Brain serotonin and blood pressure regulation: studies using in vivo electrochemistry and direct tissue assay

Hypotensive responses to tryptophan and 5-hydroxytryptophan infusions were studied in normotensive male Sprague-Dawley rats. Results showed that 5-hydroxytryptophan but not tryptophan lowered pressure in a dose dependent way in direct relation to the production of brain serotonin and 5-HIAA. Intrinsic release of serotonin from brain was also studied during periods of induced hypertension and hypotension. Brain monoamine responses to blood pressure changes induced by intravenous phenylephrine and nitroprusside were measured in dorsal raphe nucleus and nucleus tractus solitarius by in vivo electrochemistry. Results showed that 5-HIAA was increased during drug induced hypertension and during reflex hypertension which followed a period of hypotension. These changes were blocked by sinoaortic denervation indicating that these central serotonergic neurons are responding to increased pressure sensed by baroreceptors. Therefore, serotonin has a role in blood pressure regulation as a pharmacologic agent and as a neurotransmitter in homeostatic control of pressure.     

Altered serotonin and norepinephrine metabolism in rat dorsal raphe nucleus after drug-induced hypertension

The effect of drug-induced hypertension on neurotransmitter release from dorsal raphe nucleus was studied by in vivo electrochemical electrodes in urethane anesthetized male Sprague-Dawley rats. Carbon paste electrodes were stereotaxically placed into dorsal raphe nucleus and neurotransmitter release was estimated electrochemically. Blood pressure was recorded from a femoral arterial catheter. Voltammograms taken from dorsal raphe nucleus showed two distinct peaks corresponding to norepinephrine and 5-hydroxyindole acetic acid (5-HIAA). After basal blood pressure and neurotransmitter release were monitored for 30 min, blood pressure was raised 50 mmHg by continuous intravenous infusion of L-phenylephrine hydrochloride. Drug infusion was discontinued after 50 min, but blood pressure and neurotransmitter release were measured for an additional 2 hr. Results showed that the 5-HIAA response increased immediately after the initiation of hypertension and remained elevated. By contrast, norepinephrine release initially decreased, then returned to the basal level and then rose in parallel with 5-HIAA to a level above baseline as drug-induced hypertension was discontinued. The same experimental protocol was used to study the electrochemical response to drug-induced hypotension. Blood pressure was lowered 20 mmHg by intravenous infusion of sodium nitroprusside dihydrate. During hypotension, no changes were seen in either transmitter response. However, as reflex hypertension appeared following discontinuation of the sodium nitroprusside infusion, the 5-HIAA response increased and the norepinephrine response decreased. These results show that drug-induced and reflex hypertension reduce norepinephrine release and increase serotonin turnover in dorsal raphe nucleus in anesthetized normotensive rats. These reciprocal changes appear to be a part of the neural response to hypertension.     

Drug-Induced Changes in Blood Pressure Lead to Changes in Extracellular Concentrations of Epinephrine, Dihydroxyphenylacetic Acid, and 5-Hydroxyindoleacetic Acid in the Rostral Ventrolateral Medulla of the Rat

Neurochemical changes in the extracellular fluid of the rostral ventrolateral medulla (RVLM) were produced by changes in arterial blood pressure. Blood pressure was raised or lowered with systemic infusions of phenylephrine or nitroprusside and neurochemicals were recovered from RVLM by in vivo microdialysis. A dialysis probe 300 microns in diameter and 500 microns in length was stereotaxically implanted in the RVLM of the urethane-anesthetized rat. Sterile physiological Ringer's solution was perfused at a rate of 1.5 microliter/min. The perfusate was collected under ice-cold conditions every 15 min for the assay of epinephrine, dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), ascorbic acid, and uric acid. After stable baseline neurochemical concentrations were achieved, animals were infused with phenylephrine or nitroprusside intravenously to raise or lower the blood pressure. Increasing blood pressure 50 mm Hg above the baseline value by phenylephrine led to a significant reduction in heart rate and a reduction in extracellular epinephrine and DOPAC concentrations. The 5-HIAA concentration was increased during the hypertensive drug infusion. There were no changes in the concentrations of ascorbic acid or uric acid. Hypotension produced by nitroprusside (-20 mm Hg) led to neurochemical changes which were the reciprocal of those seen during hypertension. During hypotension, heart rate increased as did the extracellular fluid epinephrine concentration. The 5-HIAA concentration fell with hypotension and remained depressed following the nitroprusside infusion. Ascorbic acid and uric acid concentrations did not change during hypotension but ascorbic acid did increase after the nitroprusside infusion stopped. These data provide direct evidence that epinephrine release in RVLM is linked to changes in systemic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of arterial Windkessel in low-frequency cerebral hemodynamics during transient changes in blood pressure

The Windkessel properties of the vasculature are known to play a significant role in buffering arterial pulsations, but their potential importance in dampening low-frequency fluctuations in cerebral blood flow has not been clearly examined. In this study, we quantitatively assessed the contribution of arterial Windkessel (peripheral compliance and resistance) in the dynamic cerebral blood flow response to relatively large and acute changes in blood pressure. Middle cerebral artery flow velocity (MCA(V); transcranial Doppler) and arterial blood pressure were recorded from 14 healthy subjects. Low-pass-filtered pressure-flow responses (<0.15 Hz) during transient hypertension (intravenous phenylephrine) and hypotension (intravenous sodium nitroprusside) were fitted to a two-element Windkessel model. The Windkessel model was found to provide a superior goodness of fit to the MCA(V) responses during both hypertension and hypotension (R2 = 0.89 ± 0.03 and 0.85 ± 0.05, respectively), with a significant improvement in adjusted coefficients of determination (P < 0.005) compared with the single-resistance model (R2 = 0.62 ± 0.06 and 0.61 ± 0.08, respectively). No differences were found between the two interventions in the Windkessel capacitive and resistive gains, suggesting similar vascular properties during pressure rise and fall episodes. The results highlight that low-frequency cerebral hemodynamic responses to transient hypertension and hypotension may include a significant contribution from the mechanical properties of vasculature and, thus, cannot solely be attributed to the active control of vascular tone by cerebral autoregulation. The arterial Windkessel should be regarded as an important element of dynamic cerebral blood flow modulation during large and acute blood pressure perturbation.     

Differential cardiorespiratory control elicited by activation of ventral medullary sites in mice.

We studied the respiratory and blood pressure responses to chemical stimulation of two regions of the ventral brainstem in mice: the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively). Stimulation of the RVLM by microinjections of the excitatory amino acid L-glutamate induced increases in diaphragm activity and breathing frequency, elevation of blood pressure (BP), and a slight increase in heart rate (HR). However, activation of the CVLM induced a decrease in breathing frequency, mainly due to prolongation of expiratory time (TE), and hypotension associated with a slight slowing of HR. Because adrenergic mechanisms are known to participate in the control of respiratory timing, we examined the role of alpha(2)-adrenergic receptors in the RVLM region in mediating these inhibitory effects. The findings demonstrated that blockade of the alpha(2)-adrenergic receptors within the RVLM by prior microinjection of SKF-86466 (an alpha(2)-adrenergic receptor blocker) significantly reduced changes in TE induced by CVLM stimulation but had little effect on BP responses. These results indicate that, in mice, activation of the RVLM increases respiratory drive associated with an elevation of BP, but stimulation of CVLM induces prolongation of TE via an alpha(2)-adrenergic signal transduction pathway.     

Functional activity of the structures of the medulla oblongata in rats with arterial hypertension of renal origin (histoenzymological research)

A quantitative histochemical study of succinate dehydrogenase (SDH) and NADH-dehydrogenase (NADH-D) activity in medulla oblongata structures was accomplished in rats with arterial renovascular hypertension of the "2 kidneys-2 clips" type lasting 5 months. The systolic arterial blood pressure measured by the tail-cuff method was 179 +/- 4 mm Hg in hypertensive rats versus 108 +/- 3 mm Hg in control. There was a significant elevation of SDH activity in the ventral reticular and commissural nuclei, while in the neurons of the vagus dorsal and ambiguous nuclei it was lowered. NADH-D activity was significantly increased in the neuropil of the hypoglossal nerve nucleus and reduced in its neurons. The general trend was also revealed toward reduction of the maximal and elevation of the minimal activities in other nuclei. These metabolic alterations reflect changes in the functional activity of vasomotor and other structures of the medulla oblongata in renovascular hypertension.     

Neuroendocrine mechanisms of participation of the raphe nuclei in the development of hypertensive reactions in emotional stress

The experiments on cats and rabbits have studied electroencephalographic, endocrine and blood pressure responses to stress (5-hour immobilization with electrical foot shock) before and after coagulation of the midbrain nuclei raphe. Blood pressure and adrenal responses in advanced (4-hour) stress were elevated in intact animals, the responses attenuating after coagulation of the nuclei raphe. Background bioelectrical activity of the midbrain reticular formation and hypothalamus was found to be activated in the operated animals. Stress was followed by the reduction in bioelectrical changes of the above subcortical structures with the parallel development of "burst" activity in the dorsal hippocamp.     

Enhanced baroreflex-mediated inhibition of respiration after muscimol dialysis in the rostroventral medulla.

The rostral ventral medulla (RVM) may be important in the control of cardiorespiratory interactions. We hypothesized that inhibition of the RVM would enhance inhibition of breathing associated with transient blood pressure elevations. In 25 piglets 3-16 days of age, we studied the effect of acutely increasing blood pressure, by systemic infusion of phenylephrine, on respiratory activity before and after inhibition of neural activity in the RVM by dialysis of 10 mM muscimol, a GABA(A)-receptor agonist. Muscimol dialysis through probes that were placed along the ventral medullary surface from approximately 1 mm rostral to the facial nucleus to approximately 0.5 mm caudal to the facial nucleus augmented the respiratory inhibition associated with acute increases in blood pressure. No similar enhancement of respiratory inhibition after phenylephrine treatment was seen in six control animals that did not receive muscimol dialysis. We conclude that the piglet RVM participates in cardiorespiratory interactions and that dysfunction of homologous regions in the human infant could lead to cardiorespiratory instability and may be involved in the pathogenesis of sudden infant death syndrome.     

Cardiovascular reflex-reactions on the blood volume changes before and after pharmacological elimination of the efferent heart innervation]

Reflex changes in the heart frequency, blood pressure and respiratory frequency induced by slow changes of the blood volume are observed in the aesthetized European hamster (Cricetus cricetus L.). Tachycardia, hypertension and hyperpnoe occured during intravenous infusion and bradycardia, hypotension and respiratory inhibition during hemorrhages or local distensions of the junction between the superior vena cava and the right atrium. Various receptor organs of the heart and the great vessels and sympathetic as well as parasympathetic effector mechanisms were involved in the reflex effects. An activation of efferent vagal fibers decreased blood pressure and heart frequency; an excitation of efferent sympathetic fibers increased blood pressure and heart frequency.     

Influence of the ventral surface of the medulla on tracheal responses to CO2

These studies investigated the role of the intermediate area of the ventral surface of the medulla (VMS) in the tracheal constriction produced by hypercapnia. Experiments were performed in chloralose-anesthetized, paralyzed, and artificially ventilated cats. Airway responses were assessed from pressure changes in a bypassed segment of the rostral cervical trachea. Hyperoxic hypercapnia increased tracheal pressure and phrenic nerve activity. Intravenous atropine pretreatment or vagotomy abolished the changes in tracheal pressure without affecting phrenic nerve discharge. Rapid cooling of the intermediate area reversed the tracheal constriction produced by hypercapnia. Graded cooling produced a progressive reduction in the changes in maximal tracheal pressure and phrenic nerve discharge responses caused by hypercapnia. Cooling the intermediate area to 20 degrees C significantly elevated the CO2 thresholds of both responses. These findings demonstrate that structures near the intermediate area of the VMS play a role in the neural cholinergic responses of the tracheal segment to CO2. It is possible that neurons or fibers in intermediate area influence the motor nuclei innervating the trachea. Alternatively, airway tone may be linked to respiratory motor activity so that medullary interventions that influence respiratory motor activity also alter bronchomotor tone.     

Consequences of the saphenous artery denervation under normal and chronically lowered blood pressure in rats

We studied constrictor responses of saphenous artery after sympathetic denervation in normotensive rats and rats with chronic regional hypotension. Abdominal aorta was partially occluded in Wistar rats distally to the renal arteries, lowering blood pressure in the hindquarters by about 40%, a week later to denervate saphenous artery the femoral nerve was cut. The density of periarterial nerve plexus and neurogenic responses of the vessel restored partially in 2 weeks and completely in 6 weeks after the surgery; the chronic hypotension did not modify the dynamics of reinnervation. Arteries of both groups of rats demonstrated higher sensitivity to noradrenaline during 6 weeks after denervation, whereas vessel sensitivity to serotonin was enhanced only in normotensive rats. Therefore, chronic hypotension may prevent postdenervation hypersensitivity of vascular smooth muscle to vasoconstrictors.     

Functional magnetic resonance signal changes in neural structures to baroreceptor reflex activation.

The sequence of neural responses to exogenous arterial pressure manipulation remains unclear, especially for extramedullary sites. We used functional magnetic resonance imaging procedures to visualize neural responses during pressor (phenylephrine) and depressor (sodium nitroprusside) challenges in seven isoflurane-anesthetized adult cats. Depressor challenges produced signal-intensity declines in multiple cardiovascular-related sites in the medulla, including the nucleus tractus solitarius, and caudal and rostral ventrolateral medulla. Signal decreases also emerged in the cerebellar vermis, inferior olive, dorsolateral pons, and right insula. Rostral sites, such as the amygdala and hypothalamus, increased signal intensity as arterial pressure declined. In contrast, arterial pressure elevation elicited smaller signal increases in medullary regions, the dorsolateral pons, and the right insula and signal declines in regions of the hypothalamus, with no change in deep cerebellar areas. Responses to both pressor and depressor challenges were typically lateralized. In a subset of animals, barodenervation resulted in rises and falls of blood pressure that were comparable to these resulting from the pharmacological challenges but different regional neural responses, indicating that the regional signal intensity responses did not derive from global perfusion effects but from baroreceptor mediation of central mechanisms. The findings demonstrate widespread lateralized distribution of neural sites responsive to blood pressure manipulation. The distribution and time course of neural responses follow patterns associated with early and late compensatory reactions.     

Blood pressure regulation in the three-toed sloth, Bradypus variegatus

The aim of this study was to elucidate the role of the baroreflex in blood pressure control in sloths, Bradypus variegatus, since these animals show labile levels in this parameter. Unanesthetized cannulated sloths were positioned in an experimental chair and the arterial catheter was coupled to a strain gauge pressure transducer. Blood pressure was monitored before, during and after the administration of phenylephrine (0.0625 to 4 microg/kg) and sodium nitroprusside (0.0625 to 2 microg/kg), bringing about changes in mean blood pressure from +/-30 mmHg in relation to control values. The relation between heart rate changes due to blood pressure variation was estimated by linear regression analysis. The slope was considered the reflex baroreceptor gain. The results (means+/-SD) showed that the reflex baroreceptor gain was -0.3+/-0.1 bpm/mmHg (r=0.88) to phenylephrine and -0.5+/-0.1 bpm/mmHg (r=0.92) to sodium nitroprusside, denoting a reduced reflex baroreceptor gain when compared with other mammals, suggesting that in sloths the baroreceptors are minimally involved in the buffering reflex response to these drugs. These findings suggest that the labile blood pressure could be influenced or be a result of this lowering in the reflex baroreceptor gain.     

Cardiorespiratory failure in rat induced by severe inspiratory resistive loading.

The mechanisms underlying acute respiratory failure induced by respiratory loads are unclear. We hypothesized that, in contrast to a moderate inspiratory resistive load, a severe one would elicit central respiratory failure (decreased respiratory drive) before diaphragmatic injury and fatigue. We also wished to elucidate the factors that predict endurance time and peak tracheal pressure generation. Anesthetized rats breathed air against a severe load ( approximately 75% of the peak tracheal pressure generated during a 30-s occlusion) until pump failure (fall in tracheal pressure to half; mean 38 min). Hypercapnia and hypoxemia developed rapidly ( approximately 4 min), coincident with diaphragmatic fatigue (decreased ratio of transdiaphragmatic pressure to peak integrated phrenic activity) and the detection in blood of the fast isoform of skeletal troponin I (muscle injury). At approximately 23 min, respiratory frequency and then blood pressure fell, followed immediately by secondary diaphragmatic fatigue. Blood taken after termination of loading contained cardiac troponin T (myocardial injury). Contrary to our hypothesis, diaphragmatic fatigue and injury occurred early in loading before central failure, evident only as a change in the timing but not the drive component of the central respiratory pattern generator. Stepwise multiple regression analysis selected changes in mean arterial pressure and arterial Pco(2) during loading as the principal contributing factors in load endurance time, and changes in mean arterial pressure as the principal contributing factor in peak tracheal pressure generation. In conclusion, the temporal development of respiratory failure is not stereotyped but depends on load magnitude; moreover respiratory loads induce cardiorespiratory, not just respiratory, failure.     

Vascular reactivity and baroreflex function during hyperthermia in conscious rats

The hemodynamic responses to vasoconstrictor agents are blunted during heating in anesthetized rats. It is unknown whether reflex neural responses to these agents are also altered during hyperthermia. Therefore, the purpose of this study was to determine the effect of hyperthermia on the hemodynamic and baroreflex-mediated sympathetic neural responses to vasoactive agents in conscious, unrestrained rats. The splanchnic sympathetic nerve activity (SpNA) and systemic and regional hemodynamic responses to injections of phenylephrine and sodium nitroprusside were measured during normothermia (37 degrees C) and hyperthermia (41.5 degrees C). The hemodynamic responses to phenylephrine and sodium nitroprusside were blunted with heating, whereas the SpNA responses to both agents were augmented or unchanged. At 41.5 degrees C, the baroreflex curves relating heart rate (HR) and SpNA to mean arterial blood pressure were shifted to the right. The operating range and gain of the blood pressure (BP)-HR reflex were significantly reduced during heating, whereas the operating range of the BP-SpNA reflex was augmented at 41.5 degrees C. These results indicate that heating alters the cardiovascular and sympathetic neural responses to vasoactive agents in vivo. Furthermore, the data suggest that heating differentially affects arterial baroreflex control of HR and SpNA, shifting both curves toward higher BP values but selectively attenuating baroreflex control of HR.     

Medial vestibular nucleus mediates the cardiorespiratory responses to fastigial nuclear activation and hypercapnia.

Electrical stimulation of the cerebellar fastigial nucleus (FN) evokes hyperventilation and hypertension responses that are similar to those induced by stimulation of the medial region of the vestibular nucleus (VNM). Because there are mutual projections between these two nuclei morphologically, we hypothesized that the FN-mediated cardiorespiratory responses were related to the integrity of the VNM. Experiments were conducted on 21 anesthetized, tracheotomized, and spontaneously breathing rats. Electrical stimulation (approximately 10 s) of the FN was used to evoke cardiorespiratory responses, and the same stimulus was repeated 30-45 min after bilateral lesions of the VNM by local microinjection of ibotenic acid (100 mM, 100 nl). We found that FN stimulation-induced hyperventilation and hypertension were attenuated significantly by the lesions. The role of the VNM in the ventilatory responses to chemical challenges was subsequently defined. The animals were exposed to hypercapnia (10% CO2) and hypoxia (10% O2) for 1-2 min randomly before and after VNM lesions. The results showed that VNM lesions significantly attenuated the cardiorespiratory responses to hypercapnia but not to hypoxia, with little effect on baseline respiratory variables. These findings suggest that the VNM is required for full expression of the cardiorespiratory responses to electrical stimulation of the FN as well as to hypercapnia. However, neurons within the VNM do not appear to be critical for maintaining eupneic breathing and the cardiorespiratory responses to hypoxia.     

Modulation of respiratory motor output by cerebellar deep nuclei in the rat.

The present study was undertaken to determine what roles the various cerebellar deep nuclei (CDN) play in modulation of respiration, especially during chemical challenges. Experiments were carried out in 12 anesthetized, tracheotomized, paralyzed, and ventilated rats. The integrated phrenic nerve activity (integralPN) was recorded as an index of respiratory motor output. A stimulating electrode was sequentially placed into the fastigial nucleus (FN), the interposed nucleus, and the lateral nucleus. Only stimulation of the FN significantly altered respiration, primarily via increasing respiratory frequency associated with a pressor response. The evoked respiratory responses persisted after blocking the pressor response via pretreatment with phenoxybenzamine or use of transient stimulation (<2 s) but were abolished by microinjection of kainic acid into the FN. To test the involvement of FN neurons in respiratory chemoreflexes, ventilation with hypercapnic gases mixture and intravenous injection of sodium cyanide were applied before and after CDN lesions induced by kainic acid. CDN lesions did not significantly alter eupneic breathing, but FN lesions attenuated the respiratory response to hypercapnia and sodium cyanide. We conclude that, with respect to the CDN in the rat, FN neurons uniquely modulate respiration independent of cardiovascular effects and facilitate respiratory responses mediated by activation of CO(2) and O(2) receptors.     

Sleep states alter ventral medullary surface responses to blood pressure challenges

Ventral medullary surface (VMS) activity declines during rapid eye movement (REM) sleep, suggesting a potential for reduced VMS responsiveness to blood pressure challenges during that state. We measured VMS neural activity, assessed as changes in reflected 660-nm wavelength light, during pressor and depressor challenges within sleep/waking states in five adult, unrestrained, unanesthetized cats and in two control cats. Phenylephrine elevated blood pressure and elicited an initial VMS activity decline and a subsequent rise in VMS activity in all states, although the initial decline during quiet sleep occurred only in rostral placements. Phasic REM periods elicited a momentary recovery from the evoked activity rise, and arousals diminished the overall elevation in activity. A sodium nitroprusside depressor challenge increased VMS activity more in REM sleep than in quiet sleep, with the increase being even less in waking. Enhanced responses to depressor challenges during REM sleep suggest a loss of dampening of evoked activity during that state; state-related differential baroreflex sensitivity may result from sleep-waking changes in VMS responses to blood pressure challenges.     

Effects of 12 mT static magnetic field on sympathetic agonist-induced hypertension in Wistar rats

We investigated the combined effects of a moderate-intensity static magnetic field (SMF) and two different sympathetic agonists, an alpha(1)-adrenoceptor agonist, phenylephrine and a beta(1)-adrenoceptor agonist, dobutamine, which induced hypertension and different hemodynamics in Wistar rats. Five-week-old male rats were continuously exposed to the SMF intensity of 12 mT (B(max)) with the peak spatial gradient of 3 mT/mm for 10 weeks. A loop-shaped flexible rubber magnet was adjusted to fit snugly around the neck region of a rat (diameter-adjustable to an animal size). Sham exposure was performed using a dummy magnet. Six experimental groups of six animals each were examined: (1) sham exposure with intraperitoneal (ip) saline injection (control); (2) SMF exposure with ip saline injection (SMF); (3) sham exposure with ip phenylephrine (1.0 microg/g) injection (PE); (4) SMF exposure with ip phenylephrine injection (SMF + PE); (5) sham exposure with ip dobutamine (4.0 microg/g) injection (DOB); (6) SMF exposure with ip dobutamine injection (SMF + DOB). Fifteen minutes after the injection of each agent, the first set of parameters, arterial blood pressure (BP) and heart rate (HR), the second set of parameters, skin blood flow (SBF) and skin blood velocity (SBV), or the third set of parameters, the number of rearing (exploratory behavior) responses and body weight was monitored. Each agent was administered three times a week for 10 weeks, and each set of parameters was monitored on different days, once a week. The dose of phenylephrine significantly increased BP and decreased HR, SBF, SBV, and the number of rearing responses in the PE group compared with those in the respective age-matched control group. The dose of dobutamine significantly increased BP and HR, increased SBF, SBV, and the number of rearing responses in the DOB group compared with those in the control group. Continuous neck exposure to the SMF alone for up to 10 weeks induced no significant changes in any of the measured cardiovascular and behavioral parameters. The SMF exposure for at least 2 weeks (1) significantly depressed phenylephrine effects on BP, SBF, SBV, and rearing activity (SMF + PE group vs. PE group); (2) significantly depressed dobutamine effects on BP, SBF, and SBV, and suppressed dobutamine-induced increase in the rearing activity (SMF + DOB group vs. DOB group). These results suggest that continuous neck exposure to 12 mT SMF for at least 2 weeks may depress or suppress sympathetic agonists-induced hypertension, hemodynamics, and behavioral changes by modulating sympathetic nerve activity.     

Aortic stiffness in the DOCA-hypertensive pig

Pulsatile changes in aortic diameter and pressure were monitored in order to obtain an index of aortic stiffness in the conscious pig during the development of mineralocorticoid hypertension. The aortic stiffness index increased but to a much lesser extent than it did in response to a similar pressure elevation produced by phenylephrine infusion. This observation suggests that chronic exposure to an elevated pulsatile pressure reduces the stiffness index at the elevated pressure.