RENAL SYMPATHETIC AND HEART RATE BAROREFLEX FUNCTION IN CONSCIOUS AND ISOFLURANE ANAESTHETIZED NORMOTENSIVE AND CHRONICALLY HYPERTENSIVE RABBITS

1. Baroreflex control of heart rate (HR) has been studied in normotensive (NT) and hypertensive (HT) awake and anaesthetized animals and man, but baroreflex control of sympathetic nerve activity has not been well studied. We investigated baroreflex control of HR and renal sympathetic nerve activity (RSNA) over a wide range of arterial pressure (AP) in conscious and isoflurane (ISO) anaesthetized NT and HT rabbits. 2. Animals were instrumented to record AP, HR and RSNA. Hypertension was accomplished by renal encapsulation. AP-HR and AP-RSNA baroreflex function curves were obtained while awake and after 1.0, 1.5, 2.0 and 2.5% ISO. All baroreflex curves were fit to sigmoid or exponential functions. 3. In conscious rabbits, HT for 3–5 weeks, AP was significantly higher (75.6 ± 0.8 vs 102.3 ± 8.9 mmHg); HR significantly lower (218.0 ± 5.5 vs 189.5 ± 5.5 beats/min); and RSNA not different than NT rabbits (14.9 ± 2.2 vs 9.9 ± 3.2% max RSNA). 4. ISO shifted AP-HR and AP-RSNA baroreflex curves to the left in NT and HT animals, and significantly attenuated baroreflex range and slope. At low ISO concentrations, baroreflex compensation for decreases in AP is limited to small increases in HR and sympathetic nerve activity. At higher ISO concentrations, baroreflex responses to decreases in AP are lost. RSNA responses to increases in AP are preserved with increasing ISO concentrations while HR responses are progressively attenuated. The sole effect of chronic hypertension was to shift the AP-HR and AP-RSNA barocurves to the right along the pressure axis in both conscious and ISO anaesthetized animals with no additional change in range or slope. 5. At this stage of hypertension development, ISO anaesthesia affects baroreflex function equally in normotensive and hypertensive rabbits.     

NEURAL CONTROL OF THE CIRCULATION IN HEART FAILURE AND CORONARY ISCHAEMIA: INTRODUCTION

1. A large gap in our knowledge of the reflex control of the circulation still exits in the setting of chronic heart failure. This symposium will provide state-of-the-art experimental data on the reflex regulation of the circulation in heart failure and myocardial ischaemia. 2. Alterations in arterial baroreflex and cardiopulmonary reflexes contribute to the increase in sympathetic tone in this disease state. Additionally, changes in neurohormones, such as angiotensin, are thought to contribute. 3. Coronary ischaemia is associated with activation of both vagal and sympathetic reflexes of cardiac origin. The balance between activation of these two reflexes will determine the ultimate change in sympathetic outflow. 4. Sensory endings in the myocardium are exquisitely sensitive to local mediators, such as prostaglandins, oxygenderived free radicals, adenosine and bradykinin.     

ENALAPRILAT RESTORES SENSITIVITY OF BAROREFLEX CONTROL OF RENAL AND TOTAL NORADRENALINE SPILLOVER IN HEART FAILURE RABBIT

1. The acute effect of an angiotensin converting enzyme inhibitor (ACEI), enalaprilat, on baroreflex-mediated changes in renal and total NA spillover rate in conscious rabbits with doxorubicin-induced cardiomyopathic congestive heart failure (CHF) were investigated under resting conditions and in response to changes in arterial pressure induced by sodium nitroprusside and phenylephrine infusions. 2. Six saline-treated (N group) and 11 doxorubicin-treated rabbits (1 mg/kg administered i.v. twice weekly) were studied after 4 and 6 weeks treatment. Five CHF rabbits received saline (C group) and six enalaprilat infusion (ACEI group). 3. After 4 weeks of doxorubicin, mean arterial pressure (MAP)-renal noradrenaline (NA) spillover and MAP-total NA spillover curves did not change during enalaprilat infusion. 4. After 6 weeks, the C group showed blunted MAP-renal NA spillover and MAP-total NA spillover curves. In the ACEI group, however, both curves returned toward those seen in the N group (slope of MAP-renal NA curve: from 0.27 to 1.80 ng/min per mmHg, MAP-total NA curve: from 1.61 to 3.59 ng/min per mmHg). 5. Results of this study indicate that enalaprilat enhances baroreflex control of renal and total NA spillover in rabbits with CHF and further support the view that activation of the renin-angiotensin system contributes significantly to the attenuated baroreflex responses in CHF.     

REGIONAL DISTRIBUTION OF THE CARDIAC OUTPUT AND RENAL RESPONSES TO ATRIAL ATRIURETIC PEPTIDE INFUSION IN RABBITS WITH CONGESTIVE HEART FAILURE

1. A biventricular, low-output congestive cardiomyopathy was induced in 19 rabbits by administering adriamycin (16 mg/kg). The effects of alpha-rat atrial natriuretic peptide (ANP) infused at 0.1, 0.2 and 0.4 micrograms/kg per min, were then examined in terms of (i) central haemodynamics (ii) regional blood flow (iii) renal function and (iv) plasma norepinephrine and plasma renin. 2. In this dose range, ANP produced progressive and significant falls in stroke volume, cardiac output and mean arterial pressure, owing to a fall in venous return. The heart rate response to this was blunted. 3. Using radiolabelled microspheres, significant falls in the perfusion of cutaneous, gastrointestinal and musculoskeletal tissues were observed, due to reduced vascular conductances in these beds. These changes were accompanied by activation of the sympathetic nervous system as evidenced by a progressive rise in plasma norepinephrine. A significant increase in plasma renin was only observed with the highest infusion of ANP. 4. Renal blood flow was maintained in the face of a falling mean arterial pressure and cardiac output, but diuretic and natriuretic effects were absent. 5. It was concluded that the dominant influence of ANP infusion in this model of heart failure appeared to be a reduction in cardiac preload with detrimental overall haemodynamic consequences.     

NEURAL RESPONSES TO EXERCISE IN HUMANS: IMPLICATIONS FOR CONGESTIVE HEART FAILURE

1. During static handgrip exercise, muscle metaboreceptors are stimulated, evoking the ‘exercise pressor reflex'. As part of this reflex, sympathetic discharge to skeletal muscle is increased. The muscle ‘metaboreceptors’ are thought to be free nerve endings of unmyelinated group IV nerve fibres. These receptors are stimulated by a number of metabolites, including lactic acid, H⁺, diprotonated phosphate, adenosine and the biproducts of prostaglandin synthesis. 2. During chronic, repetitive activity, muscle metabolitesensitive afferents may be desensitized. We speculate that metaboreceptor desensitization also occurs in congestive heart failure (HF). Despite this desensitization, sympathoexcitatory responses to forearm exercise are preserved. This suggests that some other neural system aside from muscle metaboreceptors must be activated to a greater degree in HF. We speculate that in HF the activity of muscle mechanoreceptors is increased. Furthermore, we believe that limb congestion can increase the discharge of muscle mechanoreceptors, thereby evoking nonmetaboreceptor-mediated increases in sympathetic discharge. Future studies in our laboratory will examine the role limb congestion and decongestion play in evoking muscle mechanoreceptor-mediated sympathoexcitatory responses.     

SYSTEMIC AND REGIONAL HAEMODYNAMICS IN EXPERIMENTAL RENAL HYPERTENSION IN CONSCIOUS RABBITS

1. The radioactive microsphere method was used to measure the distribution of cardiac output, regional flows and resistances in conscious normotensive and hypertensive rabbits implanted with an electromagnetic flow probe on the ascending aorta or pulmonary artery. Hypertension was induced by wrapping one kidney with cellophane and removing the other, and studies were performed about 5 weeks later. 2. Heart rate, stroke volume, cardiac output and total renal mass were reduced in the hypertensive animals, while the weight of, and the cardiac output distribution to left ventricle and the remaining kidney were increased. 3. In renal hypertensive rabbits, the weight normalized regional blood flow was diminished in a number of tissues, including the kidney, and, except for some organs in the splanchnic area (stomach, small intestine, mesentery and pancreas) and the fat, there was a rather uniform increase in tissue vascular resistance.     

SHIFT IN THE BAROREFLEX-RENAL NORADRENALINE SPILLOVER CURVE DURING THE DEVELOPMENT OF CONGESTIVE HEART FAILURE IN THE RABBIT

1. Changes in renal sympathetic nerve activity (RSNA) were investigated during the development of congestive heart failure (CHF) in rabbits with doxorubicin-induced cardiomyopathy. 2. Controls (saline treated, n = 5) and doxorubicin-treated rabbits (1 mg/kg administered intravenously twice weekly, n = 5) were studied after 4 and 6 weeks treatment. 3. RSNA was estimated by measuring renal noradrenaline spillover rate under resting conditions and in response to changes in arterial pressure induced by phenylephrine and sodium nitroprusside infusions. 4. In the doxorubicin-treated group, resting renal noradrenaline spillover was increased at 4 weeks (24.2 ng/min, s.e.m. = 2.5, n = 5) compared with controls (15.2 ng/min, s.e.m. = 2.4, n = 5; P less than 0.01) and remained elevated. 5. The baroreceptor-renal noradrenaline spillover curve showed a significant upward shift in the doxorubicin-treated group at 4 weeks. After 6 weeks both heart rate and renal noradrenaline spillover responses to hypotension were significantly blunted. 6. It is suggested that increased RSNA occurs early during the development of CHF in doxorubicin-treated rabbits. The observed changes in the baroreflex responses suggest that different mechanisms may contribute to this increased RSNA at different stages of CHF.     

SYSTEMIC AND REGIONAL HAEMODYNAMIC RESPONSES TO ISOPRENALINE IN CONSCIOUS RENAL HYPERTENSIVE RABBITS

1. Using the electromagnetic flow probe and the radioactive microsphere technique, systemic and regional haemodynamic variables were measured in conscious normotensive and hypertensive rabbits. The rabbits were made hypertensive by unilateral nephrectomy combined with cellophane-wrapping of the remaining kidney and systemic and regional haemodynamic effects of isoprenaline infusions (0.5 μg-kg^?1 .min^?1) were compared in the two groups of animals. 2. Isoprenaline evoked increases in heart rate and cardiac index while the total peripheral resistance decreased. In the hypertensive rabbits the effects were similar, except for a significantly more pronounced decrease in blood pressure. 3. Isoprenaline increased the fraction of the cardiac output delivered to the heart, skin and fat, at the expense of the fractions to the brain, stomach, small intestine, pancreas, liver and kidney(s) in both normotensive and hypertensive animals. Local peripheral resistance was decreased, most prominently, in the heart, skin, skeletal muscle and fat. 4. In the normotensive rabbits pretreatment with propranolol (4 mg.kg^?1 infused in 1 h) effectively blocked the cardiovascular responses following isoprenaline infusion. 5. Since the systemic and regional haemodynamic effects of isoprenaline were not less (if anything, slightly more) in the hypertensive than in the normotensive rabbits, our results provide no evidence for subsensitivity of β-adrenoceptors as a contributory factor in the development of hypertension in this model.     

RENAL SYMPATHETIC NERVE ACTIVITY MEASURED BY NOREPINEPHRINE SPILLOVER RATE IN RESPONSE TO CHANGES IN BLOOD PRESSURE IN CONSCIOUS RABBITS

1. Renal sympathetic nerve activity (RSNA) in response to changes in mean arterial pressure (MAP) was examined by measuring renal norepinephrine (NE) spillover rate in conscious rabbits. 2. A chronic renal vein catheter was implanted for sampling renal venous blood without stress in conscious animals. 3. RSNA estimated by renal NE spillover rate significantly increased in response to moderate falls in MAP produced by sodium nitroprusside (SNP) infusion and decreased in response to moderate rises in MAP produced by phenylephrine (PE) infusion. 4. The NE spillover method is sufficiently sensitive to detect responses of RSNA to physiological stimuli in conscious rabbits.     

PROSTAGLANDINS AND THE RENAL RESPONSES TO HAEMORRHAGE, ANGIOTENSIN II AND METHOXAMINE IN CONSCIOUS RABBITS

1. The responses to 20% haemorrhage were examined in conscious rabbits with or without inhibition of prostaglandin production by indomethacin (5 mg/kg +0.5 mg/kg per h i.v.). In rabbits not pretreated with indomethacin, haemorrhage lowered mean arterial pressure by 6.3 (s.e.m. = 1.6) mmHg, renal blood flow by 22.8 (s.e.m. = 3.4) ml/min and glomerular filtration rate (GFR) by 3.4 (s.e.m. = 0.6) ml/min, and raised plasma renin activity by 5.2 (s.e.m. = 1.0) ng/ml per h. Pretreatment of the rabbits with indomethacin did not significantly alter the responses to haemorrhage. Mean arterial pressure fell by 10.9 (s.e.m. = 1.8) mmHg, renal blood flow by 24.9 (s.e.m. = 3.9) ml/min and GFR by 4.2 (s.e.m. = 1.8) ml/min and plasma renin activity rose by 3.2 (s.e.m. = 0.5) ng/ml per h. 2. In a separate group of 5 rabbits, angiotensin II was infused at 10, 25 and 50 ng/kg per min i.v. or methoxamine was infused at 10 and 25 μg/kg per min i.v. After indomethacin pretreatment, angiotensin II caused a significantly greater rise in mean arterial pressure and greater fall in renal vascular conductance, but there was no effect on the GFR response. In contrast, methoxamine caused significantly smaller falls in GFR, renal blood flow and renal vascular conductance after indomethacin pretreatment. 3. Indomethacin significantly lowered resting GFR but not renal blood flow or arterial pressure. 4. Thus, indomethacin pretreatment accentuated the renal vasoconstriction to angiotensin II, reduced the renal vasoconstriction to methoxamine and had no effect on the responses to haemorrhage. 5. The results therefore suggest that prostaglandins do not act to lessen the renal effects of all vasoconstrictor stimuli, but that the prostaglandin response depends on the nature of the ischaemic stimulus.     

ATRIAL NATRIURETIC FACTOR IN CHRONIC RENAL FAILURE: STUDIES IN MAN AND THE RAT

1. Plasma concentration and atrial content of atrial natriuretic factor (ANF) were measured in rats with chronic renal failure induced by subtotal nephrectomy. 2. Plasma ANF was higher, and atrial ANF content lower in rats with renal failure when compared with sham-operated controls. 3. Plasma renin activity (PRA) and ANF were elevated at 1 week following subtotal nephrectomy. After 1 month plasma ANF had risen further, but PRA was suppressed to below control values. 4. Plasma ANF was also measured in six patients with chronic renal failure undergoing routine haemodialysis. 5. Elevated plasma ANF levels in patients with renal failure were lowered by haemodialysis, although extraction of ANF across the dialysis membrane was negligible. 6. Secretion of ANF is increased in chronic renal failure in man and the rat, possibly mediated by increased intravascular volume.     

STRUCTURAL INFLUENCES ON RESISTANCE IN THE HINDLIMB VASCULAR BED OF THE RENAL HYPERTENSIVE RABBIT

1. The contribution of arteriolar structural change to hindlimb vascular resistance was examined in the renal wrap hypertensive rabbit. 2. Haemodynamic variables were recorded at rest and after maximal vascular dilation using sodium nitroprusside and peripheral autonomic effector blockade. In the same animals at the end of experiments, morphometric measurements of hindlimb muscle arterioles were made. 3. Mean arterial pressure (MAP) and hindlimb vascular resistance were elevated in hypertensive animals compared with normotensive animals at rest and after maximal dilation. 4. Lumen area and lumen diameter were reduced whereas wall area and wall area to lumen area ratio were increased in hypertensive animals compared with normotensive animals. 5. In the renal wrap model of hypertension, the reduction in lumen area of arterioles, < 200 pm in diameter, is sufficient to explain the increase in haemodynamic resistance.     

INFLUENCE OF CARDIAC AFFERENTS ON TIME-DEPENDENT CHANGES IN THE RENAL SYMPATHETIC BAROREFLEX OF CONSCIOUS RABBITS

1. The stability of the renal sympathetic baroreflex and nasopharyngeal reflex, and the role of cardiac sensory receptors, was studied in conscious rabbits over a 5 h experimental period. 2. Renal sympathetic nerve activity (SNA) was recorded during (i) slow ramp changes in mean arterial pressure (MAP) of 1-2 mmHg/s induced by inflating perivascular balloon cuffs, and (ii) the inhalation of cigarette smoke. Experiments were repeated in other rabbits after blocking cardiac afferents with 5% intrapericardial procaine. 3. Baroreflex responses to the first two caval cuff inflations of the day were significantly greater than subsequent responses. After this, triplicate sets of reflex curves were relatively stable during a 2 h period in the morning. When the experiment was repeated in the afternoon, there was a significant attenuation of baroreflex range and a small fall in resting renal SNA which were abolished by pericardial procaine. 4. Changes in baroreflex properties were minimal when the reflex was assessed only twice, at the beginning and end of a 5 h period. No change was seen in the nasopharyngeal reflex whether the rabbits had been subjected to few or to many cuff inflations. 5. We conclude that time dependent changes can occur in the renal sympathetic baroreflex of conscious rabbits which must be allowed for by appropriate protocol design. These include increasing inhibitory influences from cardiac sensory receptors in experimental situations requiring multiple reflex estimations.     

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.     

NEUROHUMORAL ACTIVATION IN HEART FAILURE: ROLE OF PARAVENTRICULAR NUCLEUS

1. A number of neurohumoral processes are activated in heart failure (HF), including an increase in the plasma concentration of noradrenaline. 2. Few studies have been performed to examine the role of the central nervous system (CNS) in the activation of sympathetic outflow during HF. In the present paper we review the limited studies performed to examine the role of the CNS in the activation of sympathetic outflow, with particular emphasis on our recent study that examined the activity of discrete regions of the brain as assessed by histological localization and photodensitometric quantification of the metabolic enzyme hexokinase during HF. 3. There were significant increases in hexokinase activity in the parvocellular (pPVN) and magnocellular (mPVN) divisions of the paraventricular nucleus of the hypothalamus and in the locus coeruleus (LC) in rats with HF. No changes in hexokinase activity were observed in the median preoptic area, supraoptic nucleus (SON) or posterior hypothalamus. 4. We conclude that HF is associated with changes in specific areas in the brain and that alterations in the activation of neurons in the pPVN, mPVN and LC are likely to be related to alterations in vasopressin production, blood volume regulation and sympathoexcitation observed in the HF state.     

THE EFFECTS OF MECLOFENAMATE ON RENAL AND PERIPHERAL VASCULAR BEDS IN CONSCIOUS RABBITS

1. Meclofenamate caused a dose-dependent increase in renovascular resistance in conscious rabbits. 2. This effect was greatest in inner cortical zones at the highest dose (6 mg/kg) but at the lowest dose (0-75 mg/kg) vascular resistance in the outer cortex was preferentially increased. 3. In contrast, meclofenamate increased cerebral perfusion and the proportion of cardiac output received by the testis. No effect was demonstrated on other organs studied. 4. The results suggest a local vasodilator influence of renal prostaglandins in normal conscious rabbits.     

充血性心力衰竭患者血清甲状腺激素和心功能的变化

测定５６例充血性心力衰竭（ＣＨＦ）患者甲状腺激素水平的变化，发现三碘甲状腺原氨酸（Ｔ３）明显低于正常，反三碘甲状腺原氨酸（ｒＴ３）显著升高。心衰程度越重，变化越明显。提示甲状腺激素变化对心衰患者心功能损害程度、治疗和预后具有一定意义。     

INTRARENAL MECHANISM FOR RENAL VASOCONSTRICTION RESULTING FROM STIMULATION OF THE URETER IN THE DOG

1. The mechanism responsible for ipsilateral renal vasoconstriction resulting from mechanical stimulation of the ureter was examined using the pharmacological antagonists saralasin, SQ20881, indomethacin, atropine and phentolamine. 2. A segment of PE tubing was implanted in the left ureter, patency being well maintained. Three to four days later renal blood flow was measured bilaterally and antagonists administered intravenously. 3. The mechanism responsible for vasoconstriction could not be attributed to either increased intrarenal noradrenaline or angiotensin, nor to a decreased activity of prostaglandins, kinins or acetylcholine. 4. Histological and bacteriological examination also proved negative. 5. Thus, additional evidence of an unidentified intrarenal mechanism causing vasoconstriction is presented.     

CROMAKALIM SUPPRESSES HYPERTONIC SALINE-INDUCED RENAL VASOCONSTRICTION IN ANAESTHETIZED DOGS

1. Intrarenal arterial infusion of hypertonic saline (HS) transiently increased and then gradually reduced renal blood flow (RBF) in anaesthetized dogs. Glomerular filtration rate (GFR) but not filtration fraction decreased at the end of the infusion. 2. In the presence of a potassium channel opener cromakalim (0.3 μg/kg per min), HS infusion failed to reduce RBF; the initial increase in RBF was maintained throughout the infusion. Since cromakalim also prevented the decrease in GFR, HS infusion lowered filtration fraction. 3. The results suggest that cromakalim inhibits both pre-and postglomerular vasoconstriction induced by HS infusion.