Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach—unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.

It is increasingly recognized that the practice of medicine is a “team sport” with different medical professionals working together toward the common goal of providing health care. Collaborative group testing, where students work together to answer test questions models this team environment. The act of collaborating to achieve a challenging task may be intrinsically rewarding because one feels like they contributed to the “greater good”, which for the same reason may reduce competition. Therefore, we hypothesized that prolonged participation in collaborative group testing in first and second year medical students would increase intrinsic motivation and decrease competition. We assessed intrinsic motivation and competition via administration of the Intrinsic Motivation Inventory and the Competitive Attitude Scale, respectively. Students completed the surveys at baseline and after participating in thirteen collaborative group tests in a medical physiology course over a time‐period of 10 months. We found that all measures of intrinsic motivation were significantly increased after participation in collaborative group testing, while levels of competition were not changed. We conclude that medical student participation in collaborative group testing provides the opportunity to address the core psychological needs required to increase intrinsic motivation. Further studies are needed to understand why there was no effect on competition.

Underperfusion of active skeletal muscle causes metabolites to accumulate and stimulate group III and IV skeletal muscle afferents, which triggers a powerful pressor response termed the muscle metaboreflex. Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in healthy individuals increases arterial pressure mainly via substantial increases in cardiac output (CO). The increases in CO occur via the combination of tachycardia and increased ventricular contractility. Importantly, MMA also elicits substantial central blood volume mobilization, which allows the ventricular responses to sustain the increases in CO. Otherwise preload would fall and the increases in CO could not be maintained. In subjects with systolic heart failure (HF), the ability to increase CO during exercise and MMA is markedly reduced, which has been attributed to impaired ventricular contractility. Whether the ability to maintain preload during MMA in HF is preserved is unknown. Using a conscious chronically instrumented canine model, we observed that MMA in HF is able to raise central blood volume similarly as in normal subjects. Therefore, the loss of the ability to raise CO during MMA in HF is not because of the loss of the ability to mobilize blood volume centrally. NEW & NOTEWORTHY In normal subjects during dynamic exercise muscle metaboreflex activation elicits large increases in cardiac output that occur via increases in heart rate, ventricular contractility, and, importantly, marked central blood volume mobilization that acts to maintain ventricular preload, thereby allowing the changes in cardiac function to maintain the increases in cardiac output. In subjects with heart failure, the ability to raise cardiac output during muscle metaboreflex activation is impaired. We investigated whether this is because of the inability to maintain ventricular preload. We found that this reflex is still able to elicit large increases in central blood volume, and therefore the limited ability to raise cardiac output likely stems from ventricular dysfunction and not the ability to maintain preload.

Spontaneous dynamic exercise promotes sympathoinhibition and decreases arterial pressure in two-kidney, one-clip (2K-1C) hypertensive rats. Renal sympathetic nerves stimulate renin secretion and increase renal tubular sodium reabsorption. We hypothesized that daily voluntary wheel running exercise by 2K-1C rats will decrease mean arterial pressure (MAP), plasma angiotensin II (Ang II), and aldosterone as well as normalize urinary sodium and potassium excretion independent of changes in glomerular filtration rate (GFR). Five-week-old male Sprague Dawley rats underwent sham clipping (Sham) or right renal artery clipping (2K-1C). Rats were randomized to standard caging (SED) or cages with running wheels (EX). After 12 weeks, rats were assigned to either collection of aortic blood for measurement of Ang II and aldosterone or assessment of inulin clearances and excretory function. Running distances were comparable in both EX groups. MAP was lower in 2K-1C EX vs 2K-1C SED rats (P<0.05). Plasma Ang II and aldosterone were significantly higher in 2K-1C SED rats and decreased in 2K-1C EX rats to levels similar to Sham SED or Sham EX rats. Clipped kidney weights were significantly lower in both 2K-1C groups, but GFR and urine flow rates were no different from right and left kidneys among the four groups. Total and fractional sodium excretion rates from the unclipped kidney of 2K-1C SED rats were higher vs either Sham group (P<0.05). Values in 2K-1C EX rats were similar to the Sham groups. Potassium excretion paralleled sodium excretion. These studies show that voluntary dynamic exercise in 2K-1C rats decreases plasma Ang II and aldosterone, which contribute to the lower arterial pressure without deleterious effects on GFR. The effects on sodium excretion underscore the impact of pressure natriuresis despite elevated plasma Ang II and aldosterone in sedentary 2K-1C rats. In contrast, potassium excretion is primarily regulated by circulating aldosterone and distal sodium delivery.

Failure in Medical School is preventable through early intervention. However predicting who is vulnerable to failure is challenging. The ability to predict academic success among medical students has powerful implications for the student, the school they attend and society as a whole. We hypothesized that the level of intrinsic motivation predicts academic success in our cardio‐respiratory physiology course. To test this hypothesis, we administered the Intrinsic Motivation Inventory, a multidimensional measurement device developed by Deci and Ryan (1991), to assess our students' intrinsic motivation. Since we have recently shown that gender influences intrinsic motivation for undergraduate students, we also examined if this relationship exists for a larger cohort of medical students. Results indicate that intrinsic motivation is predictive of academic success for male students. In contrast, this relationship did not exist for female students. We conclude that intrinsic motivation can be used as a factor to predict academic success for male but not female medical students.

Spontaneous baroreflex sensitivity (SBRS) in the control of heart rate (HR) is reduced in proportion to exercise intensity and magnitude of MMA. In hypertension (HTN), while SBRS is reduced at rest, the effect of exercise and MMA are unknown. In eight conscious dogs we measured SBRS in the control of HR (sequence method) at rest, during mild dynamic exercise, and during MMA (via imposed reductions of hindlimb blood flow), in the same animals before and 38±7 days after induction of HTN (via unilateral partial renal artery occlusion). HTN increased resting mean arterial blood pressure from 94±3 to 142±14 mmHg. In control, with the transition from rest to exercise, SBRS decreased from ‐4.01±0.77 to ‐2.38±0.61 bpm/mmHg and reduced further to ‐1.78±0.43 with MMA. In HTN, SBRS was significantly reduced at rest (‐2.38±0.34), during exercise (‐1.05±0.12) and MMA (‐0.90±0.14).We conclude that in HTN SBRS in the control of HR is impaired to similar degrees at rest, during exercise and MMA.Grant Funding Source: HL‐55743 and HL‐095819

Muscle metaboreflex‐induced increases in mean arterial pressure (MAP) during submaximal dynamic exercise are mediated principally by increases in cardiac output. To what extent, if any, the peripheral vasculature contributes to this rise in MAP is debatable. In several studies we observed that in response to muscle metaboreflex activation (MMA; induced by partial hindlimb ischemia), small but significant vasodilation occurred within the non‐ischemic vasculature (termed non‐ischemic vascular conductance; NIVC). We hypothesized that these increases in NIVC may stem from a metaboreflex‐induced release of epinephrine (Epi) resulting in β2‐mediated dilation. We measured NIVC and arterial plasma Epi levels in chronically instrumented dogs during rest, mild exercise (3.2 kph) and MMA before and after β‐blockade (propanolol; 2 mg/kg), α‐blockade (prazosin; 50 µg/kg) and α+β‐blockade. Both Epi and NIVC increased significantly from exercise to MMA: 81.9 ± 18.6 to 141.3 ± 22.8 pg/ml and 33.8 ± 1.5 to 37.6 ± 1.6 ml/min/mmHg, respectively. These metaboreflex‐induced increases in NIVC were abolished after β‐blockade (27.6 ± 1.8 to 27.5 ± 1.7 ml/min/mmHg) and potentiated after α‐blockade (36.6 ±2.0 to 49.7 ±2.9 ml/min/mmHg) while α+β‐blockade also abolished any vasodilation (33.7 ± 2.9 to 30.4 ± 1.9ml/min/mmHg). We conclude that MMA at mild exercise induces epinephrine release causing β2‐mediated vasodilation.Grant Funding Source: HL‐55743

Muscle metaboreflex-induced increases in mean arterial pressure (MAP) during submaximal dynamic exercise are mediated principally by increases in cardiac output. To what extent, if any, the peripheral vasculature contributes to this rise in MAP is debatable. In several studies, we observed that in response to muscle metaboreflex activation (MMA; induced by partial hindlimb ischemia) a small but significant increase in vascular conductance occurred within the nonischemic areas (calculated as cardiac output minus hindlimb blood flow and termed nonischemic vascular conductance; NIVC). We hypothesized that these increases in NIVC may stem from a metaboreflex-induced release of epinephrine, resulting in β2-mediated dilation. We measured NIVC and arterial plasma epinephrine levels in chronically instrumented dogs during rest, mild exercise (3.2 km/h), and MMA before and after β-blockade (propranolol; 2 mg/kg), α1-blockade (prazosin; 50 μg/kg), and α1 + β-blockade. Both epinephrine and NIVC increased significantly from exercise to MMA: 81.9 ± 18.6 to 141.3 ± 22.8 pg/ml and 33.8 ± 1.5 to 37.6 ± 1.6 ml·min−1·mmHg−1, respectively. These metaboreflex-induced increases in NIVC were abolished after β-blockade (27.6 ± 1.8 to 27.5 ± 1.7 ml·min−1·mmHg−1) and potentiated after α1-blockade (36.6 ± 2.0 to 49.7 ± 2.9 ml·min−1·mmHg−1), while α1 + β-blockade also abolished any vasodilation (33.7 ± 2.9 to 30.4 ± 1.9 ml·min−1·mmHg−1). We conclude that MMA during mild dynamic exercise induces epinephrine release causing β2-mediated vasodilation.

Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in normal individuals increases mean arterial pressure (MAP) via increases in cardiac output (CO) with little peripheral vasoconstriction. The rise in CO occurs primarily via increases in heart rate (HR) with maintained or slightly increased stroke volume. When the reflex is sustained during recovery (postexercise muscle ischemia, PEMI), HR declines yet MAP remains elevated. The role of CO in mediating the pressor response during PEMI is controversial. In seven chronically instrumented canines, steady-state values with MMA during mild exercise (3.2 km/h) were observed by reducing hindlimb blood flow by ~60% for 3-5 min. MMA during exercise was followed by 60 s of PEMI. Control experiments consisted of normal exercise and recovery. MMA during exercise increased MAP, HR, and CO by 55.3 ± 4.9 mmHg, 42.5 ± 6.9 beats/min, and 2.5 ± 0.4 l/min, respectively. During sustained MMA via PEMI, MAP remained elevated and CO remained well above the normal recovery levels. Neither MMA during dynamic exercise nor during PEMI significantly affected peripheral vascular conductance. We conclude that the sustained increase in MAP during PEMI is driven by a sustained increase in CO not peripheral vasoconstriction.

Sympathoactivation may be excessive during exercise in subjects with hypertension, leading to increased susceptibility to adverse cardiovascular events, including arrhythmias, infarction, stroke, and sudden cardiac death. The muscle metaboreflex is a powerful cardiovascular reflex capable of eliciting marked increases in sympathetic activity during exercise. We used conscious, chronically instrumented dogs trained to run on a motor-driven treadmill to investigate the effects of hypertension on the mechanisms of the muscle metaboreflex. Experiments were performed before and 30.9 ± 4.2 days after induction of hypertension, which was induced via partial, unilateral renal artery occlusion. After induction of hypertension, resting mean arterial pressure was significantly elevated from 98.2 ± 2.6 to 141.9 ± 7.4 mmHg. The hypertension was caused by elevated total peripheral resistance. Although cardiac output was not significantly different at rest or during exercise after induction of hypertension, the rise in cardiac output with muscle metaboreflex activation was significantly reduced in hypertension. Metaboreflex-induced increases in left ventricular function were also depressed. These attenuated cardiac responses caused a smaller metaboreflex-induced rise in mean arterial pressure. We conclude that the ability of the muscle metaboreflex to elicit increases in cardiac function is impaired in hypertension, which may contribute to exercise intolerance.

Low birth weight humans often exhibit hypertension during adulthood. Studying the offspring of rat dams fed a maternal low-protein diet is one model frequently used to study the mechanisms of low birth weight-related hypertension. It remains unclear whether this model replicates key clinical findings of hypertension and increased blood pressure responsiveness to stress or high-salt diet. We measured blood pressure via radiotelemetry in 13-wk-old male offspring of maternal normal- and low-protein dams. Neither group exhibited hypertension at baseline; however, 1 h of restraint was accompanied by a significantly greater blood pressure response in low-protein compared with normal-protein offspring. To enhance the effect of a high-salt diet on blood pressure, normal- and low-protein offspring underwent right uninephrectomy, while controls underwent sham surgery. After 5 weeks on a high-salt diet (4% NaCl), mean arterial pressure in the Low-Protein+Sham offspring was elevated by 6 +/- 2 mmHg (P < 0.05 vs. baseline), while it remained unchanged in the normal-protein offspring. In the two uninephrectomized groups, blood pressure increased further, but was of similar magnitude. Glomerular filtration rate in the low-protein uninephrectomized offspring was 50% less than that in normal-protein offspring with intact kidneys. These data indicate that, while male low-protein offspring are not hypertensive during young adulthood, their blood pressure is hyperresponsive to restraint stress and is salt sensitive, and their glomerular filtration rate is more sensitive to hypertension-causing insults. Collectively, these may predispose for the development of hypertension later in life.

The renin–angiotensin system is activated in the early phase of two‐kidney, one‐clip (2K‐1C) hypertension. The paraventricular nucleus (PVN) integrates inputs regulating sympathetic outflow. The PVN receives inputs from plasma angiotensin II via projections from circumventricular organs and from renal afferent nerves transmitted via the nucleus tractus solitarii. Nitric oxide within the PVN may exert a sympathoinhibitory effect. These studies tested whether decreasing endogenous nitric oxide by introducing dominant negative (DN) constructs for neuronal nitric oxide synthase (nNOS) into PVN chronically augments hypertension and/or modulates baroreflex function. Male 6‐week‐old Sprague–Dawley rats underwent sham surgery or right renal artery clipping and placement of radiotelemetry transmitters. One week later, the PVN was injected bilaterally with 250 nl artificial cerebrospinal fluid containing 250 ng μl −1 of RSV β‐galactosidase (β‐Gal), cytomegalovirus (CMV) wild‐type (WT nNOS), or respiratory syncytial virus (RSV) haeme domain or RSV haemeRedF (DN nNOS). Haemodynamics were monitored for 5 weeks. Then left renal nerve electrodes were placed, and 2 days later the rats underwent baroreflex testing in the conscious state. The rise in mean arterial pressure (MAP) was significantly potentiated in the DN nNOS 2K‐1C group beyond 15 days after PVN injection. By day 35, MAP in the 2K‐1C groups was 152 ± 6.3 (β‐Gal), 155.1 ± 6.6 (WT nNOS) and 179 ± 5.4 mmHg (DN nNOS; P < 0.01 versus all other groups). Sham‐clipped rats remained normotensive. All groups displayed progressive bradycardia over time that was attenuated in the DN nNOS 2K‐1C group. Baroreflex curves shifted to higher pressures, and baroreflex sensitivity of heart rate was diminished to a similar extent in all groups of 2K‐1C rats. The baroreflex response of renal sympathetic nerve activity was preserved. The PVN tissue from DN nNOS rats had decreased dimerization of nNOS and generation of total nitric oxide. These findings indicate that chronic interference of nNOS dimerization required for generation of nitric oxide within the PVN potentiates the increase of blood pressure by modulating the sympathoexcitation that accompanies renovascular hypertension.

Summary 1. Chronically increased sympathetic nerve activity is present during chronic kidney disease (CKD); however, its role in contributing to hypertension or the progression of CKD remains poorly understood. The aim of the present study was to determine whether neonatal sympathectomy attenuates hypertension in 5/6 nephrectomized rats and affects renal structure and function in a blood pressure‐independent manner. 2. We performed 5/6 nephrectomy (referred to as CKD) in both sympathetically intact and sympathectomized (injected neonatally with guanethidine; referred to as CKD + Sympath) male Sprague‐Dawley rats. Sham‐operated sympathetically intact and sympathectomized rats (Sham and Sham + Sympath, respectively) were used as controls. Radiotelemetry was used to monitor blood pressure throughout the 6 week duration of the study, after which renal function and histology were assessed. 3. Overall average systolic arterial pressure and final urinary protein excretion were significantly lower in CKD + Sympath compared with CKD rats (168 ± 7 mmHg and 33 ± 5 mg/24 h vs. 184 ± 6 mmHg and 66 ± 7 mg/24 h, respectively). However, the level of proteinuria in the CKD + Sympath group was reduced to a greater extent than what would be expected solely on the basis of lower blood pressure. All other indices of renal function and histology were comparable between both CKD groups. All measurements were comparable between Sham and Sham + Sympath groups. 4. In conclusion, sympathectomy attenuated hypertension by approximately one‐third in 5/6 nephrectomized rats. Furthermore, sympathetic nerves to the kidney during 5/6 nephrectomy may contribute to proteinuria in a blood pressure‐independent manner.

Low birth weight is correlated with the development of hypertension later in life. A rat model that is used to study this relationship is reduced protein intake during gestation, which leads to hypertension in the offspring. Previous studies have used imprecise methods to measure blood pressure, such as tail‐cuff. To determine the effect of reduced protein intake during gestation upon blood pressure, 4 day pregnant Wistar dams were placed on an iso‐caloric 6% (low) or 18% (normal) protein diet until term. Male and female offspring (n=6‐8 rats/group) were implanted with a radiotelemetry device at 8 weeks of age to continuously monitor blood pressure in conscious, freely moving rats. At 10 weeks of age, systolic arterial pressure (SAP) was similar between both male groups (118±3 vs. 122±2 mmHg, 6% offspring vs. 18% offspring, respectively, P=NS). However, SAP was significantly elevated in the 6% female offspring compared with the 18% female offspring (117±2 vs. 106±3 mmHg, respectively, P<0.05). Thus, low protein during gestation evokes sex‐dependent hypertension in the offspring. That previous studies have reported hypertension in both sexes of low protein offspring suggest that these rats may have altered responses to stress, which accompanies tail‐cuff blood pressure measurements. Future studies are warranted to determine if low protein offspring have alterations in reflex control of the cardiovascular system.

Maliszewska-Scislo M, Chen H, Augustyniak RA, Seth D, Rossi NF. Subfornical organ differentially modulates baroreflex function in normotensive and two-kidney, one-clip hypertensive rats. Am J Physiol Regul Integr Comp Physiol 295: R741–R750, 2008. First published July 2, 2008; doi:10.1152/ajpregu.00157.2008.—During activation of the renin-angiotensin system, hindbrain circumventricular organs such as the area postrema have been implicated in modulating the arterial baroreflex. This study was undertaken to test the hypothesis that the subfornical organ (SFO), a forebrain circumventricular structure, may also modulate the baroreflex. Studies were performed in rats with two-kidney, one-clip (2K,1C) hypertension as a model of endogenously activated renin-angiotensin system. Baroreflex function was ascertained during ramp infusions of phenylephrine and nitroprusside in conscious sham-clipped and 5-wk 2K,1C rats with either a sham or electrolytically lesioned SFO. Lesioning significantly decreased mean arterial pressure in 2K,1C rats from 158 7 to 131 4 mmHg but not in sham-clipped rats. SFO-lesioned, sham-clipped rats had a significantly higher upper plateau and range of the renal sympathetic nerve activity-mean arterial pressure relationship compared with sham-clipped rats with SFO ablation. In contrast, lesioning the SFO in 2K,1C rats significantly decreased both the upper plateau and range of the baroreflex control of renal sympathetic nerve activity, but only the range of the baroreflex response of heart rate decreased. Thus, during unloading of the baroreceptors, the SFO differentially modulates the baroreflex responses in shamclipped vs. 2K,1C rats. Since lesioning the SFO did not influence plasma angiotensin II (ANG II), the effects of the SFO lesion are not caused by changes in circulating levels of ANG II. These findings support a pivotal role for the SFO in the sympathoexcitation observed in renovascular hypertension and in baroreflex regulation of sympathetic activity in both normal and hypertensive states.

During activation of the renin-angiotensin system, hindbrain circumventricular organs such as the area postrema have been implicated in modulating the arterial baroreflex. This study was undertaken to test the hypothesis that the subfornical organ (SFO), a forebrain circumventricular structure, may also modulate the baroreflex. Studies were performed in rats with two-kidney, one-clip (2K, 1C) hypertension as a model of endogenously activated renin-angiotensin system. Baroreflex function was ascertained during ramp infusions of phenylephrine and nitroprusside in conscious sham-clipped and 5-wk 2K, 1C rats with either a sham or electrolytically lesioned SFO. Lesioning significantly decreased mean arterial pressure in 2K, 1C rats from 158 +/- 7 to 131 +/- 4 mmHg but not in sham-clipped rats. SFO-lesioned, sham-clipped rats had a significantly higher upper plateau and range of the renal sympathetic nerve activity-mean arterial pressure relationship compared with sham-clipped rats with SFO ablation. In contrast, lesioning the SFO in 2K, 1C rats significantly decreased both the upper plateau and range of the baroreflex control of renal sympathetic nerve activity, but only the range of the baroreflex response of heart rate decreased. Thus, during unloading of the baroreceptors, the SFO differentially modulates the baroreflex responses in sham-clipped vs. 2K, 1C rats. Since lesioning the SFO did not influence plasma angiotensin II (ANG II), the effects of the SFO lesion are not caused by changes in circulating levels of ANG II. These findings support a pivotal role for the SFO in the sympathoexcitation observed in renovascular hypertension and in baroreflex regulation of sympathetic activity in both normal and hypertensive states.

Angiotensin II (Ang II) increases blood pressure by both peripheral and central actions via AT1 receptor activation of brain circumventricular organs that lie outside the blood brain barrier. The subfornical organ projects to paraventricular nucleus (PVN) whose efferent projections influence sympathetic output. In other conditions of high sympathetic activity, nitric oxide (NO) within the PVN acutely attenuates sympathetic tone. We tested the hypothesis that 2K‐1C rats, a model of Ang II dependent hypertension, chronic blockade of NO generation within the PVN will augment blood pressure. Male Sprague Dawley rats were equipped with radiotelemetry transmitters at the time of renal artery clipping. After 6 wk, PVN were injected bilaterally with 250 nL with plasmids bearing RSV β‐galactosidase (125 ng/μL; β‐gal), the dominant negative construct for nNOS (250ng/μL; DNnNOS), or the wild type construct for nNOS (250 ng/μL; WTnNOS). Hemodynamic parameters were observed for 3 wk. After renal artery clipping, MAP progressively increased and did not differ among the groups. In the last week of observation, average MAP in the DNnNOS group (186.4±6.3 mmHg) was significantly higher than either the β‐gal (160.8±3.4 mmHg) or WTnNOS (156.9±1.5 mmHg) injected 2K‐1C rats (P< 0.001). Thus, chronic blockade of NO production by DNnNOS in PVN augments systemic arterial pressure in a model of Ang II dependent hypertension.

We have previously shown that acute intravenous injection of the angiotensin-converting enzyme (ACE) inhibitor enalapril in diabetic rats evokes a baroreflex-independent sympathoexcitatory effect that does not occur with angiotensin receptor blockade alone. As ACE inhibition also blocks bradykinin degradation, we sought to determine whether bradykinin mediated this effect. Experiments were performed in conscious male Sprague-Dawley rats, chronically instrumented to measure mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), 2 wk after streptozotocin (55 mg/kg iv, diabetic, n = 11) or citrate vehicle (normal, n = 10). Enalapril (2.5 mg/kg iv) decreased MAP in normal rats (-15 +/- 3 mmHg), while a smaller response (-4 +/- 1 mmHg) occurred in diabetic rats. Despite these different depressor responses to enalapril, HR (+44 +/- 8 vs. +26 +/- 7 bpm) and RSNA (+90 +/- 21 vs +71 +/- 8% baseline) increased similarly between the groups (P > or = 0.22 for both). Pretreatment with the bradykinin B2 receptor antagonist Hoe 140 (10 microg/kg bolus followed by 0.8.mug(-1)kg.min(-1) infusion) attenuated the decrease in MAP observed with enalapril in normal rats but had no effect in diabetic rats. Moreover, the normal group had smaller HR and RSNA responses (HR: +13 +/- 8 bpm; RSNA: +32 +/- 13% baseline) that were abolished in the diabetic group (HR: -4 +/- 5 bpm; RSNA: -5 +/- 9% baseline; P < 0.05 vs. preenalapril values). Additionally, bradykinin (20 microg/kg iv) evoked a larger, more prolonged sympathoexcitatory effect in diabetic compared with normal rats that was further potentiated after treatment with enalapril. We conclude that enhanced bradykinin signaling mediates the baroreflex-independent sympathoexcitatory effect of enalapril in diabetic rats.