EFFECT OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION ON RENAL NOREPINEPHRINE SPILLOVER RATE AND BAROREFLEX RESPONSES IN CONSCIOUS RABBITS

1. To evaluate the effects of angiotensin-converting enzyme (ACE) inhibition on sympathetic nerve activity, renal and total norepinephrine (NE) spillover rates were examined under control conditions and during enalaprilat infusion at rest and in response to sodium nitroprusside (SNP)-induced hypotension. 2. Resting renal and total NE spillover rate during enalaprilat infusion were similar to control values. 3. During SNP infusion at 10 μg/kg per min, renal NE spillover rate increased by 26% in enalaprilat-treated group and by 39% in controls, in response to falls in mean arterial pressure (MAP) of 25 and 19% respectively. 4. During sympathetic stimulation induced by SNP, total NE spillover rate was significantly increased in both groups, but the 50% (s.e.m. = 12) increase in the enalaprilat-treated group was less (P<0.05) than the 97% (s.e.m. = 16) change observed in controls. 5. Enalaprilat treatment resulted in a higher renal to total NE spillover ratio (P<0.05). The ratio fell in parallel in both groups during SNP-induced hypotension. 6. This study indicates that the sympathetic nervous system interacts dynamically with the renin-angiotensin system during hypotensive stimulation but this occurs predominantly at sites other than the kidney.     

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.     

LONG-TERM INCREASES IN RENAL SYMPATHETIC NERVE ACTIVITY AND HYPERTENSION

1. Essential hypertensive patients have been characterized by increased sympathetic nerve activity, increased peripheral vascular tone, decreased plasma volume and normal cardiac output when compared with normotensive subjects. Bilateral renal denervation reduces the magnitude or delays the onset of the blood pressure response in numerous models of experimental hypertension regardless of the aetiology of the elevation in arterial pressure. 2. Using a servocontrolled intrarenal infusion system, we have elevated intrarenal noradrenaline concentration via intermittent renal artery infusion without decreasing renal blood flow as a method of simulating selective elevation of renal sympathetic outflow. 3. Chronic intrarenal adrenergic stimulation increased arterial pressure within 24 h and this hypertension persisted for 28 consecutive days. The elevated arterial pressure was not associated with sustained increases in plasma renin activity, aldosterone, circulating catecholamines, arginine vasopressin or significant renal vasoconstriction. Urinary sodium excretion was chronically elevated and the dogs remained in negative sodium balance for the duration of the intrarenal noradrenaline infusion. 4. After 2 weeks of elevated intrarenal neurotransmitter coupled with hypertension, renal vascular reactivity to further adrenergic stimulation was significantly increased because the hypertension was maintained during continual reductions in the daily dosage of neurotransmitter allowed to be infused by the servocontroller. After only 28 days of noradrenaline infusion, renal vascular hypertrophy developed in vessels from 150–300 μm. 5. We conclude that selective and intermittent increases in intrarenal adrenergic neurotransmitter are sufficient to elicit chronic hypertension in the absence of volume expansion. This intrarenal neuroadrenergic hypertension is closely associated with the haemodynamic parameters which characterize a major subset of human essential hypertensives.     

LACK OF SYMPATHETIC AUGMENTATION IN RESPONSE TO INTRAVENOUS LOAD OF GLUCOSE IN RABBITS

1. We investigated a link between sympathetic nervous function and carbohydrate metabolism by measuring renal sympathetic nerve activity in response to intravenous load of glucose in alpha-chloralose-urethane anaesthetized rabbits. 2. Intravenous infusion of a 25% glucose solution (0.5 g/kg) over 3 min caused a transient increase in arterial blood pressure and a decrease in renal sympathetic nerve activity. Thereafter, these parameters were restored and remained around preload levels while plasma glucose and insulin concentrations were still elevated. 3. Equimolar mannitol solution produced similar patterns of change in blood pressure and nerve activity without an elevation of plasma glucose and insulin levels. 4. The transient changes in blood pressure and renal nerve activity could be attributed to acute hypervolaemia indicated by similar changes in plasma osmolality and haematocrits in the two groups of treatment. 5. The present study did not support a close relationship between carbohydrate metabolism and the sympathetic nervous system regulating cardiovascular function.     

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.     

BLOOD PRESSURE RESPONSE TO NOREPINEPHRINE AND ANGIOTENSIN II IN THE OFFSPRING OF PARATHYROIDECTOMIZED MOTHER RATS

1. The basal blood pressure and the drug-stimulated pressor response were studied in male offspring in the sixth generation (5d-PTx-F6) of rats parathyroidectomized on day 5 of pregnancy. 2. The systolic blood pressure in conscious 5d-PTx-F6 rats measured by a tail cuff was significantly higher (P less than 0.001) than in control rats. 3. Venous plasma renin activity was significantly lower (P less than 0.001) in the 5d-PTx-F6 rats. Plasma levels of calcium, sodium, and potassium in the 5d-PTx-F6 rats and in the controls did not differ. 4. Systolic arterial pressure response to intravenously (i.v.) administered angiotensin II (150 ng/kg) in the 5d-PTx-F6 rats was significantly greater than in the controls (P less than 0.05), when blood pressure was measured directly through a pressure transducer under anaesthesia. 5. Pressor responses to norepinephrine (5 micrograms/kg, i.v.) in the 5d-PTx-F6 rats were significantly lower (P less than 0.05) than in the controls, when blood pressure was measured directly under anaesthesia. 6. The findings suggest that the 5d-PTx-F6 rats undergo functional alterations of the renin-angiotensin and sympathetic nervous systems for cardiovascular regulations.     

THE DOPAMINE PRODRUG, GLUDOPA, DECREASES BOTH RENAL AND EXTRARENAL NORADRENALINE SPILLOVER IN CONSCIOUS RABBITS

1. Renal and total noradrenaline (NA) spillover rates were examined under control conditions and during graded infusions of gludopa (γ-l-glutamyl-l-dopa) in conscious rabbits. 2. Gludopa infusion at 25 and 100 μg/kg per min did not alter mean arterial pressure (MAP) and heart rate (HR), but had significant dose-related effects on the renal dopamine (DA) system. At the high dose there were pronounced increases in urinary DA excretion (>6000-fold) and renal DA content (> 100-fold); renal NA content doubled. 3. Renal venous DA increased after gludopa infusion, but arterial plasma DA concentrations were not significantly changed. Mean arterial plasma gludopa and l-dopa concentrations reached 890, 3190 ng/mL and 3, 10 ng/mL at low and high doses, respectively. 4. Gludopa resulted in a pronounced dose-dependent fall in renal NA spillover, which at 100 μg/kg per min accounted for almost half of the reduction in overall NA spillover rate. 5. The significant falls in renal and extrarenal NA spillover rate during gludopa infusion are consistent with suppression of renal and overall sympathetic activity. Gludopa-induced inhibition of renal NA spillover is likely to be due to the actions of DA generated in the kidney on presynaptic DA-2 and α-2 receptors. A central sympathoinhibitory mechanism may explain the reduced total NA spillover.     

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.     

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.     

HYPOTENSIVE RESPONSE TO ATRIAL NATRIURETIC FACTOR IN CONSCIOUS RENAL HYPERTENSIVE BEAGLES

The hemodynamic responses to i.v. infusion of 0.3 and 0.6 microgram/kg per min of human atrial natriuretic factor (hANF [102-126]) in intact, conscious, one-kidney, perinephritic, hypertensive beagles were examined and compared with the responses in ganglionic-blocked dogs. Blood pressure and heart rate were not affected but plasma ANF-like immunoreactivity was increased by as much as 627%. After hexamethonium (20 mg/kg, i.v.) blockade, a dose-dependent hypotensive response of up to 29 mmHg with no change in heart rate was observed. It is concluded that the compensatory mechanisms of the neurally mediated baroreflex system masked the depressor actions of hANF.     

VASOCONSTRICTION IN THE RENAL VASCULAR BED DURING EXERCISE: STUDIES IN CONTROL AND HEART FAILURE RABBITS

1. The effects of graded treadmill exercise on renal blood flow (RBF) were examined in seven rabbits, in which congestive heart failure (CHF) was produced by the administration of doxorubicin, 1 mg/kg, twice weekly for 8 weeks, and in seven controls. A third group of five rabbits underwent doxorubicin treatment with the addition of surgical section of the left renal sympathetic nerve. 2. During submaximal exercise, there was a small reduction in RBF in controls, which was greatly exaggerated in CHF. 3. In both control and heart failure rabbits, there was a precipitous fall in RBF as exercise fatigue developed. 4. Renal sympathectomy ablated these changes in RBF during exercise. 5. It is concluded that in heart failure there is an exaggerated, sympathetically mediated, diversion of blood flow away from the kidney. The onset of exercise fatigue in both normal and heart failure rabbits is accompanied by a marked intensification of this process.     

FUNCTIONAL SIGNIFICANCE OF THE 10 Hz RHYTHMIC DISCHARGES IN SYMPATHETIC NERVES

1. By measuring renal vascular conductance in anaesthetized and immobilized rabbits, the functional significance of the 10 Hz rhythmic discharges in the sympathetic nerves was assessed by electrical stimulation of the renal nerve. This stimulation mimicked the intermittently occurring 10 Hz rhythmic discharges. 2. Comparison of high-frequency (10-20 Hz) intermittent electrical stimulation with continuous low-frequency (5 Hz) stimulation showed that the intermittent high-frequency stimulation evoked faster (smaller time constant) and larger responses of the renal vascular conductance if the total number of stimulus pulses was the same. 3. Therefore, the intermittently occurring 10 Hz rhythmic discharges in the sympathetic nerve produces faster and larger effects on peripheral organs than effects produced by continuous discharges if the number of spikes is equal.     

NITRIC OXIDE INHIBITION DOES NOT PREVENT THE HYPOTENSIVE RESPONSE TO INCREASED RENAL PERFUSION IN RABBITS

1. The involvement of nitric oxide (NO) and platelet activating factor (PAF) in the systemic depressor responses to increased renal perfusion pressure (RPP) were investigated. 2. In anaesthetized rabbits, the left kidney was perfused via an extracorporeal circuit which allowed RPP to be increased from 65 mmHg to 125 mmHg. The response of systemic blood pressure (SBP) to increasing RPP was measured in the same rabbits. 3. One group of rabbits (n = 5) was treated with N^G-nitro-L-arginine (NOLA) to inhibit NO synthase activity (20 mg/kg i.v. bolus). Another group (n= 5), received 250mmol/L NaHCO₃ (4mL/kg bolus) as vehicle treatment. 4. Following an increase in RPP to 125 mmHg, SBP fell at a rate of 0.43 ± 0.06 mmHg/min in the vehicle treated rabbits. After NO synthase inhibition the rate of fall in SBP of 0.34 ± 0.07 mmHg/min was not significantly different from that in the vehicle group (P= 0.3). 5. Blockade of NO synthesis did not alter the renal blood flow, renal vascular resistance changes and pressure-related natriuresis and diuresis responses to increased RPP to 125 mmHg. 6. PAF receptor blockade, using WEB 2086 (0.5 mg/kg plus 0.5 mg/kg/h), did not alter the systemic, renal haemodynamic or urinary responses to increasing renal perfusion pressure to 125 mmHg. 7. These findings indicate that neither NO nor PAF play an important role in the blood pressure lowering activity, intrarenal haemodynamics and urinary excretory responses observed when RPP was increased to a level within the physiological range.     

DA-1 RECEPTORS MEDIATE RENAL EFFECTS OF THE DOPAMINE PRODRUG, GLUDOPA, IN CONSCIOUS RABBITS

1. Eight male rabbits were implanted with Doppler flow probes around the lower abdominal aorta and left renal artery. A 2 week recovery period was allowed prior to the experiment. 2. Normal saline, gludopa at 25 micrograms/kg per min and at 100 micrograms/kg per min were each infused i.v. for 60 min. One week later the same protocol was administered to four of these animals in addition to DA-1 antagonist SCH 23390 (0.3 mg/kg i.v.) before gludopa infusion. 3. Gludopa elicited significant increases in urine flow, urinary sodium excretion and renal blood flow, and decreased renal vascular resistance. These changes were abolished by the DA-1 antagonist. Blood pressure, heart rate and hindlimb blood flow remained unchanged. 4. Urine dopamine excretion was increased 1200-fold and 7800-fold after gludopa administration at 25 micrograms/kg per min and 100 micrograms/kg per min, respectively, while plasma dopamine concentration and plasma renin activity (PRA) were not significantly altered. However, PRA was elevated by gludopa with DA-1 antagonism. 5. The renal vasodilation, natriuresis and diuresis produced by gludopa in conscious rabbits appears to be mediated by locally generated dopamine via DA-1 receptors.     

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 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.