicotine in guinea-pig heart and human atrium under normoxic conditions. Consistent with an exocytotic release mechanism, NE release was dependent on the presence of extracellular calcium under all conditions tested. Furthermore, NE overflow from guinea-pig heart was accompanied by a release of the exocytosis marker neuropeptide Y (NPY; determined by radioimmunoassay). In BCC, nicotine (1-10 mumol/l) evoked a release of NE and NPY and a transient rise of [Ca2+]i (determined with fura-2) during normoxia which were both dependent on the presence of extracellular calcium. Both hyperkalemia and acidosis markedly reduced the exocytotic release of sympathetic transmitters and the corresponding [Ca2+]i-transients. These data demonstrate that nicotine-induced cardiac exocytotic NE release is markedly potentiated during short-term anoxia in combination with glucose withdrawal. In contrast, a brief period of ischaemia causes only a slight sensitization of cardiac sympathetic nerve endings to nicotine. This discrepancy may be due to an attentuation of nicotine-evoked NE release by hyperkalemia and by acidosis. The protective effect of these factors against anoxia-induced sensitization to nicotine appears to be related to the inhibition of nicotine-evoked [Ca2+]i-transients.

Dietary restriction modulates the norepinephrine content and uptake of the heart and cardiac synaptosomes.

The present study was designed to examine the effects of long-term dietary restriction on cardiac sympathetic nerves and neurotransmitter. The food intake of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control rats fed ad libitum. The body and heart weights of rats diet restricted for 4.5 months were less than those of the ad libitum fed animals, while the heart weight to body weight ratios were higher. The norepinephrine (NE) content of hearts from restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38 ng/g wet wt), although the total amount of NE per heart was unchanged. Similarly, the cardiac synaptosomal P2 fraction from restricted rats possessed a higher NE content (24.1 +/- 2.4 ng/mg protein) than the P2 fraction of ad libitum fed controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive norepinephrine uptake of the P2 fraction from restricted rats was significantly higher than that of control rats (9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg protein/hr). The NE uptakes of the two groups were similar when uptake was normalized to endogenous NE levels. These results demonstrate that long-term dietary restriction affects cardiac sympathetic nerve endings and suggest that part of the beneficial action of life-long dietary restriction on the age-related decline in cardiovascular regulation may be related to changes in cardiac sympathetic nerves.

Mechanism of decrease in heart rate by peripheral dopaminergic D2-receptors.

We performed this study in order to verify the heart rate decrease caused by the D2-receptor on cardiac sympathetic nerve endings and its relation to the concentration of norepinephrine in synaptic clefts. Sprague-Dawley rats were pithed and the heart rate was increased either by electrical stimulation of the cardiac accelerator nerve or by intravenous infusion of norepinephrine, tyramine, or isoproterenol. Increased heart rate by electrical stimulation of cardiac accelerator nerve was dose-dependently lowered by lisuride and its effect was blocked by pretreatment with sulpiride but not with yohimbine and SCH 23390. Also, the heart rate was decreased in a dose-dependent manner by clonidine and this effect was blocked by pretreatment with yohimbine, but not with sulpiride. For increased heart rate by infusion of norepinephrine, tyramine, or isoproterenol, the heart rate lowering effect of lisuride was more marked in the norepinephrine-and tyramine-infusion groups, in which the intrasynaptic concentration of norepinephrine was elevated, compared to the isoproterenol-infusion group, in which intrasynaptic concentration of norepinephrine was not elevated. In conclusion, there is a D2-receptor on the cardiac sympathetic nerve endings which decreases the heart rate and is different from the presynaptic alpha 2-receptor. Also, the heart rate lowering effect via stimulation of the D2-receptor by lisuride was more marked with increased concentration of norepinephrine in the synaptic cleft.

Actions of vasoactive intestinal peptide and neuropeptide Y on the pacemaker current in canine Purkinje fibers.

We have investigated the actions of vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) on the pacemaker current (I(f)) in canine Purkinje fibers. On voltage pulses to the middle of the I(f) activation range, VIP reversibly increases I(f), whereas NPY reversibly decreases I(f). A three-pulse voltage protocol suggests that VIP shifts I(f) activation in the positive direction and that NPY shifts I(f) activation in the negative direction on the voltage axis without changing maximal I(f) conductance. These effects of VIP and NPY on I(f) are exerted through their specific peptide receptors, since the effects are blocked by VIP and NPY receptor antagonists. VIP and NPY are colocalized in cardiac parasympathetic and sympathetic nerve endings, respectively, and can be released preferentially on high and long-lasting nerve stimulation. Given this colocalization and frequency-dependent release, these results suggest a role for these neuropeptides in controlling cardiac I(f) and consequently heart rate.

Presynaptic effects of epinephrine on norepinephrine release from cardiac sympathetic nerves in dogs.

The possible functional role of tissue epinephrine in the modulation of norepinephrine release from cardiac sympathetic nerve endings in anesthetized dog was investigated. Observations were carried out under control conditions and after a short- (10 min) and long-term (180 min) epinephrine infusion (92 ng.kg-1.min-1). An increase in the stimulation-induced release of norepinephrine after intravenous administration of a selective beta 2-agonist (fenoterol, 0.5 micrograms/kg) indicated the presence of the beta 2-facilitatory mechanism. Furthermore, the facilitatory effect of fenoterol was inhibited by intravenous administration of a selective beta 2-antagonist (ICI 118551, 1 mg/kg). Short-term epinephrine infusion did not facilitate the stimulation-induced release of norepinephrine, when tissue epinephrine content in the left ventricle was increased 1.5-fold, without, as well as with, alpha 2-blockade (yohimbine, 0.3 mg/kg). However, stimulation-induced release of norepinephrine from the myocardium was significantly potentiated in animals in which tissue epinephrine in the left ventricle was greatly increased (5.6-fold) by a prolonged infusion of epinephrine (180 min). It is concluded that a facilitatory mechanism mediated by presynaptic beta 2-adrenoceptors is present in cardiac sympathetic nerve endings of the dog. Some of our observations support the hypothesis that this mechanism may be influenced by locally released epinephrine and, thus, by tissue epinephrine content.

Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine.

Hypotheses concerning the pathophysiology of hypertension, cardiac failure and other cardiovascular disorders have imputed abnormal cardiac sympathoneural activity. Here we describe a technique to examine cardiac sympathetic innervation and function using positron emission tomographic (PET) scanning after systemic intravenous injection of 18F-6-fluorodopamine, and the effects of chemical sympathectomy by the neurotoxin, 6-hydroxydopamine (6-OHDA). Uptake of 18F-6-fluorodopamine by the heart of anesthetized dogs resulted in striking delineation of the left ventricular myocardium. Myocardial radioactivity declined bi-exponentially, with a half-life of approximately 2 h during the longer phase. In 6-OHDA-treated animals, the ventricular myocardium was barely distinguishable from the chamber; myocardial radioactivity declined rapidly and was virtually absent within 30 min after injection of 18F-6-fluorodopamine. The rates of decline in myocardial radioactivity in dogs treated with 6-OHDA were similar to those in dogs treated with reserpine, but the mechanisms of sympatholysis by these drugs were distinguished by arterial plasma levels of 6-fluorodihydroxyphenylacetic acid (6-FDOPAC). Plasma 6-FDOPAC levels were diminished in 6-OHDA-treated dogs and elevated in reserpinized dogs. The results confirm that, after injection of 18F-6-fluorodopamine, cardiac sympathetic nerve endings are radiolabeled, allowing visualization of sites of sympathetic innervation. Combined assessments of PET time-activity curves and plasma levels of metabolites of 18F-6-fluorodopamine constitute a new, potentially clinically applicable means by which to examine cardiac sympathetic function.

Sympathetic‐parasympathetic interactions at the heart, possibly involving neuropeptide Y, in anaesthetized dogs.

1. Stimulation of cardiac sympathetic nerves caused prolonged inhibition of vagal effects on heart rate, an effect which has been proposed on the basis of previous studies to be due to neuropeptide Y or a neuropeptide Y-like substance, released from the sympathetic nerves. 2. This prolonged vagal inhibitory effect was attenuated or abolished when the sympathetic stimulation responsible was given together with continuous vagal stimulation. 3. Continuous vagal stimulation alone did not modify the ability of administered neuropeptide Y to cause inhibition of cardiac vagal action. 4. The results are consistent with the cardiac vagal nerves releasing a transmitter (probably acetylcholine) which acts on cardiac sympathetic nerve endings, inhibiting them from releasing neuropeptide Y or a neuropeptide Y-like substance.

Platelet-activating factor: lack of direct action on guinea pig myocardium and possible transmitter release from cardiac sympathetic nerve endings at high concentrations

Microelectrode and mechanical studies were performed with isolated guinea pig myocardium (right ventricular free walls and papillary muscles) to examine the effects of platelet-activating factor (PAF) and lysophosphatidylcholine (LPC). Low concentrations of PAF (10(-8) to 10(-6) M, a range equivalent to the blood concentrations that produce marked hypotension in vivo) had no effects on action potential configuration and contractile force. High concentrations (10(-5) to 10(-4)M) of PAF and LPC per se elicited slow response action potentials with concomitant contraction (restored contraction) in the myocardium depolarized with elevated K+ (25 mM); they also augmented slow responses and restored contractions produced by a low concentration of isoproterenol (10(-8) M). Although these results suggested there was an increase in slow Ca current, the slow responses and restored contractions thus produced were greatly suppressed or abolished by the addition of a beta-adrenoceptor blocking agent, sotalol (10(-5) M), and by pretreatment with reserpine (5 mg/kg i.p., 24 h prior). In accordance with our previous conclusions, the present results suggest that direct cardiac action is not involved in the mechanisms of hypotension produced by PAF. It was also shown that high concentrations of PAF and LPC may act nonspecifically as amphiphilic compounds to induce transmitter release from sympathetic nerve endings, which may in turn augment the Ca current channels in the myocardial cell membrane.

The beta 1-adrenoceptor antagonist, betaxolol, is not released from the heart of the anaesthetized dog during sympathetic nerve stimulation.

1. We investigated the hypothesis that the beta 1-adrenoceptor antagonist, betaxolol, can be accumulated by cardiac sympathetic nerve endings and then released together with noradrenaline during accelerans nerve stimulation. 2. Dogs were chronically treated with betaxolol (1 mg kg-1 daily, s.c.) for 7 days. Twenty four hours after the last dose, there was a significant retention of betaxolol in the heart of these dogs treated chronically with the beta 1-adrenoceptor antagonist. However, during in vivo accelerans nerve stimulation, the concentration of betaxolol in the coronary sinus was not modified, whereas the noradrenaline concentration increased significantly. 3. Chronic betaxolol treatment antagonized the tachycardia induced by electrical stimulation of the cardiac accelerator nerves or by intravenous isoprenaline. However, the tachycardia induced by nerve stimulation was not antagonized to a greater extent than that induced by isoprenaline. 4. These findings are discussed in relation to a similar in vivo study in dogs treated with propranolol, in which the drug was found to be released into the coronary circulation during stimulation of the accelerans nerve.

Indirect adrenergic effect of histamine in cat right atrium

1. 1. Superfused cat atrial fragments preincubated with [ 3H]noradrenaline showed an increased tritium release under the action of 10 −4 M histamine. 2. 2. Reserpine pretreatment of the animals, external calcium removal or the presence of 10 −6 M cocaine, 10 −6 M diphenhydramine or 10 −3 M colchicine in the superfusion medium significantly reduced this effect of histamine (10 −4 M). 3. 3. Diphenhydramine (10 −5 M) also decreased the release of tritium brought about by 10 −6 M tyramine. 4. 4. These results suggest that histamine may release neurotransmitter from cardiac sympathetic nerve endings by means of an exocytotic process and needs to enter the nerve terminals through the amine uptake system.

Autonomic nervous control of heart rate: sympathetic-parasympathetic interactions and age related differences.

A factorial experimental design was used to quantify the changes in heart rate produced by stimulation of the cardiac sympathetic and vagal nerves in eleven adult dogs and four puppies, and to quantify the extent of the peripheral sympathetic-vagal interactions. The chronotropic responses to autonomic stimulation were significantly less in the puppies than in the adult dogs, which suggests that autonomic regulation is functionally incomplete in the puppies. In both adult dogs and puppies, the chronotropic responses to autonomic nerve stimulation were bilaterally asymmetrical. The heart rate responses to a given level of right-sided stimulation of either the sympathetic or vagal nerves were greater than those to comparable left-sided stimulation. In both adult dogs and puppies, there were significant sympathetic-vagal interactions, such that the sympathetic enhancement of heart rate was less effective the higher the background level of vagal activity. The sympathetic-vagal interactions were prominent in the puppies as well as in the adult animals, regardless of whether the stimulated sympathetic and vagal nerves were located ipsilaterally or contralaterally to one another. Thus, the mechanisms responsible for the sympathetic-vagal interactions appear to be fully developed in puppies. Also, the cardiac sympathetic nerve endings that originate from one side of the body must lie in close apposition to the cardiac vagal nerve endings that originate from either the same side or from the opposite side of the body.

Involvement of presynaptic dopamine receptors in the antihypertensive response to 2-NN-dimethylamino-5,6-dihydroxy-1,2,3,4,-tetrahydronaphthalene (M-7).

M-7, 1 and 3 mg kg-1 s.c., elicits an antihypertensive response and bradycardia in conscious spontaneously hypertensive rats (SHR) and causes inhibition of stimulation-evoked pressor response and tachycardia in pithed SHR. Metoclopramide (30 mg kg-1 i.p.), but not piperoxan (5 mg kg-1 i.p.), abolished the antihypertensive effect and inhibition of stimulation-evoked pressor responses produced by M-7 (1 mg kg-1 s.c.) in SHR. Conversely, piperoxan, but not metoclopramide, reduces the bradycardia and inhibition of stimulation-evoked tachycardia produced by M-7. Metoclopramide (30 mg kg-1 i.p.) did not affect the cardiovascular responses elicited by intracerebroventricular administration of either clonidine (1 microgram) of M-7 (3 micrograms). These results suggest that the antihypertensive effect of M-7 may be mediated by stimulation of presynaptic dopamine receptors on sympathetic nervous to the vasculature and is independent of the bradycardia, which is probably due to stimulation of presynaptic alpha 2-adrenoceptors on cardiac sympathetic nerve endings.