The role of vasopressin in the pressor response to bilateral carotid occlusion

Exogenous arginine vasopressin (AVP) has been shown to interact with the arterial baroreflex control of renal sympathetic nerve activity. In addition, we have shown that both AVP and the sympathetic nervous system (SNS) contribute to the pressor response to interruption of cardiopulmonary vagal afferents. This study examined the role and interaction of AVP and the SNS in the pressor response to a reduction of carotid sinus afferent activity by bilateral carotid occlusion (BCO). In addition the role of the area postrema (AP) in mediating the interaction between AVP and the SNS was examined. In aortic denervated conscious dogs, BCO increased mean arterial pressure 51.7 +/- 3.1 mm Hg. Specific vascular (V1) AVP antagonist D(CH2)5Tyr(Me)AVP did not alter the response to BCO (delta 50.8 +/- 7.9 mm Hg). Subsequent ganglionic blockade abolished the response to BCO (delta -10 +/- 3.8). When ganglionic blockade was induced in the absence of AVP antagonist, BCO increased MAP 25.0 +/- 2.8 mm Hg. AVP antagonist following ganglionic blockade eliminated the pressor response to BCO (delta -6.7 +/- 5.1). There was an interaction between AVP and the SNS such that the contribution of one system to the hemodynamic response was greater in the absence of the other system. Ablation of the AP abolished the interaction between reflexly released AVP and the SNS which was observed in intact dogs. These data demonstrate that both AVP and the SNS contribute to the pressor response to BCO. Reflexly released AVP appears to limit the reflex activation of the SNS. The interaction of endogenous AVP and the arterial baroreflex involves the AP. The results are consistent with the hypothesis that vasopressin interacts centrally to limit a reflex increase in sympathetic outflow and thus modulate the pressor response to BCO.     

Cardiorespiratory reflexes in a working heart-brainstem preparation of the house musk shrew, Suncus murinus

In this study, we adapted the working heart-brainstem preparation (WHBP) from rodents to the Insectivore, Suncus murinus. Suncus WHBPs had a baseline heart rate of 333 +/- 8 beats min(-1), a perfusion pressure of 69 +/- 2 mm Hg and a respiratory cycle length of 6.5 +/- 0.7 s. Administration of atropine produced an increase in heart rate of 26 +/- 9 beats min(-1) indicative of the presence of cardiac vagal tone. Activation of baroreceptors produced pressure-dependent reflex falls in heart rate and reduced respiratory cycle length. The baroreceptor reflex sensitivity in Suncus WHBP was a decrease in heart rate of 8.1 +/- 1.4 beats min(-1) mm Hg(-1). Activation of peripheral chemoreceptors with aortic injections of sodium cyanide (0.1-12.5 microg) produced a dose-dependent reflex fall in heart rate and reduced respiratory cycle length. The reflex falls in heart rate evoked by baroreceptor and peripheral chemoreceptor stimulation were both atropine-sensitive. We conclude that viable WHBP can be prepared from Suncus and that Suncus WHBP is a novel non-rodent model in which to study brainstem-mediated reflexes.     

Comparison of aortic and carotid baroreflex stimulus-response characteristics in humans

In order to characterize the stimulus-response relationships of the arterial, aortic, and carotid baroreflexes in mediating cardiac chronotropic function, we measured heart rate (HR) responses elicited by acute changes in mean arterial pressure (MAP) and carotid sinus pressure (CSP) in 11 healthy individuals. Arterial (aortic + carotid) baroreflex control of HR was quantified using ramped changes in MAP induced by bolus injection of phenylephrine (PE) and sodium nitroprusside (SN). To assess aortic-cardiac responses, neck pressure (NP) and suction (NS) were applied during PE and SN administration, respectively, to counter alterations in CSP thereby isolating the aortic baroreflex. Graded levels of NP and NS were delivered to the carotid sinus using a customized neck collar device to assess the carotid-cardiac baroreflex, independent of drug infusion. The operating characteristics of each reflex were determined from the logistic function of the elicited HR response to the induced change in MAP. The arterial pressures at which the threshold was located on the stimulus-response curves determined for the arterial, aortic and carotid baroreflexes were not significantly different (72+/-4, 67+/-3, and 72+/-4 mm Hg, respectively, P > 0.05). Similarly, the MAP at which the saturation of the reflex responses were elicited did not differ among the baroreflex arcs examined (98+/-3, 99+/-2, and 102+/-3 mm Hg, respectively). These data suggest that the baroreceptor populations studied operate over the same range of arterial pressures. This finding indicates each baroreflex functions as both an important anti-hypotensive and anti-hypertensive mechanism. In addition, this investigation describes a model of aortic baroreflex function in normal healthy humans, which may prove useful in identifying the origin of baroreflex dysfunction in disease- and training-induced conditions.     

Decreased baroreflex sensitivity in isoproterenol-treated mice with cardiac hypertrophy

The baroreflex has been shown to be impaired in rat models of cardiac hypertrophy. In the present study, we investigated the effects of beta-adrenoceptor-induced cardiac hypertrophy on the baroreflex in mice. Male Swiss Webster mice weighing 20-25 g were treated with the beta-adrenoceptor agonist isoproterenol (IPM; 15 microg/g/day, s.c.) for 7 days or with vehicle (control, CM). After treatment, IPM (n=9) and CM (n=9) were anesthetized with ketamine + xylazine (91.0: 9.1 mg/kg, i.p.) and had their carotid artery and jugular vein cannulated to test the arterial baroreflex. The baroreflex was evaluated by measuring changes in heart rate (HR) in response to acute increases and decreases in mean arterial pressure (MAP) induced by bolus injections of phenylephrine and sodium nitroprusside (1.5-24.0 microg/kg, i.v.) in conscious animals. IPM showed an increased cardiac weight/body weight (1.18 +/- 0.03 mg/g) ratio compared to CM (0.95 +/- 0.03 mg/g, p<0.05), but similar values of resting MAP (108 +/- 4 vs. 111 +/- 2 mm Hg) and HR (606 +/- 25 vs. 629 +/- 26 bpm). Sigmoidal barocurve analysis showed that isoproterenol treatment significantly reduced the following parameters: baroreflex sensitivity (IPM: -4.26 +/- 0.19 vs. CM: -5.92 +/- 0.54 bpm/mm Hg, p<0.05), reflex bradycardia plateau (IPM: 387 +/- 26 vs. CM: 318 +/- 19 bpm, p<0.05) and HR range (IPM: 369 +/- 30 vs. CM: 442 +/- 20 bpm, p<0.05). Linear regression analysis of baroreflex function also showed a diminished reflex bradycardia (CM: -8.92 +/- 0.87 bpm/mm Hg vs. IPM: -4.94 +/- 0.52 bpm/mm Hg, p<0.05), but similar reflex tachycardia (CM: -3.88 +/- 0.45 bpm/mm Hg vs. IPM: -3.52 +/- 0.43 bpm/mm Hg). In conclusion, beta-adrenoceptor-induced cardiac hypertrophy in mice led to impaired sensitivity of the cardiac baroreflex, which could be due to a diminished vagal activity to the heart.     

Normotension in conscious rats after placement of bilateral electrolytic lesions in the rostral ventrolateral medulla

The effects of bilateral electrolytic lesions of the rostral ventrolateral medulla (RVLM) on mean arterial pressure (MAP) and heart rate (HR) were examined in 8 rats at one and 5 days after placement of the lesions. The MAP (111 +/- 2 mm Hg) and HR (393 +/- 17 bpm) of the lesion group were similar to the values recorded in the control group (117 +/- 3 mm Hg, 405 +/- 11 bpm; n = 18). Blockade of the synthesis of angiotensin II with captopril in the lesion group significantly decreased MAP to 93 +/- 2 mm Hg on the first postlesion day. In contrast, the MAP of the control group after captopril fell slightly to 111 +/- 4 mm Hg. Captopril did not alter MAP or HR on postlesion day 5 in either group. Administration of chlorisondamine, an autonomic ganglionic blocking agent, reduced MAP in the lesion and control groups to similar values of 59 +/- 2 mm Hg and 64 +/- 2 mm Hg, respectively. Baroreflex-mediated tachycardia to a decrease in MAP was abolished in the lesion group at one day postlesion and attenuated at 5 days postlesion. In contrast, the baroreflex-mediated bradycardia to an increase in MAP was unaffected by the lesions. Plasma renin activity (PRA) in the lesion group was elevated by nearly 50% as compared to the control group on the first postlesion day (7.3 +/- 0.8 and 4.9 +/- 0.5 ng AI/ml/h, respectively). A 90% elevation in plasma norepinephrine (NE) concentration was also observed in the lesion group as compared to the control group (437 +/- 80 pg/ml and 228 +/- 22 pg/ml, respectively) on postlesion day one. By postlesion day 5, the PRA of the lesion and control groups were nearly identical (4.4 +/- 0.7 and 4.0 +/- 1.0 ng AI/ml/h, respectively), and the plasma NE concentrations were also very similar (201 +/- 41 pg/ml and 175 +/- 22 pg/ml, respectively). We conclude that bilateral destruction of the RVLM does not cause hypotension or bradycardia in conscious rats. Therefore, areas other than the RVLM are capable of maintaining MAP and HR. Sympathetic vasomotor and cardiomotor tone appears unaffected by the lesions. However, increased activity of the renin-angiotensin system may contribute transiently to the maintenance of vasomotor tone and, consequently, MAP after lesion of the RVLM. The RVLM may be important in mediating baroreflex increase in HR.     

Contribution of nucleus medianus to the drinking and pressor responses to angiotensin II acting at subfornical organ

The contribution of neurons in the nucleus medianus (NM) in mediating the drinking and pressor responses elicited by administration of angiotensin II (AII) either directly into the subfornical organ (SFO) or intravenously was investigated in conscious, unrestrained rats. Microinjection of AII into the SFO elicited a robust drinking (7.9 +/- 0.8 ml in 15 min; n = 24) and pressor (peak rise in mean arterial pressure (MAP), 15 +/- 1 mm Hg; n = 20) response. On the other hand, intravenous infusion of AII elicited an increase in MAP (36 +/- 3 mm Hg; n = 14) accompanied by a marked reflex bradycardia (134 +/- 18 beats/min), but not a significant drinking response. Lesions of NM cells, dorsal to the anterior commissure and between the fornical columns, with the neurotoxin kainic acid significantly (P less than 0.05) attenuated the drinking response (prelesion volume, 8.3 +/- 0.8 ml in 15 min; postlesion volume, 1.9 +/- 1.4 ml in 15 min; n = 7), but did not alter the pressor response to AII injected directly into the SFO. Similarly, kainic acid lesions of NM cells did not significantly effect the pressor response or the associated reflex bradycardia to intravenous administration of AII. Sham lesions of NM cells or control kainic acid lesions of adjacent structures did not alter the AII-induced drinking or pressor responses. These data suggest that neurons in the dorsal NM are part of a forebrain neuronal circuit that is involved in the drinking, but not the pressor responses to AII acting at the SFO in the conscious rat.     

Relative contributions of aortic and carotid sinus baroreceptors to the baroreceptor-heart rate reflex of the conscious rabbit

Conscious rabbits with previously implanted perivascular balloons for altering blood pressure were studied before and 6 days after: (i) sham-operation (n = 6); (ii) section of carotid sinus nerves alone (n = 7); (iii) section of aortic nerves alone (n = 5); and (iv) combined sino-aortic denervation (n = 5). Sigmoid mean arterial pressure (MAP)-heart period (HP) baroreflex curves were derived and were characterized by: (i) the HP range (HPR) between upper and lower plateau levels; (ii) the median blood pressure (BP50); and (iii) the average gain (G). Resting MAP and HP and the 3 baroreflex parameters were not altered significantly 6 days after sham-operation. After section of the carotid sinus nerves alone resting MAP and BP50 rose by 18 +/- 2.6 mm Hg, resting HP fell by 31 +/- 4.2 msec, whilst HPR and G fell to about 45% and 20 % respectively of initial preoperative control. After cutting the aortic nerves alone there was a similar fall in resting HP as after carotid denervation. However, the rises in resting MAP and BP50 were only about half of those observed after carotid denervation (P < 0.05) and the changes in HPR and G to 65% and 58% of control respectively were also less marked (P ? 0.01). The aortic baroreceptor zone also exerted smaller effects on the sympathetic efferent component of the baroreflex HP response. Despite the different effects exerted by each zone on the reflex parameters there was little difference in threshold pressure for producing cardiac slowing. After combined sino-aortic denervation there was a similar rise in resting MAP (19 mm Hg) as after carotid sinus denervation alone, but there was more marked tachycardia, with a fall in resting HP of 82 msec (P < 0.001) and both resting and baroreflex-mediated vagal tones were completely abolished. The small residual pressure-determined HP changes of about 8 msec were entirely sympathetic and probably mediated through cardiopulmonary baroreceptors.     

Modulation of cardiovascular and electrocortical activity through serotonergic mechanisms in the nucleus tractus solitarius of the rat

The nucleus tractus solitarius (NTS) is an integral part of the baroreceptor reflex arc. Thus, stimulation of the NTS elicits changes in arterial pressure and heart rate as well as in numerous other physiologic parameters including electrocortical activity. Serotonin (5-HT), which has been implicated in cardiovascular and electrocortical control, is present in nerve terminals within the NTS. Therefore, this study was designed to determine whether 5-HT may effect that control within the NTS. Serotonin injected into the NTS of anesthetized rats produced marked changes in the EEG, arterial pressure, and heart rate. EEG activity changed from irregular 1-5 Hz, 350-500 microV waves with an overlying 13-15 Hz, low voltage rhythm to a regular, 5 Hz, 250-300 microV rhythm. The dose-dependent cardiovascular changes were maximal at a dose of 400 pmol which produced a fall of mean arterial pressure of 48 +/- 2 mm Hg from a baseline of 96 +/- 4 mm Hg and of heart rate of 90 +/- 9 bpm from a baseline of 400 +/- 18 bpm (n = 6; P less than 0.001). Both the cardiovascular and EEG effects of 5-HT injected into the NTS were blocked by the prior injection of the 5-HT antagonist metergoline at the same site. However, the bilateral microinjection of metergoline into the NTS did not affect the baroreceptor reflex. Thus, although serotonergic mechanisms in the NTS may be involved in the modulation of electrocortical and cardiovascular activity, they are not integral to the baroreceptor reflex arc.     

Interdependence of rostral and caudal ventrolateral medullary areas in the control of blood pressure

Pharmacologic experiments were carried out to test the degree of interdependence of rostral vasopressor and caudal vasodepressor neuron pools in the ventrolateral medulla (VLPA and VLDA, respectively). In two groups of urethane-anesthetized rats, the γ-aminobutyric acid (GABA) agonist muscimol (10 ng/site) was bilaterally microinjected into both the VLPA and VLDA to inhibit neuronal activity at these sites. In one group of experiments, muscimol was microinjected first into the VLPA and then into the VLDA. Following muscimol microinjection in the VLPA the mean arterial pressure (MAP) and heart rate (HR) decreased to 40 ± 6 mm Hg and 310 ± 21 beats/min (bpm) from a control level of 90 ± 3 mm Hg and 403 ± 23 bpm. Subsequent microinjection of muscimol in the VLDA had no significant effect on BP or HR. This lack of response was not due to severe fall in BP caused by microinjection of muscimol into the VLPA. In the second group of experiments muscimol was first injected into the VLDA followed by muscimol microinjection into the VLPA. In the VLDA muscimol significantly increased MAP and HR to 139 ± 4 mm Hg and 427 ± 4 bpm from a control level of 87 ± 2 mm Hg and 356 ± 23 bpm. The aortic depressor nerve response (−37 ± 1 mm Hg and −47 ± 4 bpm) was converted to an aortic ‘pressor’ response (+20 ± 1 mm Hg and −13 ± 6 bpm). Subsequent microinjection of muscimol into the VLPA caused MAP and HR to fall to 43 ± 5 mm Hg and 338 ± 17 bpm. The aortic ‘pressor’ response was also abolished (2 ± 2 mm Hg). These results indicate that neuronal activity in the rostral VLPA is an important determinant for changes in BP and its reflex regulation mediated by the VLDA. However, BP changes mediated by the rostral VLPA are independent of the level of neuronal activity in the VLDA. Sites of VLPA and VLDA interaction are discussed.     

Effects of chronic lesions of the anteroventral third ventricle region on baroreceptor reflex function in conscious rats

This study determined baroreceptor reflex (BR) function in conscious rats which had received sham or electrolytic lesions of the anteroventral third ventricle (AV3V) 54-56 days previously. Resting mean arterial pressure (MAP) and heart rate (HR) values of the AV3V-lesion rats were similar to those of sham-lesion rats (P>0.05 for both comparisons). The sensitivity of the BR-mediated tachycardia in AV3V-lesion was greater than in sham-lesion rats (-9. 92+/-1.00 vs. -4.54+/-0.45 bpm/mmHg, P<0.05). The sensitivity of the BR-mediated bradycardia in AV3V-lesion rats was also greater than in rats with sham lesions (-3.56+/-0.38 vs. -2.06+/-0.42 bpm/mmHg, P<0. 05). The AV3V lesions did not affect other BR parameters. These findings demonstrate that chronic lesions of the AV3V region increase the sensitivity of the baroreceptor HR reflex in conscious rats.     

Attenuated pressor responses to amino acids in the rostral ventrolateral medulla after swimming training in conscious rats

The cardiovascular effects of microinjection of the amino acids glutamate and glycine within the rostral ventrolateral medulla (RVLM) after swimming training (ST) in unrestrained awake rats were investigated. Unilateral microinjection of l-glutamate (5, 20 and 50 mM, in 100 nl) produced a dose dependent increase in mean arterial pressure (MAP) in control (C) (16+/-5 mm Hg; 29+/-6 mm Hg; 43+/-6 mm Hg) and swim (SW) (1+/-1 mm Hg; 16+/-2 mm Hg; 25+/-3 mm Hg) groups. However, the magnitude of this response was lower in the swim group. Prazosin injection produced hypotension and tachycardia in both groups (C=-43+/-3 mm Hg/98+/-16 bpm; SW=-61+/-5 mm Hg/115+/-32 bpm). In the SW group the hypotension caused by prazosin was greater compared to C group, but the tachycardia was not different between them. After prazosin, glutamate response in RVLM was blocked in both groups as well. When glycine (10 mM or 1 M, in 100 nl) were microinjected into the RVLM of C group we observed two different effects: decrease in MAP with the lower dose and an increase in MAP with the higher dose (10 mM=-13+/-2 mm Hg; 1 M=47+/-6 mm Hg). However, after ST the hypertensive response to glycine was blunted with no alterations in the hypotensive response (10 mM=-14+/-1 mm Hg; 1 M=18+/-4 mm Hg). These findings suggest that RVLM is involved in the modulation of the sympathetic outflow to the cardiovascular system during exercise training.     

Effects of long-term angiotensin converting enzyme inhibition on cardiovascular variability in aging rats

We studied the effects of chronic (4 weeks) angiotensin converting enzyme inhibition with captopril on arterial pressure (AP) and heart rate (HR) variability, as well as on cardiac baroreflex sensitivity (BRS), in aged (20 months) rats. Series of basal RR interval (RRi) and systolic AP (SAP) were studied by autoregressive spectral analysis with oscillations quantified in low (LF: 0.2-0.8 Hz) and high frequency (HF: 0.8-2.5 Hz). BRS was measured by linear regression between HR and MAP changes. Captopril did not affect the spectra of RRi or SAP in young rats. Aged rats presented a reduction in variance (time domain) and in LF and HF oscillations of RRi and SAP. Captopril induced, in aged rats, a decrease in absolute and normalized LF oscillations and in LF/HF ratio of RRi. Captopril also reduced the variance, without changing its LF or HF components of SAP. Reflex tachycardia was reduced in aged as compared to young rats (-1.1+/-0.2 versus -3.4+/-0.5 bpm/mm Hg) and captopril did not affect it. Reflex bradycardia was also reduced in aged rats (-0.7+/-0.5 versus -2.0+/-0.4 bpm/mm Hg), but captopril prevented this attenuation in aged rats (-2.3+/-0.3 versus -0.7+/-0.5 bpm/mm Hg). These data indicate that there is a reduction in HR and SAP variability during aging, suggesting impairment of cardiovascular autonomic control. Captopril was able to change the power of oscillatory components of RRi, suggesting a shift in cardiac sympatho/vagal balance toward parasympathetic predominance. In addition, blockage of ACE improved the reflex bradycardia, but not the reflex tachycardia in aged rats.     

Postnatal development of blood pressure and baroreflex in mice.

Postnatal development of blood pressure, heart rate and their regulation by arterial baroreceptor reflex in mice was examined. We first confirmed that simultaneous recordings of pulsatile blood pressure by the "servo null" method and the conventional catheter method gave almost identical tracings in halothane-anesthetized adult mice. We then measured blood pressure by servo null method together with electrocardiograph in mice of various ages from newborn to adult. Mean blood pressure increased progressively with age from 19 + 2 mm Hg in P0 newborn to 74+/-1 in adult mice, while heart rate initially increased from 365+/-12 bpm in newborn to 441+/-15 in infant (7 days old), and then decreased to 337+/-15 in adult mice. Between 1 and 2 weeks of age, gain of arterial baroreceptor reflex abruptly increased from a newborn value of 0.3 to a near adult value of 1.1 ms/mm Hg. On the other hand, sensitivity to anesthesia did not differ except for P1 and P2 newborns. We conclude that pulsatile blood pressure can be accurately measured by the servo null method even in the newborn mice and that baroreflex heart rate control mature at around 2 weeks after birth in the mice.     

A differential effect of yohimbine on adrenal and neuronal catecholamine release during bilateral carotid occlusion in the dog

This study reports on the effects of yohimbine and clonidine on the release of adrenal and renal catecholamines (epinephrine, E; norepinephrine, NE; and dopamine, DA) in response to bilateral carotid occlusion (BCO, 3 min) in vagotomized dogs anesthetized with sodium pentobarbital. The model used allowed us to simultaneously compare adrenal catecholamine secretion with neuronal NE release in the kidney. In control dogs, the net output (ng/min/g tissue) of adrenal E (70.5 +/- 19.7), NE (22.2 +/- 5.9) and DA (2.6 +/- 0.8) increased markedly (P less than 0.01) during BCO to a maximum level of 265.1 +/- 87.9, 97.4 +/- 30.6 and 10.5 +/- 3.2, respectively. Similarly, the net output (ng/min/g tissue) of renal NE (0.66 +/- 0.06) and DA (0.09 +/- 0.02) increased significantly (P less than 0.01) to 1.00 +/- 0.11 and 0.15 +/- 0.04, respectively. Aortic systolic pressure (mm Hg) (140.8 +/- 8.0) and heart rate (beats/min) (162.7 +/- 5.1) also increased (P less than 0.01) to 212.5 +/- 19.3 and 179.5 +/- 5.4, respectively. In dogs treated with yohimbine (0.3 mg/kg, i.v.), the net increase in adrenal catecholamine output was diminished by approximately 47% (P less than 0.05). In contrast, the net increase in renal NE output was potentiated by 41% (P less than 0.05). The net increase in heart rate was also enhanced significantly (P less than 0.01) in the presence of yohimbine. In dogs receiving clonidine (15 micrograms/kg, i.v.) the increases in net output of both adrenal and renal catecholamine were abolished. Similarly, pressor and heart rate responses were abolished in the presence of clonidine. The results indicate that yohimbine exerted a differential effect on renal sympathetic nerves (increase) and adrenal medullae (decrease) in modulating catecholamine release in response to BCO, while clonidine abolished both neural NE release and adrenal catecholamine secretion. This study suggests that a presynaptic alpha 2-adrenoceptor-mediated mechanism, the blockade of which enhances neural NE release at peripheral sympathetic nerve terminals in many tissues, may not be involved in the modulation of adrenal catecholamine secretion during BCO.     

Autonomic control of the heart and renal vascular bed during autonomic dysreflexia in high spinal cord injury

Autonomic function and hemodynamics were studied in nine spinal cord injured (SCI) subjects, at rest and during peripheral afferent stimulation, bladder percussion. Nine able-bodied subjects were studied for comparison during unstimulated conditions. Spontaneous baroreceptor reflex sensitivity was calculated from recordings of ECG and intraarterial blood pressure. An index of sympathetic activity was provided by measuring total body noradrenaline (NA) spillover by isotope dilution technique. Renal vascular resistance was calculated from PAH-clearance. SCI subjects had lower total body NA spillover (1011 ± 193 vs 2261 ± 328 pmol/min, P < 0.01), but similar baroreceptor reflex sensitivity and hemodynamics compared to able-bodied subjects at rest. In SCI group, during bladder percussion, mean arterial pressure increased (79 ± 5 vs 113 ± 8 mm Hg, P < 0.01), whereas heart rate was reduced during the first minute of the manoeuvre (62 ± 2 vs 56 ± 2 bpm, P < 0.05). Baroreceptor reflex sensitivity remained unchanged. Total body NA spillover and renal vascular resistance increased by 332 % (from 1004 ± 218 pmol/min, P < 0.05) and 55 % (from 0.078 ± 0.011 mmHg/ml/min, P < 0.05), respectively. SCI subjects demonstrated lower total body sympathetic outflow but normal baroreceptor reflex sensitivity at rest, suggesting a balanced autonomic output to the heart. Bladder percussion caused a substantial increase in renal vascular resistance and blood pressure, which was partly due to marked generalised sympathetic activation. This activation was counterbalanced by an increased vagal activity as evidenced by reduction of the heart rate. Received: 6 March 2002, Accepted: 28 August 2002 Correspondence to Sinsia A. Gao, MD     

ACTH-Suppressive and Vasodilator Actions of Adrenomedullin in Conscious Sheep

Adrenomedullin (ADM) is a 52 amino-acid peptide which is a potent vasodilator in rats, and suppresses basal and CRF-induced ACTH release from cultured pituitary cells. The present study examines the hemodynamic and hormonal actions of human ADM (1–52) infusion in conscious, chronically instrumented sheep. Five sheep were infused intravenously (IV) or intracerebroventricularly (ICV) with ADM at 100 pg/h for 60 min, and mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), coronary blood flow (CF), coronary conductance (CC), peak aortic flow (Fmax), and left ventricular dF/dt were monitored by a computer-based data collection system every 2 min. Plasma concentrations of adrenocorticotropin (ACTH), arginine vasopressin (AVP) and renin were measured after 60 min of infusion. IV ADM produced a small fall in MAP of 3 ± 1 mmHg, associated with a reflex increase in HR of 14 ± 3 b/min. CO increased by 1.3 ± 0.3 1/min, whereas SV remained unchanged. TPC was markedly increased by 20 ± 3 ml/min/mmHg. Changes in CF were also seen with an increase of 10 ± 2ml/min, and CC increased in parallel by 0.15 ± 0.02 ml/min/mmHg. Fmax and dF/dt showed small increases of 2.1 ± 0.5 Vmin and 85 ± 20 1/min/sec respectively. Plasma concentrations of ACTH and cortisol were reduced by 58% and 55% respectively, whereas plasma renin concentration increased by 106%. There was no change in plasma levels of AVP. ICV infusion of ADM had no effect on any parameter measured. These data suggest that systemic ADM produces a sustained vasodilator action to lower blood pressure in sheep, and this is the first study to report the ACTH-suppressor action of ADM in conscious animals. ADM may therefore be an important hormone involved in the regulation of pituitary/adrenal function, in addition to its cardiovascular and fluid regulatory actions in mammals.     

Reflex control of renal nerve activity originating from the osmoreceptors in the hepato-portal region.

The reflex effects of hepatic osmoreceptors on the renal sympathetic nerve activity (RNA) were studied in 30 pentobarbital anesthetized, vagotomized and sino-aortic baroreceptor denervated (SAD + VD) rabbits. The changes in mean arterial pressure (MAP), heart rate (HR), and RNA were examined when 9% NaCl, 6.5% LiCl or 50% glucose solution was infused into the hepatic portal vein at a rate of 0.15 ml/kg/min for 10 min. Infusion of 9% NaCl solution into the hepatic portal vein increased the plasma osmolality by 10.8 +/- 1.0 mOsmol/kg from the control level in the blood of the hepatic portal vein and by 2.8 +/- 2.0 mOsmol/kg from the control level in the systemic blood. MAP was significantly elevated by 10.2 +/- 5.0 mmHg but HR did not change with hepatic portal infusion of 9% NaCl solution. Intraportal infusion of 9% NaCl solution significantly decreased the RNA by 28.6-34.2% from the control level, 6.5% LiCl solution by 28.6 +/- 4.7%, and 50% glucose solution by 26.2 +/- 3.0%. Femoral arterial infusion of hypertonic NaCl solution, however, did not evoke any significant change in RNA in SAD + VD rabbits. These findings suggest that increases in osmolality and NaCl concentration in the systemic circulation do not result in a decrease of RNA. Furthermore, after section of the anterior and posterior plexus of the hepatic nerve, hepatic portal infusion of hypertonic NaCl solution elicited no change in RNA. The present data indicate that an increase in osmolality in the hepatic portal venous blood results in a reflex decrease of RNA. This reflex may be important for restoration of a postprandial increase in osmolality.     

Activation of gastric afferent fibers increases coronary arterial resistance in anesthetized dogs

Stimulation of chemically sensitive receptors in the stomach with capsaicin is known to reflexly increase heart rate, arterial pressure, left ventricular contractility, and systemic vascular resistance. What is not known, however, is if activating these gastric afferents can also evoke reflex changes in coronary arterial resistance. Therefore, in 24 chloralose-anesthetized dogs, we used a Gregg cannula and a constant flow preparation to assess left circumflex coronary arterial (LCCA) resistance while stimulating chemically sensitive gastric receptors with capsaicin. Capsaicin (60 micrograms), applied topically to the serosal surface of the stomach, produced significant (P less than 0.05) increases in heart rate (8 +/- 2 bpm), mean arterial pressure (22 +/- 1 mm Hg), LCCA pressure (7 +/- 1 mm Hg), and LCCA resistance (0.30 +/- 0.04 mm Hg/ml/min). These responses were still present after bilateral thoracic vagotomy, but were eliminated by bilateral thoracic splanchnicotomy. alpha-adrenergic blockade eliminated and beta-adrenergic blockade enhanced the increases in LCCA pressure and resistance that were evoked by capsaicin. Thus, stimulating chemically sensitive receptors in the stomach can reflexly increase coronary arterial resistance by alpha-adrenergic vasoconstriction. The possibility exists, therefore, that physiological or pathological events which activate gastric afferents can affect reflexly the coronary circulation.     

Cardiovascular responses to microinjection of AMPA into the rostral commissural nucleus tractus solitarius of awake rats

Previous studies have shown that microinjection of NMDA or non-NMDA receptor agonists into the nucleus tractus solitarius of anesthetized rats produces bradycardia and hypotension. In the present study, we evaluated the autonomic components of the cardiovascular responses to the microinjection of alpha-amine-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) into the nucleus tractus solitarius of awake rats. AMPA (0.05 nmol 50 nl(-1)) was microinjected into the nucleus tractus solitarius before and at 2, 10, 30 and 180 min after intravenous injection of methylatropine (2 mg kg(-1)). The control response to the microinjection of AMPA into the lateral aspect of the commissural nucleus tractus solitarius consisted of bradycardia and hypotension, (-190+/-20 bpm and -49+/-7 mm Hg), which were effectively blocked at 2 min (-5+/-2 bpm and -4+/-5 mm Hg), 10 min (-3+/-2 bpm and -6+/-3 mm Hg) and 30 min (-9+/-4 bpm and -5+/-5 mm Hg) after methylatropine. Although the bradycardic and hypotensive responses remained significantly reduced 180 min after injection of methylatropine, the responses tended to normalize. The data show that microinjection of AMPA into the rostral commissural nucleus tractus solitarius of awake rats produced intense bradycardia essentially mediated by parasympathetic excitation, which was the cause of the concomitant hypotensive response.     

Parasympathetic dysfunction is associated with baroreflex and chemoreflex impairment in streptozotocin-induced diabetes in rats

This study explored physiological mechanisms of diabetic dysfunction in baroreceptors and chemoreceptors-mediated hemodynamic responses, and cholinergic neurotransmission in 30-day diabetic rats (n = 14) and controls (n = 14). Basal hemodynamic data and vagal response to electrical stimulation and methacholine injection were also evaluated. Muscarinic receptors were characterized using a radioligand receptor binding assay ([3H]N methylscopolamine). Experimental diabetes (50 mg/kg of STZ, i.v.) decreased systolic, diastolic, and mean arterial pressure and basal heart rate. Heart rate (HR) responses to vagal electrical stimulation (16, 32, and 64 Hz) were 15%, 11%, and 14% higher in diabetics vs non-diabetics, as were HR responses to methacholine injection (-130+/-24, -172+/-18, -206+/-15 bpm vs. -48+/-15, -116+/-12, -151+/-18 bpm, P < 0.05). Muscarinic receptor density was higher (267.4+/-11 vs 193.5+/-22 fmol/mg/prot, P < 0.05) in the atria of diabetic rats than in those of controls; the affinity was similar between groups. Diabetes-induced reduction of reflex responses to baro- (reflex bradycardia: -3.4+/-0.3 and -2.7+/-0.2 bpm/mm Hg; reflex tachycardia: -1.6+/-0.1 and -1.4+/-0.07 bpm/mm Hg, in control and diabetics, P < 0.05) and chemoreceptor stimulation, enhancement of HR responsiveness to cardiac vagal electrical stimulation and methacholine stimulation, plus an increase in the number of atrial muscarinic receptors indicates reduced parasympathetic activity, which is probably derived from central nervous system derangement.