REFLEXES MEDIATED BY CARDIAC SYMPATHETIC AFFERENTS DURING MYOCARDIAL ISCHAEMIA: ROLE OF ADENOSINE

1. Myocardial ischaemia and infarction activate vagal and sympathetic sensory endings in the ischaemic myocardium, resulting in powerful reflex effects. The vagal afferents are either mechano- or chemosensitive, whereas sympathetic afferents may be mechano-, chemosensitive or both. 2. Activation of vagal afferents results in sympathoinhibitory, cardioinhibitory, vasodepressor responses. Cardiac sympathetic afferents activated during myocardial ischaemia mediate sympathoexcitatory, vasoconstrictor cardioaccelerator responses. 3. The focus of the present review is on the activation of sympathetic afferents by myocardial ischaemia and on the resulting reflex responses that they mediate. 4. These endings are more likely to be activated as the degree of ischaemia progresses from subendocardial towards transmural. They are evenly distributed between the anterior and inferoposterior wall. Although it has been suggested that these endings are activated by bradykinin, recent evidence indicates that they are activated by adenosine released from the ischaemic myocardium. Results from our laboratory indicate that this effect is due to the activation of adenosine A₁, but not adenosine A₂ receptors. 5. Activation of ventricular vagal and sympathetic afferent fibres during myocardial ischaemia in humans is responsible for the autonomic changes observed and, in the case of the sympathetic afferents, for the sensation of angina pectoris.     

REPRODUCIBILITY OF CONVENTIONAL AND POWER SPECTRAL MEASUREMENTS OF CARDIOVASCULAR SYMPATHETIC ACTIVATION IN NORMAL SUBJECTS

1. Normal subjects (n = 5; age 20-42 years; mean resting blood pressure (± 1 s.d.) 116±21/61±11 mmHg) underwent cardiovascular reflex testing five times each. On every occasion systolic blood pressure (SBP) responses to sustained handgrip (GRIP) and cold pressure (COLD) tests were measured and continuous non-invasive SBP and heart period (RRINT) data were analysed in the frequency domain using fast Fourier transforms. Power spectral (PS) density estimates of high frequency/total power (HF%; a measure of vagal activity), low frequency/HF ratio (LF/HF; a measure mainly of cardiovascular sympathetic activity for heart period) and low frequency/total power (LF%; a proposed measure of sympathetic activity for SBP) at rest, during and 2min after the end of stimuli were calculated. 2. The data from the rest and recovery periods did not differ and showed that cardiovascular recovery to baseline measures following sympathetic stimulation occurred within 2 min. 3. There was a significant rise in SBP with GRIP and COLD. The LF/HF(RRINT) rose significantly with GRIP, but not with COLD. The LF%(SBP) did not change significantly with GRIP or COLD. 4. The SBP and PS analyses showed low intra-individual reproducibility of responses to reflex tests, with coefficients of variation for PS measures at rest of 25-41% and on sympathetic stimulation of up to 80%. 5. The high variability of these observations indicates that PS methods may not be suitable for the analysis of transient cardiovascular reflexes.     

ENALAPRIL DECREASES PLASMA NORADRENALINE LEVELS DURING THE COLD PRESSOR TEST IN HUMAN HYPERTENSIVES

1. The effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril on the responses of blood pressure and plasma catecholamine levels to the cold pressor test in human hypertensives were examined. 2. Systolic and diastolic blood pressure decreased significantly after treatment with enalapril (5 mg/day for 4 weeks) as did the resting level of plasma noradrenaline. 3. The cold pressor test induced a rise in blood pressure and plasma noradrenaline levels. After 2 and 4 weeks enalapril treatment, the rises in the plasma noradrenaline level and systolic and diastolic pressure due to cold pressor test were reduced significantly. 4. These results suggest that ACE inhibition has a sympatho-inhibitory effect. One possible explanation is that enalapril reduces angiotensin II formation thus decreasing the activation of release-enhancing angiotensin II receptors on postganglionic sympathetic nerve endings.     

EFFECTS OF ADENOSINE ANTAGONISM AND β-BLOCKADE DURING LOW-FLOW ISCHAEMIA IN RAT HEART

1. The effects of adenosine antagonism (8-phenyltheophylline) and beta-blockade (1-propranolol) were examined during low-flow ischaemia (0.5 mL/min per g for 20 min) in rat heart. 2. Myocardial adenosine release, heart rate, and left ventricular developed pressure were monitored to determine whether endogenous adenosine affected ischaemic function directly, and/or via interaction with endogenous catecholamines. 3. Adenosine release increased more than 10-fold during low-flow ischaemia. Release displayed a phasic pattern, with maximal release occurring at 10 min. Ischaemia produced bradycardia (-180 beats/min) which was reduced by 8-phenyltheophylline infusion (P less than 0.001, n = 10). Adenosine antagonism also significantly increased left ventricular developed pressure in the initial 5 min of ischaemia (P less than 0.001, n = 10). 4. beta-blockade alone was without effect in ischaemic hearts, however, beta-blockade significantly reduced the initial increases in heart rate and developed pressure observed during infusion of 8-phenyltheophylline (P less than 0.001, n = 10). The effect of beta-blockade was transient, occurring in the initial 5-6 min of ischaemia. 5. The data indicate that endogenous adenosine directly mediates greater than 30% of the bradycardia associated with low-flow ischaemia, and that endogenous adenosine inhibits the release and/or the effects of endogenous catecholamines produced during the initial 5-6 min of ischaemia.     

THE SYMPATHETIC NERVOUS SYSTEM AND LONG-TERM REGULATION OF ARTERIAL PRESSURE: WHAT ARE THE CRITICAL QUESTIONS?

1. The role of the sympathetic nervous system in long-term control of arterial pressure remains unclear despite decades of intense research. 2. Previous studies have shown that denervation of arterial baroreceptors does not chronically increase arterial pressure. As baroreceptors are thought to provide the primary ‘error signal’ to the autonomic nervous system, this has been interpreted as evidence against neural control of arterial pressure over long periods of time. 3. The possibility that other ‘error signals’ are important in the long-term control of sympathetic activity (and arterial pressure) is introduced. 4. The following ‘Critical Questions’ are presented for subsequent discussion: (i) is the sympathetic nervous system a ‘major player’ in the long-term control of arterial pressure; (ii) why doesn't arterial pressure remain at hypertensive levels after arterial baroreceptor denervation; and (iii) which ‘error signals’ are most important in the long-term control of sympathetic outflow?     

CONTRIBUTION OF THE SYMPATHETIC NERVOUS SYSTEM TO THE CENTRALLY-INDUCED PRESSOR ACTION OF ANGIOTENSIN II IN RATS

Angiotensin II (ANG II) may increase blood pressure by central nervous system mechanisms. The involvement of the sympathetic nervous system in the centrally-induced pressor effect of ANG II in the rat was investigated. 2 Plasma noradrenaline concentrations, measured as an index of sympathetic nervous system activity, increased after intracerebroventricular (i.e.v.) injection of pressor doses of ANG II, both in normotensive and in spontaneously hypertensive rats. 3 To assess the functional significance of this, the sympathetic nervous system was inhibited by phentolamine, reserpine, and guanethidine. In phentolamine-infused rats, low doses of i.c.v. ANG II elicited a blood pressure decrease, but at maximal pressor doses, no difference between phentolamine-treated and control rats was observed. In reserpinized rats, the central pressor effect of ANG II was greater than in controls. Guanethidine pretreatment did not affect the blood pressure response to i.c.v. injected ANG II. 4 It is concluded that the central pressor effects o f ANG II are accompanied by a stimulation of the sympathetic nervous system. In the rat, this stimulation may be functionally important for the initial phase of the central pressor action. This could not be established for the maximal pressor responses.     

EFFECTS OF V2 RECEPTOR ACTIVITY ON THE PRESSOR RESPONSE TO VASOPRESSIN IN THE RAT

1. To determine the contribution of V1 and V2 receptor activity on the enhancement of reflex buffering of the pressor response to arginine-vasopressin (AVP), mean arterial pressure (MAP) and heart rate (HR) changes were examined in response to graded injections of phenylephrine, AVP, or Phe2Orn8OT, a potent, selective V1-receptor agonist in the absence and presence of Val4DArg8VP, a potent, selective V2-receptor agonist. 2. There were no significant differences in MAP responses to the V1 agonist in the absence and presence of the V2 agonist in either conscious intact or autonomic-blocked rats. 3. Autonomic blockade with methscopolamine and hexamethonium increased the pressor sensitivity to phenylephrine threefold. In contrast, the pressor sensitivities to AVP and Phe2Orn8OT were increased 14-fold and 11-fold, respectively, by autonomic blockade. 4. V2-receptor activity does not have any inherent vasocative action or synergistic vasoactive action with V1-receptor activity. 5. V2 receptors do not play a role in enhancing reflex buffering of the pressor response to AVP; V1 receptors are suggested to play the role.     

IDENTIFICATION OF CARDIOVASCULAR PATHWAYS IN THE SYMPATHETIC NERVOUS SYSTEM

1. Sympathetic autonomic neurons show distinct patterns of expression of a range of neurochemicals that can be detected immunohistochemically. Often, functionally homologous neurons in the autonomic nervous system express identical combinations of substances that serve as a chemical code that allows them to be identified among other autonomic neurons. 2. In the rat stellate ganglion, where many neurons express either immunoreactivity (IR) to neuropeptide Y (NPY) or the calcium-binding protein calbindin, a population of large postganglionic neurons found along the medial border of the stellate ganglion, around the origin of the cardiac nerves, expressed intense IR to both substances at all ages examined, from early postnatal to adult. 3. In the heart, in the first few postnatal weeks, many nerve terminals were IR for both NPY and calbindin, but, with increasing age, calbindin-IR was progressively lost from NPY-IR terminals. Nerve terminals IR for both calbindin and NPY were not seen around pulmonary blood vessels or in the trachea or the thymus. 4. Nerve terminals IR for calretinin, another calcium-binding protein, were present in dense pericellular baskets around neurons in the stellate IR for both calbindin and NPY. The terminals also contained nitric oxide synthase (NOS)-IR. 5. It is suggested that the calbindin- and NPY-IR neurons in the stellate ganglion are the post-ganglionic neurons that innervate the heart and that the nerve terminal containing calretinin and NOS-IR that surround them are the cardiac preganglionic terminals. It thus appears possible, in the rat, to identify the sympathetic cardiac pathway arising in the spinal cord and controlling the heart purely on the basis of chemical coding.     

ATTENUATION BY CAPTOPRIL OF PRESSOR RESPONSES TO PERIPHERAL SYMPATHETIC NERVE STIMULATION IN RATS IS ABOLISHED AFTER BILATERAL NEPHRECTOMY AND DURING MINERALOCORTICOID HYPERTENSION

Intravenous administration of captopril (0.1-0.3 mg/kg) to normotensive pithed rats, with or without unilateral nephrectomy, was followed by a sustained fall in arterial blood pressure. Concomitantly pressor responses to electrical stimulation of the spinal sympathetic outflow (T11-L3), ganglion stimulation with McNeil-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride) or intravenous injection of noradrenaline were reduced. Attenuation by captopril (1 mg/kg) of pressor responses to McNeil-A-343 persisted after intravenous propranolol (1 mg/kg). Tachycardia caused by electrical stimulation of the spinal sympathetic nerves (C7-T2) was unchanged after 3.0 mg/kg captopril. After procedures reducing the activity of the renin angiotensin system, bilateral nephrectomy or induction of mineralocorticoid hypertension by unilateral nephrectomy and administration of desoxycorticosterone acetate, pressor responses to McNeil-A-343 or noradrenaline were unchanged after 1 mg/kg captopril. It is concluded that in the pithed rat, basal arterial blood pressure and the height of pressor responses to either postganglionic sympathetic nerve activation or intravenous noradrenaline depend on converting enzyme activity maintaining circulating angiotensin II levels.     

EFFECTS OF NEUROPEPTIDE Y ON THE PRESSOR RESPONSES TO PHENYLEPHRINE AND TO ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN ANAESTHETIZED RATS

1. The effects of neuropeptide Y (NPY) on the pressor responses to intravenous injections of phenylephrine and to reflex activation of the sympathetic nervous system by stimulation of the sciatic nerve were examined in anaesthetized rats. 2. NPY (10-20 micrograms/kg) always potentiated the pressor response to exogenous phenylephrine (by a mean of 28.1 +/- 5.0%). The effect of the same dose of NPY on the pressor response to sciatic nerve stimulation was variable (sometimes inhibition, sometimes potentiation). 3. NPY appears to act by potentiating post-synaptic alpha-adrenoceptor-mediated vasoconstrictor effects. It may also inhibit noradrenaline release by a presynaptic action. Thus the net effect of NPY on sympathetic activation in vivo may depend on the balance between these two opposing actions.     

Effects of N6-cyclohexyladenosine (CHA) on responses to adrenergic and cholinergic nerve stimulation in the peripheral autonomic nervous system

The adenosine derivative N⁶-cyclohexyladenosine (CHA), was studied in various cardiovascular and autonomic experiments. In hemodynamic studies in dogs, CHA 0.5 mg/kg, i.v., caused moderate hypotension and bradycardia. Additional studies in dogs showed that a portion of the bradycardia was the result of an inhibitory effect on the sympathetic nerves to the heart since the chronotropic reponses to cardioaccelerator nerve stimulation were inhibited while the responses to isoproterenol were slightly potentiated. CHA was more potent than adenosine in this experiment and caffeine, 3 mg/kg, i.v., antagonized the effects of CHA. CHA was also found to inhibit the pressor effects of lumbar sympathetic nerve stimulation in rats while responses to intraarterial norepinephrine(NE) were potentiated. In the isolated stimulated guinea pig ileum, both CHA and adenosine inhibited the stimulation-evoked twitches, with CHA being the more potent. Caffeine, 0.1 mM, antagonized the inhibitory effects of both compounds. CHA had no significant effect on the negative chronotropic responses to vagus nerve stimulation in dogs. These findings indicate that CHA is qualitatively similar to adenosine but is more potent and longer lasting. CHA, like adenosine, appears to alter reponses to both adrenergic and cholinergic nerve stimulation.     

EFFECTS OF HYPERINSULINAEMIA ON RENAL FUNCTION AND THE PRESSOR SYSTEM IN INSULIN-RESISTANT OBESE ADOLESCENTS

1. In the present study, using the euglycaemic hyperinsulinaemic glucose clamp technique, we investigated the effects of hyperinsulinaemia on sodium-water metabolism and the pressor system in obesity, both of which have been reported to be closely associated with insulin resistance and/or hyperinsulinaemia.
2. Sixteen obese young subjects and 24 non-obese young subjects who were all normotensives, participated in this study. The 2h euglycaemic hyperinsulinaemic glucose clamp was performed in a fasting state. The mean glucose infusion rate needed to maintain a fasting blood sugar level (FBS) during the last 30 min of the clamp was used as an indicator of insulin sensitivity (M-value). Before and after the clamp, the following parameters were measured: creatinine clearance (Ccr); urinary excretion of sodium (UNaV); fractional excretion of sodium (FENa); plasma renin activity (PRA); plasma aldosterone concentration (PAC) and plasma noradrenaline concentration (PNA).
3. The M-value was significantly lower in obese subjects compared with non-obese subjects, although FBS and fasting immunoreactive insulin levels were similar in both groups. UNaV and FENa fell only in obese subjects during the clamp, while Ccr showed no significant change in either group. PNA and PRA increased significantly and PAC tended to increase in both groups.
4. These results suggest that obese subjects have insulin resistance with respect to glucose metabolism, but that urinary sodium excretion and the pressor system remain insulin-sensitive; the sensitivity of the sodium retaining action to hyperinsulinaemia was actually higher in obese subjects than in non-obese subjects. Therefore, if compensatory endogenous hyperinsulinaemia was raised by insulin resistance, these two factors may lead to chronic sodium retention and pressor system stimulation and, in turn, to hypertension in obesity.     

AUTONOMIC NERVOUS SYSTEM AS A TARGET FOR CARDIOVASCULAR DRUGS

1. Drugs acting within the autonomic nervous system (ANS) are of particular interest when autonomic abnormalities are implicated in the development and maintenance of various cardiovascular pathologies. For example, it has been documented that in the early stages of hypertensive disease (i.e. hyperkinetic borderline hypertension) a sympathetic hyperactivity associated with a decreased parasympathetic activity results in increased cardiac output and heart rate.
2. Several classes of drugs acting within the central, as well as the peripheral ANS, are very efficient in treating hypertensive disease. One of these classes of drugs, the second generation of centrally acting drugs, has proved beneficial in this respect because, in addition to their therapeutic efficacy, these drugs are well tolerated.
3. The central nervous system may also be the target for drugs with the potential to treat other cardiovascular diseases. Some recent experimental and clinical data supporting such new perspectives concerning idiopathic dysrhythmias, angina pectoris and congestive heart failure will be summarized.     

EFFECTS OF DOXAPRAM ON BODY TEMPERATURE OF THE RAT DURING RADIOFREQUENCY IRRADIATION

Central nervous system stimulants can cause changes in body temperature and changes in susceptibility to high levels of radiofrequency radiation (RFR). In the present study, the effects of the central nervous system stimulant, doxapram, on thermal responses to 2.8 GHz pulsed RFR were examined in anaesthetized rats. During intermittent exposure to an average power density of 60 mW/cm2, doxapram significantly increased the time required for temperature to return to the pre-exposure level when irradiation was discontinued. When exposure was continued until lethal temperatures resulted, doxapram administration caused no significant change in survival time when compared to saline controls. Thus, although the drug decreased thermoregulatory efficiency during intermittent exposure to RFR, no change in susceptibility to terminal RFR exposure was observed.     

AFFERENT CONTROL OF VASOPRESSIN AND RENIN RELEASE DURING HAEMORRHAGE IN NORMAL AND AUTONOMICALLY BLOCKED RABBITS

1. The role of the arterial and cardiac baroreceptors on the arginine vasopressin (AVP) and plasma renin activity (PRA) responses to haemorrhage was studied in conscious rabbits. They were bled at a rate of approximately 3% of their blood volume (BV)/min, both when the autonomic nervous system (ANS) was intact and during ANS blockade, which markedly enhances the AVP response due to the much greater haemodynamic disturbance. Under each condition of ANS function 2 x 2 factorial analysis was performed, each with four groups of rabbits, including animals with both sets of baroreceptors working, one or other set working and neither set working. 2. With intact ANS, haemorrhage had to be terminated at different times in the four groups. This presents problems for factorial analysis due to differences in the relationship between plasma AVP (or PRA) and release rate. A method for overcoming this was developed by extrapolating the BV-log AVP curves to a common time from the start of bleeding. 3. Under both conditions of ANS function the arterial and cardiac baroreceptors together accounted for 90-95% of the rise in AVP during haemorrhage. With normal ANS function, the rise in AVP was about 70% through cardiac (probably ventricular) baroreceptors (P = 0.01) and about 30% through arterial baroreceptors (P = 0.08). This compares with an earlier study at a rate of bleeding of 1.8% BV/min, where the entire drive came from the cardiac receptors. During ANS blockade, plasma AVP was enhanced approximately five-fold, which was mostly mediated through the arterial baroreceptors, but the cardiac baroreceptor component was also greater; arterial/cardiac baroreceptor drive was 2/1. 4. Baroreflexes played no role in renin release during haemorrhage, but the experiments with ANS blockade suggest that a hormonal factor, which was related to the cardiac innervation, may limit the rise in PRA in the latter part of haemorrhage.     

EFFECTS OF NEUROPEPTIDE Y ON BAROREFLEX CONTROL OF HEART RATE AND MYOCARDIAL CONTRACTILITY IN CONSCIOUS RABBITS

1. The effects of intravenous (i.v.) neuropeptide Y (NPY, 10 micrograms/kg bolus) on the stimulus-response curves relating changes in heart period (HP) and in peak left ventricular (LV) dP/dt to acute changes in mean arterial pressure (MAP) were determined in conscious, normotensive rabbits. 2. The relationship between increases and decreases in MAP and the subsequent changes in HP were represented by a sigmoid-shaped curve described by a logistic function. Following NPY administration there was a baroreflex-dependent increase in the maximum slope (sensitivity) at the midpoint of this MAP-HP curve from 7.0 +/- 0.5 to 10.6 +/- 1.3 ms/mmHg (P less than 0.05). NPY caused an upward shift in the whole curve which reflected the NPY-induced bradycardia and was independent of baroreflexes. 3. The relationship between increases in MAP and decreases in peak LV dP/dt was determined during fixed-rate atrial pacing to prevent the effects of the accompanying bradycardia. Increases in MAP and the corresponding reductions in peak LV dP/dt were represented by an exponential function. The slope of the curve, measured at its origin 5-15 min after NPY administration, was reduced from -0.9 +/- 0.2 to -0.4 +/- 0.1 units (P less than 0.05). 4. The effects of NPY are consistent with an action on efferent connections of the arterial baroreceptor reflex, mediated through a reduction in cardiac beta-adrenergic tone. They would also be explained through actions on the afferent or central neural connections of the baroreflex.     

SERUM DOPAMINE β-HYDROXYLASE (DβH) LEVELS DURING TILTING IN PATIENTS WITH SPINAL CORD INJURIES*

The activity of dopamine-β-hydroxylase (DβH) in the serum was measured in patients with quadriplegia and in healthy subjects. We assume that the plasma DβH levels reflect sympathetic tone. Quadriplegics had significantly lower DβH levels at rest. After head-up tilting a significant decrease in DβH levels occurred in patients with spinal cord injury suggesting failure of the sympathetic nervous system. However, a considerable overlap exists between normals and quadriplegics, making this test of limited value in the assessment of autonomic function in individual subjects.