Sinoaortic Deafferentation Research Articles

The pressor effect of water: mechanism and location of action

Water ingestion induces a robust, sustained pressor response in patients with baroreflex impairment and in mice with sinoaortic deafferentation (SAD). The mechanism of water's effect on blood pressure remains unknown. In order to isolate the location at which water acts, SAD mice were given water via intragastric or intraduodenal routes. In both cases a similar pressor response appeared. The presence of a pressor response following intraduodenal infusion indicates that the pharynx, esophagus, and stomach are not critical sites for water's pressor action. Administering an identical volume of physiological saline did not induce a significant pressor response. Osmolality of portal and systemic circulations was measured 15 minutes post intraduodenal water infusion and found to be 292.7 and 304.4 mOsm/kg, respectively. TRPV4 is an osmo‐sensitive cation channel found throughout the body, and has been reported to be activated under hypotonic conditions. To investigate the potential role of TRPV4 in water's pressor response, animals lacking TRPV4 were given water intraduodenally. Compared to wild type, TRPV4 ‐/‐ animals had a greatly diminished pressor response to water. We conclude that the pressor effect of water is not dependent on pharyngeal, esophageal, nor gastric mechanisms; portal osmolality is reduced following water administration; and that the TRPV4 channel is essential for water's effect.

Endothelial Nitric Oxide Has Inhibitory Effects on Rhythmic Contractions in the Aortas of Sinoaortic Deafferented Rats

Sinoaortic deafferentation (SAD) is characterized by arterial pressure lability, without sustained hypertension. Although SAD rats did not become hypertensive, their isolated aortas exhibit RCs. We have investigated whether these RCs are influenced by endothelium. Aortic rings were placed in an organ chamber, and the frequency and amplitude of the RCs were measured in SAD rat aortas with intact and denuded endothelium. Moreover, the participation of endothelial NO and cGMP pathways on the RCs were analyzed through the use of such drugs as L-NAME, acetylcholine, ODQ, L-arginine, and oxyhemoglobin. Indomethacin was used to evaluate the influence of prostanoids on the RCs. Under phenylephrine stimulus, 100% of SAD rat aortas presented RCs, with higher frequency and amplitude in denuded endothelium (8.5 +/- 0.50 cycles/2 min and 0.465 +/- 0.05 g, respectively) compared with intact endothelium (4.5 +/- 0.50 cycles/2 min and 0.311 +/- 0.04 g, respectively). In intact-endothelium aortas, L-NAME, ODQ, and oxyhemoglobin raised the frequency and amplitude of the RCs to values similar to those found in denuded endothelium. L-arginine and indomethacin did not alter the RCs. In conclusion, SAD rat aortas present rhythmic contractions, which are negatively modulated by endothelial NO. Our results indicate that endothelium-derived NO (and not prostanoids), acting through the cGMP pathway, has an inhibitory effect on the oscillations.

Frequency-dependent baroreflex modulation of blood pressure and heart rate variability in conscious mice

The goal of this study was to determine the baroreflex influence on systolic arterial pressure (SAP) and pulse interval (PI) variability in conscious mice. SAP and PI were measured in C57Bl/6J mice subjected to sinoaortic deafferentation (SAD, n = 21) or sham surgery (n = 20). Average SAP and PI did not differ in SAD or control mice. In contrast, SAP variance was enhanced (21 +/- 4 vs. 9.5 +/- 1 mmHg2) and PI variance reduced (8.8 +/- 2 vs. 26 +/- 6 ms2) in SAD vs. control mice. High-frequency (HF: 1-5 Hz) SAP variability quantified by spectral analysis was greater in SAD (8.5 +/- 2.0 mmHg2) compared with control (2.5 +/- 0.2 mmHg2) mice, whereas low-frequency (LF: 0.1-1 Hz) SAP variability did not differ between the groups. Conversely, LF PI variability was markedly reduced in SAD mice (0.5 +/- 0.1 vs. 10.8 +/- 3.4 ms2). LF oscillations in SAP and PI were coherent in control mice (coherence = 0.68 +/- 0.05), with changes in SAP leading changes in PI (phase = -1.41 +/- 0.06 radians), but were not coherent in SAD mice (coherence = 0.08 +/- 0.03). Blockade of parasympathetic drive with atropine decreased average PI, PI variance, and LF and HF PI variability in control (n = 10) but had no effect in SAD (n = 6) mice. In control mice, blockade of sympathetic cardiac receptors with propranolol increased average PI and decreased PI variance and LF PI variability (n = 6). In SAD mice, propranolol increased average PI (n = 6). In conclusion, baroreflex modulation of PI contributes to LF, but not HF PI variability, and is mediated by both sympathetic and parasympathetic drives in conscious mice.

Rostral ventrolateral medulla catechol involvement upon sino-aortic deafferentation: An in vivo voltammetric study

Pharmacologically-induced hypertension engages few aminergic ventrolateral medullary cells. To further address this issue, reflex hypertension evoked by acute sino-aortic deafferentation was chosen as a model. Adrenergic rostral ventrolateral neurons were recorded with a continuous, catechol-specific tool, i.e. in vivo voltammetry. Controlled hypotension led to the expected increase in catechol signal in sham rats (n=4) but not in deafferented (vagi, superior laryngeal and glossopharyngeal nerves) rats (n=5). Thus, the central responsiveness to known stimuli remained intact in this preparation following acute sino-aortic deafferentation. However, acute sino-aortic deafferentation itself induced no increase in catechol signal (n=4 or 5 respectively). No increase in catechol signal was observed when deafferentation was performed a) under hyperoxic conditions (O2=100%, n=5) b) by extensive deafferentation involving also the cervical sympathetic trunk under halothane (n=5) c) upon restrictive deafferentation leaving the vagi intact under pentobarbital (n=5) d) in decerebrate animals (n=4). Adrenergic rostral ventrolateral medullary barosensitive bulbospinal neurons may be primarily involved during hypotension.

Role of Vagal Afferents and the Rostral Ventral Medulla in Intravenous Serotonin-Induced Changes in Nociception and Arterial Blood Pressure

THURSTON–STANFIELD, C. L., J. T. RANIERI, R. VALLABHAPURAPU AND D. BARNES–NOBLE. Role of vagal afferents and the rostral ventral medulla in intravenous serotonin-induced changes in nociception and arterial blood pressure. PHYSIOL BEHAV 67(5) 753–767, 1999.—Intravenous administration of serotonin inhibits the nociceptive tail-flick (TF) reflex, partially through activation of vagal afferents. The present study examined the role of the rostral ventral medulla (RVM) in i.v. serotonin-produced inhibition of the TF reflex. In Experiment 1, the effects of anesthetic blockade of the RVM on serotonin-produced inhibition of the TF were determined. Lidocaine attenuated the serotonin-produced inhibition of the TF reflex, but had no effect on the cardiovascular effects of serotonin. In Experiment 2, the effects of i.v. serotonin on neural activity in the RVM in intact and cardiopulmonary deafferented rats were determined. Neurons in the RVM were classified as ON and OFF cells, where ON cells were excited by noxious heat, and OFF cells were inhibited. The effects of i.v. serotonin on TF latency, blood pressure, and ON or OFF cell activity were then determined. In intact rats, serotonin produced a dose-dependent increase in TF latency, triphasic changes in blood pressure, and bi- or triphasic changes in ON or OFF cell activity. The changes in blood pressure included an initial sharp decrease in blood pressure (Bezold–Jarisch reflex), followed by a brief pressor response, followed by a delay depressor response. ON cells were generally excited, although there was a period during which the excitation decreased. OFF cells were initially excited, followed by a period of inhibition, followed by a second period of excitation. Bilateral cervical vagotomy attenuated the increase in TF latency, the Bezold–Jarisch reflex, and the excitation of OFF cells, and potentiated the excitation of ON cells and the pressor response. Bilateral sinoaortic deafferentation attenuated the Bezold–Jarisch reflex and potentiated the pressor response. These findings indicate that i.v. serotonin inhibits the TF reflex through at least two distinct mechansims, one of which requires the RVM. In addition, serotonin produces a vagally mediated excitation of OFF cells and inhibition of ON cells that may mediate some of the antinociception.

Effect of sinoaortic deafferentation on renal wrap hypertension.

The purpose of this study was to determine whether sinoaortic deafferentation (SAD) alters the severity of hypertension or sympathoadrenal contribution to mean blood pressure (MAP) during renal wrap hypertension. Male Sprague-Dawley rats were implanted with radiotelemetry transmitters for 24-hour recording of MAP and heart rate. All rats underwent either SAD or sham SAD (Intact) surgery and were allowed to recover for 10 to 14 days. The rats were then assigned to a normotensive (Sham) group or a hypertensive (Wrap) group in which 1-kidney figure-8 renal wrap was performed. SAD increased the acute MAP response to renal wrap (Intact-Sham=5+/-1 mm Hg, Intact-Wrap=45+/-3 mm Hg, SAD-Sham=3+/-3 mm Hg, SAD-Wrap=58+/-4 mm Hg) and increased the lability of MAP (SD of MAP; Intact-Sham=3.8+/-0.2, Intact-Wrap=4.2+/-0.3, SAD-Sham=9. 6+/-1.4, SAD-Wrap=9.7+/-1.4). MAP was not different between SAD and Intact rats during 4 weeks after renal wrap or sham surgery; however, induction of hypertension produced additional MAP variability that was independent of SAD (Intact-Sham=4.6+/-0.4, Intact-Wrap=6.2+/-0.6, SAD-Sham=6.3+/-0.5, SAD-Wrap=10.8+/-1.5). In a separate group of rats, the sympathoadrenal contribution to MAP was assessed by the depressor response to ganglionic blockade and plasma norepinephrine at rest and after neuronal uptake inhibition with desipramine. The depressor response to ganglionic blockade was significantly increased by renal wrap and by SAD (Intact-Sham=-49+/-2 mm Hg, Intact-Wrap=-73+/-4 mm Hg, SAD-Sham=-77+/-5 mm Hg, SAD-Wrap=-96+/-6 mm Hg). In the 3 groups with enhanced ganglionic blockade responses, desipramine caused a significant increase in plasma norepinephrine. These results indicate that SAD does not alter the development of renal wrap hypertension but does increase the sympathoadrenal contribution to MAP in both normotensive and hypertensive animals.

Influence of sympathetic blockade on the acute hypertensive response to aortic constriction.

The objective of the present study was to determine the contribution of the sympathetic nervous system to the hypertensive response to acute (45-min) aortic coarctation in conscious intact or sinoaortic-denervated (SAD) rats. Rats were treated chronically (5 wk) with guanethidine (50 mg.kg-1.day-1 i.p.) to induce sympathetic nerve degeneration or acutely with the alpha 1-adrenergic receptor antagonist prazosin. (1 mg/kg i.v.). Aortic constriction elicited a prompt and sustained rise in mean carotid pressure that was significantly greater in SAD than in intact rats. The increase in pressure was associated with reflex bradycardia only in the intact rats, whereas the heart rate of SAD rats did not change. Guanethidine treatment did not affect the arterial pressure or heart rate responses to aortic coarctation of intact rats but blunted the hypertensive response of SAD rats to the same values exhibited by intact rats. Prazosin administered 10 min after the beginning of aortic coarctation reduced the hypertensive response of SAD rats to the same level as that of intact rats. In conclusion, the data obtained by means of the association of sinoaortic deafferentation with chronic sympathectomy with guanethidine or acute alpha 1-adrenergic receptor blockade with prazosin indicate that the greater hypertensive response of SAD rats involves a lack of suppression of the sympathetic activity in the maintenance of the rise in pressure elicited by aortic coarctation.

Absence of evidence for a powerful tonic baroreflex-mediated inhibition on catechol activity in the rat rostral ventrolateral medulla: in vivo voltammetric evidence during sino-aortic deafferentation.

To test in a catechol-specific and dynamic manner for the existence of a powerful long-lasting inhibition arising from barosensitive afferents that depresses the activity of adrenergic neurons in the rostral ventrolateral medulla (RVLM), in vivo voltammetry was used before and after acute sino-aortic deafferentation. Rats were anaesthetized with pentobarbital or halothane and ventilated with a mixture of air and oxygen. Snares were inserted around the vagus, the glossopharyngeal and the superior laryngeal nerves. After placing the animal prone in the stereotaxic frame and stabilization at a high mean arterial pressure (MAP approximately 120 mmHg), the snares were rapidly closed to produce complete barodeafferentation, assessed by loss of heart rate responses and changes in renal nerve sympathetic activity in response to vasoactive agents. Recording of a catechol signal was maintained in the RVLM during deafferentation. Under pentobarbital-induced anaesthesia (n = 5), deafferentation did not lead to a significant change in the catechol signal within the deafferented group. Under halothane-induced anaesthesia and phenylephrine-induced high baseline pressure (n = 5), no changes in the catechol signal were observed upon deafferentation (not significant vs. sham animals: n = 5). This failure to demonstrate a major increase in catechol activity upon deafferentation does not fit with the hypothesis that a powerful tonic baroreflex-mediated inhibition depresses the activity of adrenergic RVLM barosensitive bulbospinal neurons, even when the baseline MAP is high. Rather, these data are compatible with weak or no inhibition of catechol activity by the baroreceptors and a nonessential role of adrenergic neurons within the baroreceptor reflex arc itself: the adrenergic neurons may not be in series within this arc but in parallel with the arc. This interpretation is in keeping with newer schemas of autonomic core circuitry that are devoid of adrenergic neurons.

Spectral analysis of arterial pressure lability in rats with sinoaortic deafferentation

Traditionally, the standard deviation (SD) of the mean arterial pressure (AP) has been used as an index for the AP lability produced by interruption of baroreceptor afferents. Although a useful measure of variance about the mean, the SD does not provide any information about the temporal characteristics of this variability. We employed two different spectral analytic techniques to characterize AP waveforms in rats with sinoaortic deafferentation (SAD) and in sham-operated (Sham) rats to determine if the AP waveform in SAD animals was qualitatively and/or quantitatively different from that of Sham animals. The SAD and Sham animals exhibited qualitatively different spectral profiles, suggesting that lability of AP in SAD animals is not simply an exaggeration of normal fluctuations. In addition, a low-frequency (0.3-0.5 Hz) spectral peak was found in Sham but not SAD animals, suggesting that it is associated with the baroreflex. Finally, we observed in both normal rats and rats without intact baroreceptors that the spectral components of AP are not static but rather vary continuously across time.

Responses of on and off cells in the rostral ventral medulla to stimulation of vagal afferents and changes in mean arterial blood pressure in intact and cardiopulmonary deafferented rats

The relationships between mean arterial blood pressure (MAP) and the activity of putative pain modulatory neurons of the rostroventral medulla (ON and OFF cells) were determined in intact and cardiopulmunary deafferented rats. A total of 173 neurons were recorded from 97 rats as follows: 32 ON cells and 25 OFF cells from 39 intact rats; 32 ON cells and 20 OFF cells from 24 rats with bilateral sino-aortic deafferentation (SAD); 12 ON cells and 20 OFF cells from 19 rats with bilateral cervical vagotomy (CVAG); and 20 ON cells and 12 OFF cells from 15 rats with both SAD and CVAG. ON and OFF cells showed spontaneous fluctuations in activity such that ON cell activity was negatively correlated with MAP whereas OFF cell activity was positively correlated with MAP under conditions of no applied stimuli. These correlations were present in both intact and cardiopulmonary deafferented rats. Further, experimentally induced increases in MAP decreased ON cell activity and increased OFF cell activity in intact rats, but not in rats with SAD, CVAG, or the combination of SAD and CVAG. Experimentally induced decreases in MAP decreased OFF cell activity in intact rats and rats with CVAG, but not in rats with SAD or the combination of SAD and CVAG. These findings indicate that ON and OFF cells are modulated by baroreceptor activity, but baroreceptor input is not necessary for the spontaneous fluctuations in ON and OFF cell activity. Electrical stimulation of vagal afferents (VAS) inhibited 60% of the OFF cells studied, excited 4%, and produced biphasic effects consisting of excitation at low intensities and inhibition at greater intensities in 28% of all OFF cells. In general, VAS excited the majority of the ON cells studied, although there were significant differences between effects in intact and cardiopulmonary deafferented rats. Greater intensities of VAS that inhibited OFF cells and excited ON cells also inhibited the tail flick. Thus, inhibition of OFF cells and excitation of ON cells was correlated with antinociception. The effects of intravenous (i.v.) administration of 1.0 mg/kg morphine on neuronal activity did not differ between intact and cardiopulmonary deafferented rats. Intravenous administration of morphine produced a sustained inhibition of 20.7% of all ON cells studied, produced a biphasic effect consisting of a brief excitation followed by a sustained inhibition in 62.1% of the ON cells, and had no effect on the activity of 17.2% of the ON cells. Morphine-produced inhibition of ON cell activity was reversed by i.v. administration of naloxone HCl, but was not affected by i.v. administration of naloxone methobromide (NMB). However, pre-treatment with NMB attenuated the initial morphine-produced excitation of ON cells. In studies of OFF cells, i.v. administration of morphine excited 40.0% of the OFF cells, produced a biphasic effect consisting of an initial inhibition followed by excitation in 33.3% of the OFF cells, and had no effect on the activity of 26.7% of the OFF cells. Naloxone HCl reversed the effects of morphine within 1 min after administration, whereas NMB had no effect on the morphine-produced excitation of OFF cells. Intravenous administration of morphine following pre-treatment with NMB excited the 2 OFF cells studied. These data suggest that ON and OFF cells in the rostroventral medulla not only receive converging input from cardiopulmonary and somatic afferents, but may also function in the regulation of both systems. Specifically, the excitation of ON cells and inhibition of OFF cells may decrease MAP and nociception, whereas the inhibition of ON cells and excitation of OFF cells may increase MAP and nociception. This hypothesis contradicts previous hypotheses suggesting that inhibition of ON cells and excitation of OFF cells attenuates nociception indicating that current hypotheses on the function of ON and OFF cells require further analyses.

Spinal nociceptive transmission in the spontaneously hypertensive and Wistar-Kyoto normotensive rat

Background and noxious heat-evoked responses of wide-dynamic-range (WDR) and high-threshold (HT) lumbosacral spinal dorsal horn neurons were recorded in spontaneously hypertensive rats (SHRs), Wistar-Kyoto normotensive rats (WKYs), lifetime captopril-treated SHRs, SHRs with bilateral cervical vagotomy, SHRs with bilateral sino-aortic deafferentation (SAD), and SHRs with either a single or repeated administration of naloxone methobromide (NMB). Stimulus-response functions (SRFs) were generated for neurons using 15 sec of heating of the foot at temperatures ranging from 38 to 52°C. Comparisons were made of neuronal response thresholds, slopes of the SRFs, mean discharge frequency during heat stimulation, arterial blood pressure (ABP), and heart rate (HR). The primary finding was that group mean SRFs for both WDR and HT neurons were shifted in a parallel, rightward fashion in SHRs compared to WKYs. Heat-evoked response thresholds were increased and asymptotic discharge frequencies were decreased in WDR and HT neurons of SHRs compared to WKYs. Analyses of group mean SRFs for WDR and HT neurons of SHRs receiving lifetime captopril treatment indicated they were normalized to the SRFs of WKYs, but detailed comparisons using discharge frequency during heat stimulation revealed that this was due to a statistical averaging effect. Specifically, lifetime captopril-treated SHRs not only showed enhanced neuronal responses to the onset of noxious heat but also enhanced adaptation of neuronal responses with continued heating compared to WKYs. Bilateral SAD in SHRs significantly increased the total discharge frequency of WDR neurons to heat stimuli between 44 and 52°C, but produced no change in the response threshold for heat-evoked activation of these neurons. A similar effect of SAD was observed in HT neurons of SHRs, but the greater response thresholds of HT neurons precluded detection of any significant effect. Bilateral cervical vagotomy did not affect response thresholds, slopes, or total discharge frequencies of SHRs, although only WDR neurons were studied. SRFs of WDR and HT neurons in SHRs obtained pre- and post-administration of a single dose of NMB did not differ. However, repeated administration of NMB in SHRs resulted in a parallel, leftward shift in SRFs of both WDR and HT neurons. In all strains and treatments studied, there were no significant differences in background activities of these neurons that might contribute to the observed outcomes. In conclusion, the hypoalgesia reported in human essential hypertensives and animals with chronic hypertension may be due to a significant attenuation in spinal nociceptive transmission. Our data are not definitive on whether increased ABP produced the attenuation of spinal nociceptive transmission in SHRs because the use of the lifetime captopril treatment to lower systemic ABP of SHRs to levels of WKYs may also have affected endogenous facilitatory and inhibitory opioid systems. However, it was possible to demonstrate an inhibitory influence of both sino-aortic afferents and endogenous central opioids on spinal nociceptive transmission in the SHR.

Lesions in rostral ventromedial or rostral ventrolateral medulla block neurogenic hypertension.

Neurogenic hypertension results from the removal of inhibitory baroreceptor afferent input to vasomotor systems in the central nervous system. We sought to determine whether the bilateral destruction of neurons in the rostral ventrolateral or rostral ventromedial medulla, made using microinjections of N-methyl-D-aspartic acid (30 nmol in 200 nL), would block the acute increase in arterial pressure after sinoaortic deafferentation in pentobarbital-anesthetized rats. Bilateral lesions of the rostral ventrolateral or rostral ventromedial medulla decreased mean arterial pressure (107 +/- 4 to 78 +/- 5 and 115 +/- 3 to 94 +/- 3 mm Hg, respectively). In rostral ventrolateral or rostral ventromedial medulla lesioned rats, sinoaortic deafferentation failed to increase arterial pressure. Sham lesions or lesions placed rostral to the rostral ventrolateral or rostral ventromedial medulla did not significantly lower arterial pressure. Subsequent sinoaortic deafferentation significantly increased mean arterial pressure (109 +/- 3 to 145 +/- 4 and 109 +/- 5 to 141 +/- 3 mm Hg, respectively). In eight rats we used an infusion of angiotensin II to return arterial pressure to control levels after lesion of the rostral ventrolateral (n = 4) or rostral ventromedial (n = 4) medulla. In these animals, sinoaortic deafferentation failed to increase arterial pressure. We conclude that neurons in the rostral ventrolateral and rostral ventromedial medulla are involved in the normal maintenance of arterial pressure and the development of hypertension after sinoaortic deafferentation in pentobarbital-anesthetized rats.

Loss of osmotic thirst in multiple system atrophy: association with sinoaortic baroreceptor deafferentation.

We evaluated plasma osmolality (pOsm), thirst, and vasopressin response to hypertonic saline infusion in 14 patients with multiple system atrophy (MSA). This disease is characterized by the degeneration of noradrenergic neurons in the central nervous system and severe orthostatic hypotension. Seven patients were also characterized by the lack of vasopressin response to hypotension (group B) and seven by a preserved response (group A). In group A pOsm rose from 290 +/- 2 to 312 +/- 6 mosmol/kgH2O, vasopressin from 0.9 +/- 0.3 to 5.7 +/- 0.5 pmol/l, and thirst from 1.1 +/- 0.1 to 8.7 +/- 1.1 cm on the visual analog scale. After saline, patients drank 1,215 +/- 150 ml of water (no different from healthy controls). In group B patients' pOsm rose from 296 +/- 3 to 325 +/- 6 mosmol/kgH2O and vasopressin from 1.2 +/- 0.1 to 19.6 +/- 0.4 pmol/l (P < 0.01 vs. group A and controls). Group B patients had no thirst during saline and drank little after the challenge (175 +/- 50 ml; P < 0.01 vs. group A and control). Forced drinking decreased vasopressin in patients before changes in pOsm, showing that inhibitory afferents from oropharyngeal mucosa were intact. In MSA patients with altered afferent control of vasopressin there is a dissociation between the osmotic control of thirst and the osmotic control of vasopressin.

Baroreceptor reflex-linked changes in catechol metabolism in the rat rostral ventrolateral medulla.

1. Using in vivo voltammetry, this study relates catecholamine metabolism within the rat rostral ventrolateral medulla to the level of mean arterial pressure (MAP) under halothane anaesthesia. 2. A vasopressor region was circumscribed with electrical stimulations in an area located 1000-1700 microns rostral to the obex. A catechol signal was then ascertained within this area. The recording site was surrounded with phenyl-N-methyl-ethanolamine transferase immuno-positive cell bodies. 3. Three levels of decrease of arterial pressure were induced with nitroprusside infusion: -15, -35 and -55 mmHg (n = 5 in each group) from baseline for 30 min. This led to increases in the catechol signal which were inversely related to the degree of hypotension (P < 10(-4) vs. saline for the 35 and 55 mmHg groups, P < 0.05 for the 35 mmHg group as compared to the 15 and 55 mmHg groups following recovery from hypotension). 4. Following sino-aortic deafferentation, nitroprusside-induced hypotension (-35 mmHg) did not lead to any change in the catechol signal in the rostral ventrolateral medulla (n = 5). Furthermore, controlled hypotension induced in intact rats did not evoke any change in the catechol signal recorded in a dopaminergic area of the midbrain, the ventral tegmental area (A10 area; n = 5). 5. An infusion of phenylephrine increased MAP by 35 mmHg from a baseline pressure of 105 mmHg for 30 min and evoked a non-significant decrease in the catechol signal (n = 5). In another group of rats a lower baseline pressure (80 mmHg) was stabilized (n = 5) with a higher concentration of halothane. An identical increment in pressure was then produced by a phenylephrine infusion and led to a significant reduction in the catechol signal (P < 0.05 vs. saline under similar conditions; n = 5). 6. The new findings of this study are that the level of activity of the metabolism of catecholamine in the rostral ventrolateral medulla (i) is continuously related to the level of arterial pressure, (ii) functions close to its resting level under baseline conditions and is primarily engaged during hypotension and (iii) is baroreflex linked. 7. Given the lack of direct evidence for a link between unit activity and catechol metabolism, these changes in catechol activity, recorded continuously in vivo next to adrenergic cell bodies, may represent the biochemical-specific counterpart of changes in the level of electrical unitary activity of presumed adrenergic cardiovascular medullospinal sympathoexcitatory neurons. Therefore, it provides evidence that adrenaline-synthesizing neurons in the rostral ventrolateral medulla respond to baroreceptor inputs.

Relative contributions of cardiopulmonary and sinoaortic baroreflexes in causing sympathetic activation in the human skeletal muscle circulation during orthostatic stress.

The aim of this study was to reexamine the hypothesis that cardiopulmonary baroreflexes are more important than sinoaortic baroreflexes in causing vasoconstriction in the skeletal muscle circulation during orthostatic stress. We recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve (and forearm blood flow with venous occlusion plethysmography) in normal subjects (innervated ventricles) and in heart transplant recipients (denervated ventricles) during graded lower body negative pressure (LBNP) performed alone and in combination with intravenous infusion of phenylephrine, which was titrated to eliminate the orthostatically induced fall in blood pressure and thus the unloading of both carotid and aortic baroreceptors. The principal new findings are as follows: (1) The increases in both MSNA and forearm vascular resistance during multiple levels of LBNP were not attenuated by heart transplantation, which causes ventricular but not sinoaortic deafferentation. (2) In heart transplant recipients, a small increase in MSNA during mild LBNP was dependent on a decrease in arterial pressure, but in normal subjects, a similar increase in MSNA occurred in the absence of any detectable decrease in the aortic pressure stimulus to the sinoaortic baroreceptors. (3) In normal subjects, the large increase in MSNA during a high level of LBNP was dependent on a decrease in arterial pressure and could be dissociated from the decrease in central venous pressure. Taken together, the findings strongly suggest that sinoaortic baroreflexes are much more important and ventricular baroreflexes are much less important than previously thought in causing reflex sympathetic activation and vasoconstriction in the human skeletal muscle circulation during orthostatic stress.

Effects of central serotonin on autonomic control of heart rate in intact and baroreceptor deficient rats

The intracerebroventricular (i.c.v.) injection of serotonin (5-HT) increases blood pressure and decreases heart rate (HR) in conscious rats by activation of 5-HT 2/1C receptors. Since the bradycarbia is eliminated by pretreatment with a ganglionic or V 1-vasopressin antagonist, we proposed that the decrease in HR results from an effect on cardiac autonomic activity which is potentiated by vasopressin. The present study aimed first, to further characterize mechanisms by which the i.c.v. injection of 5-HT (2.5 μg) decreases HR in consious rats, and second to determine the cardiovascular responses to 5-HT (2.5 μg, i.c.v.) in rats with chronic sinoaortic deafferentation (SAD). In intact rats, the bradycardia elicited by 5-HT was eliminated by a combination of the muscarinic antagonist atropine and the β-adrenoceptor antagonist sotatol; neither antagonist was effective alone. In rats with SAD, 5-HT produced a larger increase in blood pressure and a marked tachycardia, both of which were eliminated by the 5-HT 2/1C antagonist LY 53857. Furthermore, in rats with SAD the 5-HT-induced increase in HR was blocked by sotalol alone. In conclusion, 5-HT (2.5 μg, i.c.v.) acts on cenrtal 5-HT 2/1C receptors to increase arterial pressure. In intact rats this decreases HR by vasopressin-potentiated activation of baroreceptor reflexes and subsequent increase in vagal tone and decrease in cardiac sympathetic tone. In the absence of baroreflexes, a direct central effect of 5-HT to produce a β-adrenoceptor-mediated cardioacceleration is unmasked.

Transient changes in blood pressure during spontaneous deep breaths in rats with sinoaortic deafferentation.

Sinoaortic deafferentation (SAD) in rats produces moderate increases in mean arterial pressure (MAP) along with a large augmentation of arterial pressure lability (APL). The mechanisms generating this APL are incompletely understood. To study the possible influence of breathing activity on APL in conscious SAD rats, we simultaneously recorded pulmonary ventilation and arterial blood pressure. The general pattern of pulmonary ventilation was the same in normal, sham-operated, and SAD rats. In all groups single large tidal volumes were regularly interposed in 1- to 2-min periods of shallower breathing. In SAD rats these single large inspirations were consistently accompanied by substantial and abrupt reductions of MAP, whereas this effect was markedly smaller or absent in normal and sham-operated rats. The data reflect the lack of fast moment-to-moment control of arterial pressure normally exerted by the aortic and carotid baroreceptors. In this context, effects of ventilatory changes must be considered along with humoral and neurogenic factors to explain APL after SAD.

Chemical renal medullectomy and arterial pressure response to sinoaortic denervation.

We investigated in conscious Wistar-Kyoto rats the effect of chemical renal medullectomy on the responses of mean arterial pressure, arterial pressure lability, and heart rate to sinoaortic deafferentation (SAD). Chemical medullectomy was obtained by the intravenous administration of 2-bromoethylamine hydrobromide (2-BEA) 2-3 weeks before SAD or sham SAD. Chemically medullectomized rats were compared with control rats treated with saline. In control rats, the increase in mean arterial pressure elicited by SAD was not significantly greater than that produced by sham SAD. In medullectomized rats, SAD significantly increased mean arterial pressure compared with sham SAD. No direct relation was observed between the response of mean arterial pressure to SAD and the grade (1, 2, or 3) of lesion of the renal papilla. In control rats, SAD increased significantly arterial pressure lability. Chemical medullectomy did not affect basal lability or the increased lability after SAD. No direct relation was observed between increased arterial pressure lability due to SAD and the grade of lesion of the renal papilla. SAD produced a conspicuous tachycardia in control rats. Chemical medullectomy did not affect basal heart rate or the tachycardia produced by SAD. No direct relation was observed between the extent of this tachycardia and the grade of lesion of the renal papilla. These data indicate that lesions of the renal papilla lead to a significant increase in mean arterial pressure after SAD, without affecting basal pressure or heart rate. In addition, SAD per se did not increase significantly the mean arterial pressure in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Central nervous system and the pathogenesis of hypertension. Sites and mechanisms.

A large body of evidence indicates that the central nervous system plays an essential role in the pathogenesis of hypertension. However, in many cases the specific brain regions involved and the mechanisms by which these regions promote hypertension are not known. In recent years, research in this and other laboratories has attempted to determine the mechanisms by which neural and humoral signals arising in response to pathological conditions (often occurring in the periphery) interact with the central nervous system to produce hypertension. In this article, we illustrate the coupling of peripheral and central factors in the pathogenesis of hypertension by examining the central actions of angiotensin II and mineralocorticoids in the expression of renal hypertension and mineralocorticoid-salt hypertension, respectively. We also review recent data from this laboratory illustrating the involvement of medullary vasomotor centers in the development of neurogenic hypertension after sinoaortic deafferentation and in the maintenance of hypertension in the spontaneously hypertensive rat.

Antinociception and cardiovascular responses produced by intravenous morphine: the role of vagal afferents

The mechanisms of the antinociceptive, depressor and bradycardic responses produced by intravenous (i.v.) administration of morphine were examined in rats lighyly anesthetized with pentobarbital sodium. Intravenous administration of 0.1, 0.25, 0.5, 1.0 or 2.5 mg/kg of morphine produced dose-dependent inhibition of the nociceptive tail flick (TF) reflex, hypotension, and bradycardia. Bilateral cervical vagotomy (CVAG) significantly attenuated the antinociception produced by i.v. morphine and the degree of attenuation was inversely related to drug dose. CVAG had no effect on the depressor response produced by lesser doses of morphine (0.1 or 0.5 mg/kg), but at greater doses converted the depressor response into either a pressor response (1.0 mg/kg) or an initial pressor response followed by a depressor response (2.5 mg/kg). Morphine-induced bradycardia was blocked by CVAG at all drug doses tested (0.1, 0.5, 1.0 and 2.5 mg/kg). In selective tests of either 0.5 or 2.5 mg/kg of i.v. morphine, prior administration of the peripherally acting opiod receptor antagonist naloxone methobromide (NMB) attenuated the antinociception to the same degree as CVAG. NMB also completely blocked the depressor and bradycardic responses of these doses of morphine. Bilateral subdiaphragmatic vagotomy (SDVAG) resulted in a marginal attenuation of antinociception at 0.5 mg/kg but not 2.5 mg/kg of morphine, and the attenuation produced by SDVAG was delayed in onset following morphine administration relative to that produced by CVAG. Bilateral sino-aortic deafferentation (SAD) had no significant effect on the antinociception in tests with 0.5 mg/kg of morphine. SDVAG and SAD had little effect on cardiovascular responses produced by these doses of morphine. The spinal antinociceptive systems activated by vagal afferents following i.v. morphine administration were characterized with the 0.5 mg/kg dose. Spinal cold block significantly antagonized the antinociception, hypotension and bradycardia produced by this dose of morphine. Intrathecal administration of naloxone (1.5, 15 or 30 μg) significantly antagonized the antinociception compared to saline controls, whereas intrathecal administration of methysergide (30 μg), phentolamine (30 μg), or the combination of methysergide with phentolamine (30 μg each) had no significant effect on the antinociception. These intrathecal doses of naloxone also antagonized the depressor and bradycardic responses produced by morphine. However, the antagonism produced by 1.5 μg of intrathecal naloxone was not due to spread to the systemic circulation, since i.v. administration of 1.5 μg of naloxone did not significantly affect either the antinociceptive or cardiovascular responses produced by morphine. These findings indicate that vagal afferents play a significant role in the antinociception produced by i.v. administration of morphine. Lesser doses of i.v. morphine produce antinociception primarily by activating vagal afferents that engage a spinopetal inhibitory system using spinal opioids. At greater doses of i.v. morphine, the vagal influence is masked to a large extent, presumably by direct spinal/supraspinal actions of morphine. Depressor responses produced by lesser doses of i.v. morphine are not due to activation of vagal afferents, although at greater doses of morphine, the vagi are clearly important for the expression of morphine-induced changes in arterial blood pressure. Bradycardic responses produced by i.v. morphine appear to reflect activation of vagal afferents.