The renin-angiotensin system and the central nervous system.

One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons in the brain merits investigation.     

Effect of DuP 753, a nonpeptide angiotensin II receptor antagonist, on the drinking responses to acutely administered dipsogenic agents in rats.

The present studies examine the effect of the nonpeptide angiotensin II (AII) type 1 receptor antagonist, DuP 753, on water intake in rats treated with dipsogenic stimuli, which are thought to induce drinking via release of renin and subsequent formation of AII. Subcutaneous administration of DuP 753 in doses that are known to inhibit drinking induced by AII failed to inhibit the water intake of rats following subcutaneous administration of the beta-adrenoceptor agonist isoproterenol. The peptide antagonist1 Sar, 8Ileu-AII, which blocks both AII type 1 and AII type 2 receptors, also failed to inhibit isoproterenol-induced drinking, suggesting that neither subtype is involved in this drinking response. Additional studies verified previous reports that acute subcutaneous administration of both the beta-adrenoceptor antagonist propranolol and the angiotensin I-converting enzyme inhibitor captopril could block the drinking response to subcutaneous administration of isoproterenol. Subcutaneous administration of DuP 753 also failed to inhibit the drinking responses to subcutaneous administration of serotonin, 5-hydroxytryptophan, hypertonic saline, and polyethylene glycol. However, central intraventricular administration of DuP 753 inhibited the drinking response to subcutaneous administration of isoproterenol. The results are discussed in terms of the importance of AII in mediating isoproterenol-, serotonin-, and 5-hydroxytryptophan-induced water intake and suggest a need to readdress this mechanism.     

A prolonged pressor response to intraventricular angiotensin II following bilateral nephrectomy

Intravenous injections of renin have been reported to produce a prolonged pressor response in nephrectomized rats which is mediated by angiotensin II (AII) and is shortened by anesthesia. Here we report a similar prolonged blood pressure increase for intraventricular AII but not for intravenous injections of AII. The extended pressor effects of central AII injections following nephrectomy are not due to water intake but may be partially accounted for by a prolonged action of antidiuretic hormone. The central effects of AII may explain the prolonged pressor action of intravenous renin injections in unanesthetized, nephrectomized rats, although an interaction with the sympathetic nervous system at two different sites of action is also possible. It is suggested that the anti-hypertensive action of the kidneys is through the release of a humoral agent, possibly prostaglandins.     

Renin and hemodynamic changes via central adrenergic, cholinergic, and sodium receptor mechanisms in conscious rats.

The effects of centrally administered autonomic drugs and hypertonic saline on renin release were studied in the conscious rat. A 0.3 mug intraventricular dose of isoproterenol, which is one-thirtieth of the intraperitoneal dose required to stimulate renin release, induced the release of renin into the systemic circulation. Norepinephrine had no effect on renin release in the same dose range. Hypertonic saline and carbachol suppressed renin release. Alterations in renin release were preceded by a reciprocal change in blood pressure. These results suggest a central nervous system site for sodium, beta-adrenergic, and cholinergic receptors in altering renin release and blood pressure.     

Pressor inhibition of angiotensin-induced ACTH secretion

We investigated whether the pressor effects of systemically administered angiotensin II (AII) influence ACTH secretion. Adrenalectomized barbiturate-anesthetized mongrel dogs with constant low resting cortisol concentrations due to slow constant cortisol infusion received either bolus injections (2.5 micrograms kg-1) or 15-min i.v. infusions of a low dose (12.5 ng kg-1min-1) of AII during which blood samples were taken for ACTH and cortisol determinations. In sequential continuous experiments in each dog, blood pressure was allowed to increase in response to AII administration or was controlled by means of concurrent i.v. injections or infusions of the hypotensive drug papaverine, or by blood withdrawal from the vena cava. When the arterial pressure rise induced by AII was substantially attenuated or prevented by papaverine administration or blood withdrawal, mean ACTH secretion rates increased 400-800% and mean ACTH concentrations increased by 280-500%. On the other hand, AII administration alone caused large increases in mean arterial blood pressure but did not increase ACTH secretion significantly above control levels. These data suggest that when endogenous AII levels are elevated without a concurrent increase in blood pressure, as occurs during hypovolemia or sodium depletion, AII may have a significant influence on ACTH secretion.     

Chronic dietary administration of tryptophan prevents the development of deoxycorticosterone acetate salt induced hypertension in rats

Hypertension developed within 3 to 5 weeks in uninephrectomized rats administered deoxycorticosterone acetate (DOCA) at a dose of 850 micrograms X kg-1 X day-1 via Silastic tubes and given isotonic saline to drink. Chronic dietary administration of tryptophan (25 and 50 g/kg of food) to DOCA-treated rats reduced their exaggerated intake of NaCl solution and attenuated the elevation of blood pressure induced by treatment with DOCA alone. Treatment with tryptophan also protected against the reduction in urinary concentrating ability during a 24-h dehydration that is characteristic of DOCA-treated rats. Other tests assessed the responsiveness to the beta-adrenergic agonist, isoproterenol. These included measurement of drinking and heart rate following acute administration of isoproterenol. The characteristically depressed drinking and chronotropic responses of DOCA-treated rats to acute administration of isoproterenol were unaffected by tryptophan. Responsiveness to angiotensin II (AII) was also tested by assessment of dipsogenic and metabolic responses to acute administration of AII. The increased drinking and tail skin temperature responses to administration of AII, characteristic of DOCA-treated rats, were reduced in a graded fashion by treatment with graded doses of tryptophan. The specific binding of AII to its receptors in membranes form the diencephalon of the brain was increased by treatment with DOCA but was returned to control level by concomitant treatment with tryptophan. The content of serotonin in the mesencephalon of the brain was not changed significantly by treatment with tryptophan, but the content of 5-hydroxyindole acetic acid in the same region increased significantly, suggesting that turnover of serotonin was increased by chronic treatment with tryptophan. The cardiac hypertrophy characteristic of treatment with DOCA was attenuated significantly by chronic treatment with tryptophan, while the low, resting plasma renin activity of the DOCA-treated group was unchanged. These results suggest that tryptophan provides significant protection against the development of DOCA-induced hypertension, polydipsia, polyuria, and cardiac hypertrophy in rats. It also reduces the hyperresponsiveness to treatment with AII, possibly by decreasing the specific binding of AII to its receptors. It also appears to increase the turnover of serotonin in the brain. Whether either one or all of these is responsible for the antihypertensive effect of tryptophan remains for further study.     

RV instantaneous intraventricular diastolic pressure and velocity distributions in normal and volume overload awake dog disease models

Intraventricular diastolic right ventricular (RV) flow field dynamics were studied by functional imaging using three-dimensional (3D) real-time echocardiography with sonomicrometry and computational fluid dynamics in seven awake dogs at control with normal wall motion (NWM) and RV volume overload with diastolic paradoxical septal motion. Burgeoning flow cross section between inflow anulus and chamber walls induces a convective pressure rise, which represents a "convective deceleration load" (CDL). High spatiotemporal resolution dynamic pressure and velocity distributions of the intraventricular RV flow field revealed time-dependent, subtle interactions between intraventricular local acceleration and convective pressure gradients. During the E-wave upstroke, the total pressure gradient along intraventricular flow is the algebraic sum of a pressure decrease contributed by local acceleration and a pressure rise contributed by a convective deceleration that partially counterbalances the local acceleration gradient. This underlies the smallness of early diastolic intraventricular gradients. At peak volumetric inflow, local acceleration vanishes and the total adverse intraventricular gradient is convective. During the E-wave downstroke, the strongly adverse gradient embodies the streamwise pressure augmentations from both local and convective decelerations. It induces flow separation and large-scale vortical motions, stronger in NWM. Their dynamic corollaries on intraventricular pressure and velocity distributions were ascertained. In the NWM pattern, the strong ring-like vortex surrounding the central core encroaches on the area available for flow toward the apex. This results in higher linear velocities later in the downstroke of the E wave than at peak inflow rate. The augmentation of CDL by ventriculoannular disproportion may contribute to E wave and E-to-A ratio depression with chamber dilatation.     

Ventilatory response to moderate and severe hypoxia in adult dogs: role of endorphins

To determine the role of opioids in modulating the ventilatory response to moderate or severe hypoxia, we studied ventilation in six chronically instrumented awake adult dogs during hypoxia before and after naloxone administration. Parenteral naloxone (200 micrograms/kg) significantly increased instantaneous minute ventilation (VT/TT) during severe hypoxia, (inspired O2 fraction = 0.07, arterial PO2 = 28-35 Torr); however, consistent effects during moderate hypoxia (inspired O2 fraction = 0.12, arterial PO2 = 40-47 Torr) could not be demonstrated. Parenteral naloxone increased O2 consumption (VO2) in severe hypoxia as well. Despite significant increases in ventilation post-naloxone during severe hypoxia, arterial blood gas tensions remained the same. Control studies revealed that neither saline nor naloxone produced a respiratory effect during normoxia; also the preservative vehicle of naloxone induced no change in ventilation during severe hypoxia. These data suggest that, in adult dogs, endorphins are released and act to restrain ventilation during severe hypoxia; the relationship between endorphin release and moderate hypoxia is less consistent. The observed increase in ventilation post-naloxone during severe hypoxia is accompanied by an increase in metabolic rate, explaining the isocapnic response.     

Effect of daily hyperhydration on fluid-electrolyte changes in endurance-trained volunteers during prolonged restriction of muscular activity

The aim of this investigation was to evaluate the effect of a daily intake of fluid and salt supplementation on fluid and electrolyte losses in endurance-trained volunteers during prolonged restriction of muscular activity (hypokinesia). The studies were performed on 30 long-distance runners aged 23–26 who had a peak oxygen uptake of 65.5 mL/kg/min and had taken 13.8 km/d on average prior to their participation in the study. The volunteers were divided into three groups: The volunteers in the first group were placed under normal ambulatory conditions (control subjects), the second group of volunteers subjected to hypokinesia alone (hypokinetic subjects), and the third group of volunteers was submitted to HK and consumed daily 0.1 g sodium chloride (NaCl)/kg body wt and 26 mL water/kg body wt (hyperhydrated subjects). The second and third group of volunteers were kept under an average of 2.7 km/d for 364 d. During the pre-experimental period of 60 d and during the experimental period of 364 d sodium, potassium, calcium, and magnesium in urine and plasma were determined. Blood was also assayed for osmolality, hemoglobin, hematocrit, plasma volume, plasma renin activity and plasma aldosterone. Mean arterial blood pressure was also determined. In the hyperhydrated volunteers plasma volume and arterial blood pressure increased, whereas plasma osmolality, plasma renin activity, plasma aldosterone, hematocrit, hemoglobin concentration, and urinary excretion and concentrations of electrolytes in plasma decreased. In the hypokinetic volunteers, plasma volume and arterial blood pressure decreased significantly, whereas hematocrit values, hemoglobin concenfration, plasma osmolality, plasma renin activity, plasma aldosterone, and electrolytes in urine and plasma increased significantly during the experimental period. It was concluded that chronic hyperhydration may be used in minimizing fluid and electrolyte losses in endurance-trained volunteers during prolonged restriction of muscular activity.     

Atriopeptin alters the vasopressin and renin responses elicited by hemorrhage

This study was designed to investigate whether an infusion of atrial peptide is capable of modulating the hormonal and hemodynamic responses elicited by acute hemorrhage. Conscious dogs were bled at a rate of 0.8 ml.kg-1.min-1 until 20 ml of blood/kg body wt had been removed. Two experiments were performed on each dog; in one experiment the animal was given alpha-human atrial natriuretic peptide (alpha-hANP) (50 ng.kg-1.min-1) dissolved in saline; in the other only the saline vehicle was given. Right and left atrial pressures decreased during hemorrhage in all experiments; the absolute decreases were greater when the animals received atriopeptin, but the differences between treatments were statistically significant only for right atrial pressure. Cardiac output decreased (P less than 0.05) and total peripheral resistance increased (P less than 0.05) during hemorrhage when atriopeptin was infused; although these variables showed similar trends when vehicle alone was infused during hemorrhage, no significant changes occurred. Infusion of atrial peptide did not affect the decrease in arterial blood pressure that occurred during hemorrhage. The increase in plasma vasopressin induced by hemorrhage was potentiated, but the increase in plasma renin activity was attenuated when alpha-hANP was infused. Hemorrhage increased circulating aldosterone levels in each experiment, but the response was less pronounced when alpha-hANP was given during the experiment. Intravenous administration of alpha-hANP modulates the hemodynamic responses elicited by hemorrhage, potentiates the rise in plasma vasopressin, and attenuates the rise in plasma renin activity induced by acute blood loss in conscious dogs.     

Effect of plasma carbonic anhydrase on ventilation in exercising dogs

Recent studies suggest pH sampled by arterial chemoreceptors may not equal that sampled by external pH electrodes, because the uncatalyzed hydration of CO2 in plasma is a slow reaction (t 1/2 approximately 9 S). The importance of this reaction rate to ventilatory control (particularly during exercise) is not known. We studied the effect of catalyzing the CO2-pH reaction in three awake exercising dogs with chronic tracheostomies and carotid loops; the dogs were trained to run on a treadmill. Respiration frequency, tidal volume, total ventilation, and end-tidal partial pressure of CO2 (PCO2) were continuously monitored. Periodically, carotid artery blood was drawn and analyzed for partial pressure of O2 (PO2), PCO2, pH, and plasma carbonic anhydrase (CA) activity. Measurements were made during steady-state exercise (3 mph and 10% grade), during a control period, after injection of a 5 ml bolus of saline, and after injection of 5 mg/kg of bovine CA dissolved in 5 ml of saline. This dose of CA increased the reaction rate by more than 80-fold. Neither the control nor the CA injections significantly altered the ventilatory parameters. Saline and CA date differed by less than 5% in ventilation, 1 Torr in arterial PCO2, 0.01 in pH units, and 1.5 Torr in end-tidal PCO2. Thus the of CO2 hydration in plasma is not a significant factor in ventilatory control.     

Intrarenal blood flow distribution: effect of carotid occlusion.

In this study we have examined the influence of bilateral carotid occlusion on intrarenal blood flow distribution. Using labeled microspheres to determine intrarenal hemodynamics, bilateral carotid ligation in mannitol or saline expanded dogs resulted in an increase in outer cortical blood flow and a decrease in inner cortical flow. Total renal blood flow and glomerular filtration rate did not change significantly during carotid occlusion whereas the average mean arterial blood pressure rose from 130 to 166 mmHg. Inner cortical flow resistance increased substantially after carotid occlusion; outer cortical resistance was unchanged. These results suggest that bilateral carotid occlusion selectively activates inner cortical renal sympathetic fibers.     

Changes in platelet function and gastrointestinal bleeding following repeated administration of acetylsalicylic acid in the rat and the dog.

Two dogs were prepared with Pavlov pouches of the fundic area of the stomach using standard techniques. During treatment periods of 14 days, 200 mg acetylsalicylic acid (ASA) was introduced into the pouch twice daily by insufflation. One hour after each drug administration the pouch was washed with saline and the fluid assayed for blood. Bleeding from the pouch increased to a maximum on the 3rd or 4th day of the treatment period and subsequently declined such that by the 8th day blood loss was minimal and approximated that found during control periods. Platelet aggregation (in vitro) responses to adenosine diphosphate were significantly (p less than 0.01) inhibited on day 3 when aggregation curve heights were reduced by 66.2 +/- 13.11% (mean +/- SEM) from control values. On day 7 and during the ensuing 7-day period when ASA was given twice daily, the heights of aggregation responses were reduced by only 20-30% from controls. These responses were significantly (p less than 0.001) greater than those found on day 3. Similar changes in platelet reactivity were found in plasma from rats given ASA twice daily for 7 days. Aggregation responses to collagen were depressed by 95.5 +/- 4.49% on day 1 following two doses of ASA. As the treatment period continued, the aggregation responses increased in magnitude until the 7th day they were similar in height to those from control animals. The mechanism involved in this adaptation to ASA treatment seen with these platelets is not known.     

Controlled trial of enalapril in patients with chronic fluid overload undergoing dialysis

About one third of patients receiving dialysis for end stage renal failure have chronic fluid overload despite advice to restrict their oral fluid intake. To investigate the potential of an angiotensin converting enzyme inhibitor in reducing the urge to drink and consequent gain in weight, a double blind, placebo controlled crossover trial of enalapril was conducted in 25 patients receiving dialysis who had fluid overload. The trial comprised a baseline period of four weeks; two periods of treatment, each of four weeks, during which patients received either placebo or enalapril 5 mg twice each week; and a follow up period of four weeks. Five patients withdrew from the trial, one because of an adverse drug reaction to enalapril. A range of biochemical and behavioural variables was measured during the baseline period, at the completion of periods 1 and 2, and during follow up. These variables included gain in weight between dialysis sessions; blood pressure; plasma concentrations of sodium, angiotensin II, and vasopressin; plasma renin and angiotensin converting enzyme activities; osmolality; and estimations of thirst, intake of fluid, and control of drinking. Enalapril caused a significant reduction in gain in weight between dialysis sessions, thirst, and oral intake of fluid in parallel with significantly increased renin activity, significantly decreased angiotensin converting enzyme activity, and decreased concentrations of angiotensin II. Gain in weight and angiotensin converting enzyme activity returned to baseline values once patients stopped taking enalapril.These results suggest that enalapril may act on the renin-angiotensin system and reduce intake of fluid by inhibiting angiotensin converting enzyme.     

The role of cholecystokinin octapeptide in the central control of food intake in the dog

Cholecystokinin octapeptide (CCK-8, 1, 190 pmol/5 min) decreased food intake and water consumption in two models of ingestive behavior, i.e., food deprivation-induced feeding and insulin-induced feeding, when administered into the third (3V) and lateral (LV) cerebral ventricles. In fasted dogs, the suppression of food intake was more prominent after 3V CCK-8, whereas intravenously administered CCK-8 was without effect. Neuropeptide Y (NPY, 1, 190 pmol) had no significant stimulatory effect on food intake and water consumption in fasted as well as satiated dogs, and actually reduced both food and water intake in insulin-treated dogs. There was a slight but significant decrease in food and water intake after 275 nmol naloxone administration in both feeding models, and some of the dogs vomited. In insulin-treated animals, CCK-8 reversed, but NPY potentiated the hypothermic phase of temperature response observed after saline administration, whereas naloxone failed to alter rectal temperature. These results suggest that the effect of CCK-8 on feeding seems to involve central mechanisms in the dog, and that the mechanisms by which CCK-8, NPY and naloxone affect feeding behavior are different.     

Unloading arterial baroreceptors causes neurogenic hypertension

We developed a new model to examine the role of arterial baroreceptors in the long-term control of mean arterial pressure (MAP) in dogs. Baroreceptors in the aortic arch and one carotid sinus were denervated, and catheters were implanted in the descending aorta and common carotid arteries. MAP and carotid sinus pressure (CSP) averaged 104 +/- 2 and 102 +/- 2 mmHg (means +/- 1 SE), respectively, during a 5-day control period. Baroreceptor unloading was induced by ligation of the common carotid artery proximal to the innervated sinus (n = 6 dogs). MAP and CSP averaged 127 +/- 7 and 100 +/- 3 mmHg, respectively, during the 7-day period of baroreceptor unloading. MAP was significantly elevated (P < 0.01) compared to control, but CSP was unchanged. Heart rate and plasma renin activity increased significantly in response to baroreceptor unloading. Removal of the ligature to restore normal flow through the carotid resulted in normalization of all variables. Ligation of the carotid below a denervated sinus (n = 4) caused a significant decrease in CSP but no systemic hypertension. These results indicate that chronic unloading of carotid baroreceptors can produce neurogenic hypertension and provide strong evidence that arterial baroreceptors are involved in the long-term control of blood pressure.     

Changes in the blood flow of the primary carotid and its branches during modifications of the O2 and CO2 composition of alveolar gas]

We measured common carotid blood flow using a range gated Doppler velocimeter, and internal and external blood velocities using a continuous Doppler in 20 lowlanders at sea level, under normal barometric pressure, in 10 subjects in an altitude chamber under a barometric pressure of 462 Torr (61.6 KPa) and then in 5 of them over a 3-weeks period at 3850 m of elevation (475 Torr = 63.3 KPa). The same measurements were also performed in 20 permanent residents at 3850 m. Common carotid blood flow was 15% higher in all subjects exposed to high altitude, due to a lowering in downstream resistances since systemic blood pressure did not change at high altitude. The increase in common carotid blood flow was the result of an immediate increase in internal carotid blood velocities observed in the altitude chamber as well as after the arrival at high altitude, but a few days later those velocities in the internal carotid artery declined to values similar to those observed at sea level. In the same time velocities in external carotid artery rose at high altitude, remained steadily elevated and the result is a permanent increase in common carotid blood flow at altitude. In all subjects we performed the same measurements, during an acute inhalation of gas mixtures to try to quantify the mechanisms controlling the changes in common carotid blood flow while changing gas inhalation. In the limits of the variations in PO2 (60 to 400 Torr) and in PCO2 (30 to 50 Torr) the stimulation by CO2 is twice more efficient than the O2 stimulation on vasomotion.     

Central administration of angiotensin II receptor antagonists and arterial pressure regulation: a note of caution.

The blunting of arterial pressure increases to a variety of pressor agents or the lowering of arterial pressure in some models of hypertension following intracerebroventricular administration of an angiotensin II (AII) antagonist, has been interpreted as prima facie evidence for the involvement of the central AII system in these situations. Central administration of vasopressin or carbachol (a cholinergic agonist) produces pressor effects which have been reported to be due to an increase in the activity of the sympathetic nervous system. We now report that central administration of AII antagonists [either (Sar-1, Ile-8) AII or (Sar-1, Ala-8) AII] in rats prevents the majority (greater than 70%) of the pressor effects of intraventricular vasopressin or carbachol. These results can be interpreted in two ways. The first is that all of these pressor agents use a central angiotensinergic mechanism(s) to increase sympathetic nervous system activity. An alternative hypothesis is that centrally administered AII antagonists non-specifically inhibit sympathetic nervous system function.     

Difference between intracarotid and intravenous infusions of angiotensin II on baroreflex sensitivity and vasopressin release in conscious rats

A carotid infusion of angiotensin (AII) (10 ng/kg/min) has been found to increase significantly higher mean arterial pressure (MAP) and produces significantly lower bradycardia than AII intravenous infusions at the same dose and rate. Besides, i.v. administration of AII elicits greater impairment on baroreflex sensitivity than carotid infusion of AII does. On the other hand, vasopressin vascular receptor blockade did not modify the baroreflex sensitivity either in the carotid or in the i.v. infusions of AII, and plasma AVP measurements did not change significantly in any group. It clearly indicates that neither AVP nor baroreflex impairment plays any role on the pressor action of AII intracarotid infusions at a low dose. The present results further suggest that baroreflex impairment in rats may unlikely be located in the region irrigated by the carotid artery.     

Inhibition of renin release following left circumflex bradykinin injection in dogs

We examined the renin secretory response to bradykinin (BK) injection into the left circumflex coronary artery (LCx) in dogs. Studies were conducted in anesthetized, carotid sinus denervated dogs which had been maintained on a low sodium diet. A 25 ga needle was inserted into the LCx for injection of BK (0.15 micrograms/kg). The rate of renin secretion (RS) was obtained during a 30 min control period, at 5 min after a non-hypotensive hemorrhage (10 ml/kg), at 1, 3 and 5 min after BK injection and at 15 min after the reinfusion of withdrawn blood. Four series of studies were conducted. Series I: BK injection into the LCx, Series II: saline injection into the LCx (sham), Series III: intravenous injection of BK, and Series IV: BK injection into the LCx in dogs with prior renal denervation. RS was suppressed by 80% (P less than 0.05) 5 min after injection of BK into the LCx. Saline injection (sham) into the LCx or intravenous BK administration did not inhibit RS. Furthermore, suppression of RS was not present in dogs with prior renal denervation. These results indicate that BK injection into the LCx causes a prompt reduction in the rate of RS and that this response is reflexively mediated by the renal nerves.