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Rostral pontine and caudal mesencephalic control of arterial Pressure and Iliac, celiac and renal vascular resistance. II. Separate control and topographic organization
Brain Research, 361 (1985)301-308
301
Elsevier BRE 11323
Rostral Pontine and Caudal Mesencephalic Control of Arterial Pressure and Iliac, Celiac and Renal Vascular Resistance. II. Separate Control and Topographic Organization DANIEL N. DARLINGTON* and DAVID G. WARD
Department of Physiology, University of Virginia, Charlottesville, VA 22908 (U.S.A.) (Accepted April 23rd, 1985)
Key words: pons - - mesencephalon - - electrical stimulation - - vascular resistance - - separate control - - topographic organization
A dense mapping of the rostral pons and caudal mesencephalon was performed in 26 cats using electrical stimulation while measuring arterial pressure and iliac, celiac and renal vascular resistance to determine if these vascular beds are controlled separately. It was found that the central tegmental fields (CTF) of the mesencephalon contained a large area active in control of iliac vascular resistance and a smaller area active in control of renal vascular resistance. It was also found that the marginal nucleus of the brachium conjunctivum (BCM) contained areas active in control of all three vascular beds studied. To determine if the BCM controlled regional vascular beds differently, the relationship between changes in vascular resistance in each bed and changes in arterial pressure were examined quantitiatively using regression analysis and the slopes of the regression lines were shown to be different (P < 0.001). Further analysis of the relationships of changes in vascular resistance of pairs of vascular beds indicated that vascular beds are controlled differently in response to electrical stimulation of the BCM.
INTRODUCTION There have been many studies suggesting that central neural control of arterial pressure and vascular resistance is organized in a t o p o g r a p h i c or differential manner. Electrical stimulation of the cortex 8, cyngulate gyrus zS, hypothalamus, mesencephalon 2.34, cerebellum 11, pons 3°, medulla 33 and spinal cord 3 has been r e p o r t e d to elicit changes in vascular resistance of varying intensities and of opposing directions in different vascular beds. Reflex activation of central neural structures elicits changes in vascular resistance that also suggest separate or differential control of vasoconstriction. Activation of somatic or renal afferents, and activation of stretch receptors or c h e m o r e c e p t o r s with electrical6.16.26 or chemical stimulation7,32, mechanical distension21, hemorrhagel.19,27.35, hypoxia, hypercapnia 41 and exercise 13.31 elicit vascular changes varying in character, intensity and direction. Since somatic and cardiovascular signals reach the rostral
pons
and
caudal mesencephalon4.6.9,1s,22, 23, it is
possible that this brainstem a r e a is involved in differential vascular control during activation of these reflexes 3°,4°. F u r t h e r , since descending pathway from higher brain centers that ultimately control spinal preganglionics37:0 travel through and terminate in the caudal m e s e n c e p h a l o n and rostral pons, it is possible that these brainstem areas d e m o n s t r a t e some topographic organization for control of vascular beds. The purpose of the following experiments is to anatomically m a p the rostral pons and caudal mesencephalon for control of iliac, celiac and renal vascular resistance, to ascertain if neural control of these vessels is differentiated and to d e t e r m i n e if a topographic organization exists for control of these beds. MATERIALS AND METHODS Experiments were p e r f o r m e d on 26 cats of either sex. They were housed in the University of Virginia
* Present address: Department of Physiology, UCSF, San Francisco, CA 94143, U.S.A.
Correspondence: D.G. Ward. Present address: H.M. Ward Memorial Laboratory, P.O. Box 207, Valley Home, CA 95384, U.S.A. 0006-8993/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)
302 Vivarium for a period of 1-3 months and were maintained on a 12-h on, 12-h off light cycle. The weights of the animals ranged between 2.5 and 4.4 kg. Each animal was brought into the laboratory at 08.00-09.00 h and sedated with chloroform gas or ketamine (5 mg/lb). Infusion catheters were placed in the cephalic vein and chloralose/urethane was administered (40 mg/kg and 200 mg/kg). Supplementary doses of chloraiose/urethane (up to 40 mg/200 mg) were given if pupillary dilation or retraction of the nictitating membranes occurred. Atropine, 0.04 mg, was administered intramuscularly to prevent nasal and oral secretions from interfering with respiration. The animal was placed on a water-filled heating pad that was regulated between 37 and 39 °C by a rectal probe monitor feeding back to a temperature controller. An endotracheal tube was inserted to prevent obstruction and to allow positive ventilation of paralyzed animals. The animals were paralyzed with Gallamine (10 mg) and maintained on positive ventilation with a Harvard pump to minimize the mechanical effects of breathing on changes in mean arterial pressure and vascular resistance. Supplemental doses (10 mg) were administered as needed when spontaneous breathing occurred. The femoral artery and vein were cannulated for measurement of arterial pressure and administration of drugs, respectively. For any given experiment. electromagnetic flow probes were placed on two of the three arteries: iliac, celiac and renal. The renal and celiac arteries were approached retroperitoneally on the left side, and the iliac artery was approached through a cutdown on the right side of the femoral region. The animal's head was placed in a stereotaxic frame and a line of burr holes was drilled laterally from the interparietal ridge in the parietal bone. The rostral pons and caudal midbrain was approached stereotaxically at a 45 ° angle to the horizontal plane. Electrical stimulation was carried out using monophasic square waves of constant current derived from a Grass S-88 stimulator through bipolar coaxial electrodes (Rhodes SNE100, tip to barrel separation 0.25 mm) with cathodal current at the tip. The tip of the electrode at the end of a track was marked by passing a D.C. current of 100flA for 10 s. The electrode was raised 5 mm and a second marking lesion was made. Upon completion of the stimulation protocol (6-8 h, see below) the animal was hemorrhaged to zero flow
for baseline calibration of flow probes. In these sorts of experiments, this method provides meastlres of 'zero' flow that corresponds extremely well to measures obtained using occluding devices. The brains were removed after perfusion through the left ventrical with saline followed by 10% formalin, and stored in formalin for 1 week, sectioned frozen at 35/~m in the sagittal plane, and stained with thionin in order to locate the electrode tracks and marking lesions. Stimulation parameters were based oil previous studies of the thresholds for eliciting consistent changes in arterial pressure and in release of adrenocorticotrophin (ACTH) 3s, and consist of: current intensity, i00/~A; frequency. 50 Hz; pulse duration, 0.2 ms; stimulus duration, 30 s. All parameters were monitored on an oscilloscope. In each animal, a total of six electrode penetrations were made in a pseudorandom order l mm apart in the medial-lateral plane. For each penetration, a total of sixteen stimulations were applied 0.5 mm apart and at time intervals of 3-5 rain. Systolic and diastolic measures of arterial pressure and blood flows were obtained immediately before and between 5-10 s after onset of stimulation when peak pressure and flow changes occurred. Care was taken to obtain all measurements during the same phase of respiration in all experiments. Mean arterial pressure and mean blood flow at each time of measurement were calculated as diastolic + (systolic-diastolic)/3. Resistance in each artery was calculated by dividing the mean arterial pressure by the mean flow in each artery at the same time point. Changes in mean arterial pressure and regional vascular resistance were determined by subtracting the appropriate measures before stimulation from the corresponding measures during stimulation. Negative and positive changes were interpreted as dilations and constrictions, respectively. If an electrode track could not be located histologically, then the results of electrical stimulation of that track were ignored. Each stimulation site was plotted on standard sagittal sections and then transferred to standard coronal sections derived from Berman 5. Composite drawings of all stimulation sites were prepared. Adjacent sites from which electrical stimulation led to consistent changes in arterial pressure or regional vascular resistance were grouped together into areas. Changes in pressure and resistance within areas and between areas was evaluated using analysis of variance for re-
303 peated measures 43. The topography of the regions from which areas were constructed was modified systematically until the areas contained sites of stimulation associated with the least variability within areas and the most difference compared to adjacent areas. The areas representing vasoconstriction in iliac celiac and renal vascular beds were then plotted on the same coronal sections for comparison. Scatterplots of percent change in mean arterial pressure versus percent change in vascular resistance was prepared as a more quantitative approach for studying differential control of the three vascular beds during stimulation of the marginal nucleus of the brachium conjunctivum (after the method of Kumada et al.20). Scatterplots of percent change in vascular resistance in one bed versus the percent change in vascular resistance in another bed were prepared to compare the nonuniformity of vasoconstriction in the three beds during electrical stimulation in the marginal nucleus of the brachium conjunctivum. Analysis of covariance was used to compare slopes from scatterplots of percent change in mean arterial pressure versus percent change in vascular resistance in each bed studied. Modified Student's t-tests were used to compare correlation coefficients and slopes from scatterplots of percent change in vascular resistance in one bed versus the percent change in vascular resistance in another bed 42. RESULTS
Fig. 1. Overlap of areas active in increasing vascular resistance in the iliac, celiac and renal vascular beds in the rostral pons and caudal mesencephalon. Dot stippling represents increases in iliac vascular resistance. Vertical lines represent increases in renal vascular resistance. Horizontal lines represent increases in celiac vascular resistance. See accompanying paper for identification of nucleil°.
To examine the control of separate vascular beds by the mesencephalon, the anatomical areas from which electrical stimulation led to changes in iliac, celiac and renal vascular resistanceS0 were compared by plotting them on the same coronal sections. Fig. 1 illustrates the areas that elicited increases in vascular resistance in the three vascular beds. It can be seen that areas active in control of vasoconstriction in each of the three vascular beds overlap in the marginal nucleus of the brachium conjunctivum (P4.0 and P3.1). The areas active in increasing iliac and renal vascular resistance overlap almost completely (P4.0 and P3.1) except for the most rostral extent of the pons (P2.1-P1.5) where the size of the renal area diminishes. The celiac area is small and overlaps the renal and iliac areas only in the dorsal lateral aspect of the marginal nucleus of the brachium conjunctivum
(P4.0 and P3.1). More rostrally, only areas active in increasing iliac vascular resistance are present (P0.9-A3.3). Since electrical stimulation of the marginal nucleus of the brachium conjunctivum elicited changes in mean arterial pressure and in the vascular resistance of iliac, celiac and renal vascular beds, there appeared to be no obvious anatomical separation for control of these three beds in the marginal nucleus of the brachium conjunctivum. Therefore, a more quantitative approach was used to examine the role of the marginal nucleus of the brachium conjunctivum in differential control of these vascular beds. The relationship between changes in vascular resis-
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Fig. 2. Scatterplots of % change in mean arterial pressure (MAP) vs % change in vascular resistance for the lilac (IVR), celiac (CVR) and renal (RVR) vascular beds in response to electrical stimulation (100/~A, 0.2 ms, 50 Hz) in the marginal nucleus of the brachium conjunctivum (coronal sections P4.0, P3.1, P2.1 of Fig. 1). The regression lines were calculated by least square. The y-intercept, slope and correlation coefficient are shown in the table in the lower right-hand corner of the figure. The correlation coefficients were compared to 0.0 using the Student's t-test. The slopes were compared to each other using analysis of covariance. Statistical differences are indicated.
tance and mean arterial pressure, and the relationship between changes in vascular resistance in paired vascular beds was examined. Fig. 2 shows the relationship between the percent change in mean arterial pressure vs the percent change in vascular resistance in each vascular bed studied during electrical stimulation in the BCM. A least-squares linear regression was performed on each set of d a t a for the three beds to give a y-intercept, slope a n d correlation coefficient as shown in the table in the lower fight-hand corner• The correlation coefficient for each set of data was found to be statistically different from 0.0 (P < 0.01). The slopes of the resistance-arterial pressure relationship were o r d e r e d renal > lilac > celiac. The slopes of the relationships between vascular resistance and arterial pressure were c o m p a r e d among all three vascular beds using analysis of c o v a n a n c e
and found to be statistically different (P < 0.001), thereby suggesting differential control of these beds. Electrical stimulation of the marginal nucleus of the brachium conjunctivum elicited non-uniform changes in vascular resistance in the three vascular beds studied. Fig. 3 shows the relationship between changes in vascular resistance m paired vascular beds. Regression analysis of the responses was performed for each pairing of vascular beds using least squares. The correlation coefficients for the itiac-celiac pair and the iliac-renal pair were statistically different from 0.0 (P < 0.05), but the correlation coefficient for the renal-celiac pair was not significantly different from 0.0 (P > 0.05). The slope for each pair of vascular beds was compared to 1.0 to determine if both beds in each pair responded equally to stimulation. It was found that all slopes were statistically dif-
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Fig. 3. Scatterplots of % change in resistance of one bed vs % change in resistance of another during electrical stimulation (100pA, 0.2 ms, 50 Hz) of the marginal nucleus of the brachium conjunctivum (coronal sections P4.0, P3.1, P2.1 of Fig. 1). The regression lines were calculated by least squares. The y-intercept and slope for each graph are in a table in the lower right-hand corner of the figure. The correlation coefficients were compared to 0.0 using a modified Student's t-test, The slopes were compared to 1.0 using a modified Student's t-test. Statistical differences are indicated.
ferent from 1.0 (P < 0.001), again suggesting differential control of these beds. DISCUSSION It has previously been suggested that areas in the mesencephalon and pons control separate vascular beds 3°,34. In the accompanying paper10, areas active in iliac, celiac and renal vasoconstriction were plotted on separate coronal sections of the mesencephalon and pons. When these areas are plotted on the same coronal sections (Fig. 1), a pattern emerges showing the relationship of one area to another. All the active areas overlap in the marginal nucleus of the brachium conjunctivum. Iliac and renal areas overlap almost entirely, while the celiac area overlaps both iliac and renal areas only in the dorsolateral marginal nucleus of the brachium conjunctivum. This
suggests common areas of vascular control in the marginal nucleus of the brachium conjunctivum. Rostrally, the area active in celiac vasoconstriction disappears and the renal area gets smaller and is contained inside the iliac area (Fig. 1, P4.0-P1.5). More rostraUy in the mesencephalon, control of only the iliac bed is seen. Control of separate vascular beds is anatomically apparent in the mesencephalon. However, control of vascular beds appears to overlap in the marginal nucleus of the brachium conjunctivum. It was suggested by Mroavitch et al. that the marginal nucleus of the brachium conjunctivum controls vascular beds differentially 30. This conclusion was based on analysis of changes in mean arterial pressure and vascular resistance in each bed during electrical stimulation in the marginal nucleus of the brachium conjunctivum. They compared the slopes of the relationship be-
306 tween arterial pressure and vascular resistance in the mesenteric, renal and iliac beds. The slopes from the three plots were different (6.57, 3,21, 1.32) and it was therefore assumed that the marginal nucleus of the brachium conjunctivum controlled the three vascular beds non-uniformly. Differentiated vascular control was suggested in order of superiority: mesenteric > renal > iliac. The same analysis was performed in the present study on renal, iliac and celiac beds with stimulation of sites in the marginal nucleus of the brachium conjunctivum located at P4.0, P3.1 and P2.1, and showed slopes of 2.44, 1.39 and 0.17, respectively, thereby suggesting differentiated vascular control in the order: renal > iliac > celiac. The slopes and order for the renal and iliac beds agrees remarkably well with Mroavitch 30. Combining the results of both studies suggests that the marginal nucleus of the brachium conjunctivum controls vasoconstriction differentially in the order of superiority: mesenteric > renal > iliac > celiac. Further analysis was performed to test the degree at which the marginal nucleus of the brachium conjunctivum controls vascular beds separately by comparing the slopes of the resistance changes in the paired beds. If the marginal nucleus of the brachium conjunctivum controls vascular beds equally rather than differentially, then stimulation in any part of the marginal nucleus of the brachium conjunctivum should cause any two vascular beds to constrict to the same degree. It would follow that a scatterplot of the percent change of one bed versus another would have a slope equal to 1. However, each slope was found to be statistically different from 1.0 (P < 0.001), thereby suggesting differential rather than equal control of the vascular beds studied. Previous reports have suggested that central neural structures control arterial pressure and vascular resistance in a separate or differential manner. Ueda et al. demonstrated that the intensity of constriction in the iliac, mesenteric and renal vascular beds was different during electrical stimulation at different depths in the mesencephalon of dogs 34. Other authors have reported simultaneous increases and decreases in skin and muscle vascular resistance, respectively, during mesencephalic and hypothalamic stimulation in cats 2. Stimulation of the rostral cyngulate gyrus leads to non-uniform changes in muscle, skin, intestines and renal blood flow25. Electrical
stimulation of the fastigial nucleus in cats results in larger vascular resistance changes in the renal bed as compared to the femoral or mesenteric bed I f. A recent report has demonstrated non-uniform changes in vascular resistance in response to glutamate stimulation of the A5 cell group 33. It is apparent that many areas of the brain known to control the cardiovascular system exert their influence in a separate and/or differential manner. There is much evidence for separate and/or differential control of vascular beds during reflex activation of central neural structures. Stimulation of renal afferent has been shown to elicit simultaneous renal and mesenteric vasoconstriction and hindlimb dilation 6.26 while somatic afferent stimulation has been reported to increase flow in both mesentery and hindlimb with no change in renal flow ~6. Stimulation of carotid chemoreceptors with nicotine, cyanide, hypoxia or hypercapnia leads to muscle vasoconstriction and cutaneous vasodilationT,32, 41. Distention of the left atrio-pulmonary junction has been reported to elicit vasodilation in the skin, skeletal muscle and large intestine with no apperent change in vascular resistance in the small intestines 20. Mild hemorrhage in conscious and anesthetized dogs lead to hindlimb and mesenteric constriction but there is no change in renal vascular resistance until blood loss becomes severe1,20,27, 35. Since most of these receptor signals enter the dorsal medulla and are then distributed to cardiovascular centers in the brain 6.9,23, it is possible that each reflex is mediated by a different neural structure or specific group of structures. Finally, a rather clear topographic organization for the control of vascular beds seems to exist in the mesencephalon. Areas controlling iliac vasoconstriction are centrally located and large. Areas controlling renal vasoconstriction tend to be located more laterally and are smaller. As the areas approach the marginal nucleus of the brachium conjunctivum, they merge and overlap to a greater extent. Such an organization is not surprising, since similar organizations have been shown in the spinal cord3 and cortex 8. It has also been suggested that sensory projections from the NTS to the marginal nucleus of the brachium conjunctivum are topographically arranged 18. It is also apparent that areas within nuclear complexes subserve different functions and are topographically distinct. The rostral ventromedial border of the fastigial
307 nucleus and the lateral and central divisions of the
differential control of vascular beds by the marginal
amygdala are involved in cardiovascular control 14.
nucleus of the braehium conjunctivum.
15,17,28,29 while other parts of these nuclei subserve
other functions.
ACKNOWLEDGEMENTS
In summary, the present data suggests strongly that there is an anatomic topographic organization in
The authors gratefully acknowledge the superb technical assistance of Jane H. Ward. This research
the mesencephalon for control of separate vascular beds. Although this topographic organization seems
was supported by Grants HL26349, RR05431 and
to disappear in the marginal nucleus of the brachium
HL00837 to D . G . W . from the U n i t e d States Public
conjunctivum, further analysis of these data indicates
Health Service, National Institutes of Health.
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301
Elsevier BRE 11323
Rostral Pontine and Caudal Mesencephalic Control of Arterial Pressure and Iliac, Celiac and Renal Vascular Resistance. II. Separate Control and Topographic Organization DANIEL N. DARLINGTON* and DAVID G. WARD
Department of Physiology, University of Virginia, Charlottesville, VA 22908 (U.S.A.) (Accepted April 23rd, 1985)
Key words: pons - - mesencephalon - - electrical stimulation - - vascular resistance - - separate control - - topographic organization
A dense mapping of the rostral pons and caudal mesencephalon was performed in 26 cats using electrical stimulation while measuring arterial pressure and iliac, celiac and renal vascular resistance to determine if these vascular beds are controlled separately. It was found that the central tegmental fields (CTF) of the mesencephalon contained a large area active in control of iliac vascular resistance and a smaller area active in control of renal vascular resistance. It was also found that the marginal nucleus of the brachium conjunctivum (BCM) contained areas active in control of all three vascular beds studied. To determine if the BCM controlled regional vascular beds differently, the relationship between changes in vascular resistance in each bed and changes in arterial pressure were examined quantitiatively using regression analysis and the slopes of the regression lines were shown to be different (P < 0.001). Further analysis of the relationships of changes in vascular resistance of pairs of vascular beds indicated that vascular beds are controlled differently in response to electrical stimulation of the BCM.
INTRODUCTION There have been many studies suggesting that central neural control of arterial pressure and vascular resistance is organized in a t o p o g r a p h i c or differential manner. Electrical stimulation of the cortex 8, cyngulate gyrus zS, hypothalamus, mesencephalon 2.34, cerebellum 11, pons 3°, medulla 33 and spinal cord 3 has been r e p o r t e d to elicit changes in vascular resistance of varying intensities and of opposing directions in different vascular beds. Reflex activation of central neural structures elicits changes in vascular resistance that also suggest separate or differential control of vasoconstriction. Activation of somatic or renal afferents, and activation of stretch receptors or c h e m o r e c e p t o r s with electrical6.16.26 or chemical stimulation7,32, mechanical distension21, hemorrhagel.19,27.35, hypoxia, hypercapnia 41 and exercise 13.31 elicit vascular changes varying in character, intensity and direction. Since somatic and cardiovascular signals reach the rostral
pons
and
caudal mesencephalon4.6.9,1s,22, 23, it is
possible that this brainstem a r e a is involved in differential vascular control during activation of these reflexes 3°,4°. F u r t h e r , since descending pathway from higher brain centers that ultimately control spinal preganglionics37:0 travel through and terminate in the caudal m e s e n c e p h a l o n and rostral pons, it is possible that these brainstem areas d e m o n s t r a t e some topographic organization for control of vascular beds. The purpose of the following experiments is to anatomically m a p the rostral pons and caudal mesencephalon for control of iliac, celiac and renal vascular resistance, to ascertain if neural control of these vessels is differentiated and to d e t e r m i n e if a topographic organization exists for control of these beds. MATERIALS AND METHODS Experiments were p e r f o r m e d on 26 cats of either sex. They were housed in the University of Virginia
* Present address: Department of Physiology, UCSF, San Francisco, CA 94143, U.S.A.
Correspondence: D.G. Ward. Present address: H.M. Ward Memorial Laboratory, P.O. Box 207, Valley Home, CA 95384, U.S.A. 0006-8993/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)
302 Vivarium for a period of 1-3 months and were maintained on a 12-h on, 12-h off light cycle. The weights of the animals ranged between 2.5 and 4.4 kg. Each animal was brought into the laboratory at 08.00-09.00 h and sedated with chloroform gas or ketamine (5 mg/lb). Infusion catheters were placed in the cephalic vein and chloralose/urethane was administered (40 mg/kg and 200 mg/kg). Supplementary doses of chloraiose/urethane (up to 40 mg/200 mg) were given if pupillary dilation or retraction of the nictitating membranes occurred. Atropine, 0.04 mg, was administered intramuscularly to prevent nasal and oral secretions from interfering with respiration. The animal was placed on a water-filled heating pad that was regulated between 37 and 39 °C by a rectal probe monitor feeding back to a temperature controller. An endotracheal tube was inserted to prevent obstruction and to allow positive ventilation of paralyzed animals. The animals were paralyzed with Gallamine (10 mg) and maintained on positive ventilation with a Harvard pump to minimize the mechanical effects of breathing on changes in mean arterial pressure and vascular resistance. Supplemental doses (10 mg) were administered as needed when spontaneous breathing occurred. The femoral artery and vein were cannulated for measurement of arterial pressure and administration of drugs, respectively. For any given experiment. electromagnetic flow probes were placed on two of the three arteries: iliac, celiac and renal. The renal and celiac arteries were approached retroperitoneally on the left side, and the iliac artery was approached through a cutdown on the right side of the femoral region. The animal's head was placed in a stereotaxic frame and a line of burr holes was drilled laterally from the interparietal ridge in the parietal bone. The rostral pons and caudal midbrain was approached stereotaxically at a 45 ° angle to the horizontal plane. Electrical stimulation was carried out using monophasic square waves of constant current derived from a Grass S-88 stimulator through bipolar coaxial electrodes (Rhodes SNE100, tip to barrel separation 0.25 mm) with cathodal current at the tip. The tip of the electrode at the end of a track was marked by passing a D.C. current of 100flA for 10 s. The electrode was raised 5 mm and a second marking lesion was made. Upon completion of the stimulation protocol (6-8 h, see below) the animal was hemorrhaged to zero flow
for baseline calibration of flow probes. In these sorts of experiments, this method provides meastlres of 'zero' flow that corresponds extremely well to measures obtained using occluding devices. The brains were removed after perfusion through the left ventrical with saline followed by 10% formalin, and stored in formalin for 1 week, sectioned frozen at 35/~m in the sagittal plane, and stained with thionin in order to locate the electrode tracks and marking lesions. Stimulation parameters were based oil previous studies of the thresholds for eliciting consistent changes in arterial pressure and in release of adrenocorticotrophin (ACTH) 3s, and consist of: current intensity, i00/~A; frequency. 50 Hz; pulse duration, 0.2 ms; stimulus duration, 30 s. All parameters were monitored on an oscilloscope. In each animal, a total of six electrode penetrations were made in a pseudorandom order l mm apart in the medial-lateral plane. For each penetration, a total of sixteen stimulations were applied 0.5 mm apart and at time intervals of 3-5 rain. Systolic and diastolic measures of arterial pressure and blood flows were obtained immediately before and between 5-10 s after onset of stimulation when peak pressure and flow changes occurred. Care was taken to obtain all measurements during the same phase of respiration in all experiments. Mean arterial pressure and mean blood flow at each time of measurement were calculated as diastolic + (systolic-diastolic)/3. Resistance in each artery was calculated by dividing the mean arterial pressure by the mean flow in each artery at the same time point. Changes in mean arterial pressure and regional vascular resistance were determined by subtracting the appropriate measures before stimulation from the corresponding measures during stimulation. Negative and positive changes were interpreted as dilations and constrictions, respectively. If an electrode track could not be located histologically, then the results of electrical stimulation of that track were ignored. Each stimulation site was plotted on standard sagittal sections and then transferred to standard coronal sections derived from Berman 5. Composite drawings of all stimulation sites were prepared. Adjacent sites from which electrical stimulation led to consistent changes in arterial pressure or regional vascular resistance were grouped together into areas. Changes in pressure and resistance within areas and between areas was evaluated using analysis of variance for re-
303 peated measures 43. The topography of the regions from which areas were constructed was modified systematically until the areas contained sites of stimulation associated with the least variability within areas and the most difference compared to adjacent areas. The areas representing vasoconstriction in iliac celiac and renal vascular beds were then plotted on the same coronal sections for comparison. Scatterplots of percent change in mean arterial pressure versus percent change in vascular resistance was prepared as a more quantitative approach for studying differential control of the three vascular beds during stimulation of the marginal nucleus of the brachium conjunctivum (after the method of Kumada et al.20). Scatterplots of percent change in vascular resistance in one bed versus the percent change in vascular resistance in another bed were prepared to compare the nonuniformity of vasoconstriction in the three beds during electrical stimulation in the marginal nucleus of the brachium conjunctivum. Analysis of covariance was used to compare slopes from scatterplots of percent change in mean arterial pressure versus percent change in vascular resistance in each bed studied. Modified Student's t-tests were used to compare correlation coefficients and slopes from scatterplots of percent change in vascular resistance in one bed versus the percent change in vascular resistance in another bed 42. RESULTS
Fig. 1. Overlap of areas active in increasing vascular resistance in the iliac, celiac and renal vascular beds in the rostral pons and caudal mesencephalon. Dot stippling represents increases in iliac vascular resistance. Vertical lines represent increases in renal vascular resistance. Horizontal lines represent increases in celiac vascular resistance. See accompanying paper for identification of nucleil°.
To examine the control of separate vascular beds by the mesencephalon, the anatomical areas from which electrical stimulation led to changes in iliac, celiac and renal vascular resistanceS0 were compared by plotting them on the same coronal sections. Fig. 1 illustrates the areas that elicited increases in vascular resistance in the three vascular beds. It can be seen that areas active in control of vasoconstriction in each of the three vascular beds overlap in the marginal nucleus of the brachium conjunctivum (P4.0 and P3.1). The areas active in increasing iliac and renal vascular resistance overlap almost completely (P4.0 and P3.1) except for the most rostral extent of the pons (P2.1-P1.5) where the size of the renal area diminishes. The celiac area is small and overlaps the renal and iliac areas only in the dorsal lateral aspect of the marginal nucleus of the brachium conjunctivum
(P4.0 and P3.1). More rostrally, only areas active in increasing iliac vascular resistance are present (P0.9-A3.3). Since electrical stimulation of the marginal nucleus of the brachium conjunctivum elicited changes in mean arterial pressure and in the vascular resistance of iliac, celiac and renal vascular beds, there appeared to be no obvious anatomical separation for control of these three beds in the marginal nucleus of the brachium conjunctivum. Therefore, a more quantitative approach was used to examine the role of the marginal nucleus of the brachium conjunctivum in differential control of these vascular beds. The relationship between changes in vascular resis-
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Fig. 2. Scatterplots of % change in mean arterial pressure (MAP) vs % change in vascular resistance for the lilac (IVR), celiac (CVR) and renal (RVR) vascular beds in response to electrical stimulation (100/~A, 0.2 ms, 50 Hz) in the marginal nucleus of the brachium conjunctivum (coronal sections P4.0, P3.1, P2.1 of Fig. 1). The regression lines were calculated by least square. The y-intercept, slope and correlation coefficient are shown in the table in the lower right-hand corner of the figure. The correlation coefficients were compared to 0.0 using the Student's t-test. The slopes were compared to each other using analysis of covariance. Statistical differences are indicated.
tance and mean arterial pressure, and the relationship between changes in vascular resistance in paired vascular beds was examined. Fig. 2 shows the relationship between the percent change in mean arterial pressure vs the percent change in vascular resistance in each vascular bed studied during electrical stimulation in the BCM. A least-squares linear regression was performed on each set of d a t a for the three beds to give a y-intercept, slope a n d correlation coefficient as shown in the table in the lower fight-hand corner• The correlation coefficient for each set of data was found to be statistically different from 0.0 (P < 0.01). The slopes of the resistance-arterial pressure relationship were o r d e r e d renal > lilac > celiac. The slopes of the relationships between vascular resistance and arterial pressure were c o m p a r e d among all three vascular beds using analysis of c o v a n a n c e
and found to be statistically different (P < 0.001), thereby suggesting differential control of these beds. Electrical stimulation of the marginal nucleus of the brachium conjunctivum elicited non-uniform changes in vascular resistance in the three vascular beds studied. Fig. 3 shows the relationship between changes in vascular resistance m paired vascular beds. Regression analysis of the responses was performed for each pairing of vascular beds using least squares. The correlation coefficients for the itiac-celiac pair and the iliac-renal pair were statistically different from 0.0 (P < 0.05), but the correlation coefficient for the renal-celiac pair was not significantly different from 0.0 (P > 0.05). The slope for each pair of vascular beds was compared to 1.0 to determine if both beds in each pair responded equally to stimulation. It was found that all slopes were statistically dif-
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Fig. 3. Scatterplots of % change in resistance of one bed vs % change in resistance of another during electrical stimulation (100pA, 0.2 ms, 50 Hz) of the marginal nucleus of the brachium conjunctivum (coronal sections P4.0, P3.1, P2.1 of Fig. 1). The regression lines were calculated by least squares. The y-intercept and slope for each graph are in a table in the lower right-hand corner of the figure. The correlation coefficients were compared to 0.0 using a modified Student's t-test, The slopes were compared to 1.0 using a modified Student's t-test. Statistical differences are indicated.
ferent from 1.0 (P < 0.001), again suggesting differential control of these beds. DISCUSSION It has previously been suggested that areas in the mesencephalon and pons control separate vascular beds 3°,34. In the accompanying paper10, areas active in iliac, celiac and renal vasoconstriction were plotted on separate coronal sections of the mesencephalon and pons. When these areas are plotted on the same coronal sections (Fig. 1), a pattern emerges showing the relationship of one area to another. All the active areas overlap in the marginal nucleus of the brachium conjunctivum. Iliac and renal areas overlap almost entirely, while the celiac area overlaps both iliac and renal areas only in the dorsolateral marginal nucleus of the brachium conjunctivum. This
suggests common areas of vascular control in the marginal nucleus of the brachium conjunctivum. Rostrally, the area active in celiac vasoconstriction disappears and the renal area gets smaller and is contained inside the iliac area (Fig. 1, P4.0-P1.5). More rostraUy in the mesencephalon, control of only the iliac bed is seen. Control of separate vascular beds is anatomically apparent in the mesencephalon. However, control of vascular beds appears to overlap in the marginal nucleus of the brachium conjunctivum. It was suggested by Mroavitch et al. that the marginal nucleus of the brachium conjunctivum controls vascular beds differentially 30. This conclusion was based on analysis of changes in mean arterial pressure and vascular resistance in each bed during electrical stimulation in the marginal nucleus of the brachium conjunctivum. They compared the slopes of the relationship be-
306 tween arterial pressure and vascular resistance in the mesenteric, renal and iliac beds. The slopes from the three plots were different (6.57, 3,21, 1.32) and it was therefore assumed that the marginal nucleus of the brachium conjunctivum controlled the three vascular beds non-uniformly. Differentiated vascular control was suggested in order of superiority: mesenteric > renal > iliac. The same analysis was performed in the present study on renal, iliac and celiac beds with stimulation of sites in the marginal nucleus of the brachium conjunctivum located at P4.0, P3.1 and P2.1, and showed slopes of 2.44, 1.39 and 0.17, respectively, thereby suggesting differentiated vascular control in the order: renal > iliac > celiac. The slopes and order for the renal and iliac beds agrees remarkably well with Mroavitch 30. Combining the results of both studies suggests that the marginal nucleus of the brachium conjunctivum controls vasoconstriction differentially in the order of superiority: mesenteric > renal > iliac > celiac. Further analysis was performed to test the degree at which the marginal nucleus of the brachium conjunctivum controls vascular beds separately by comparing the slopes of the resistance changes in the paired beds. If the marginal nucleus of the brachium conjunctivum controls vascular beds equally rather than differentially, then stimulation in any part of the marginal nucleus of the brachium conjunctivum should cause any two vascular beds to constrict to the same degree. It would follow that a scatterplot of the percent change of one bed versus another would have a slope equal to 1. However, each slope was found to be statistically different from 1.0 (P < 0.001), thereby suggesting differential rather than equal control of the vascular beds studied. Previous reports have suggested that central neural structures control arterial pressure and vascular resistance in a separate or differential manner. Ueda et al. demonstrated that the intensity of constriction in the iliac, mesenteric and renal vascular beds was different during electrical stimulation at different depths in the mesencephalon of dogs 34. Other authors have reported simultaneous increases and decreases in skin and muscle vascular resistance, respectively, during mesencephalic and hypothalamic stimulation in cats 2. Stimulation of the rostral cyngulate gyrus leads to non-uniform changes in muscle, skin, intestines and renal blood flow25. Electrical
stimulation of the fastigial nucleus in cats results in larger vascular resistance changes in the renal bed as compared to the femoral or mesenteric bed I f. A recent report has demonstrated non-uniform changes in vascular resistance in response to glutamate stimulation of the A5 cell group 33. It is apparent that many areas of the brain known to control the cardiovascular system exert their influence in a separate and/or differential manner. There is much evidence for separate and/or differential control of vascular beds during reflex activation of central neural structures. Stimulation of renal afferent has been shown to elicit simultaneous renal and mesenteric vasoconstriction and hindlimb dilation 6.26 while somatic afferent stimulation has been reported to increase flow in both mesentery and hindlimb with no change in renal flow ~6. Stimulation of carotid chemoreceptors with nicotine, cyanide, hypoxia or hypercapnia leads to muscle vasoconstriction and cutaneous vasodilationT,32, 41. Distention of the left atrio-pulmonary junction has been reported to elicit vasodilation in the skin, skeletal muscle and large intestine with no apperent change in vascular resistance in the small intestines 20. Mild hemorrhage in conscious and anesthetized dogs lead to hindlimb and mesenteric constriction but there is no change in renal vascular resistance until blood loss becomes severe1,20,27, 35. Since most of these receptor signals enter the dorsal medulla and are then distributed to cardiovascular centers in the brain 6.9,23, it is possible that each reflex is mediated by a different neural structure or specific group of structures. Finally, a rather clear topographic organization for the control of vascular beds seems to exist in the mesencephalon. Areas controlling iliac vasoconstriction are centrally located and large. Areas controlling renal vasoconstriction tend to be located more laterally and are smaller. As the areas approach the marginal nucleus of the brachium conjunctivum, they merge and overlap to a greater extent. Such an organization is not surprising, since similar organizations have been shown in the spinal cord3 and cortex 8. It has also been suggested that sensory projections from the NTS to the marginal nucleus of the brachium conjunctivum are topographically arranged 18. It is also apparent that areas within nuclear complexes subserve different functions and are topographically distinct. The rostral ventromedial border of the fastigial
307 nucleus and the lateral and central divisions of the
differential control of vascular beds by the marginal
amygdala are involved in cardiovascular control 14.
nucleus of the braehium conjunctivum.
15,17,28,29 while other parts of these nuclei subserve
other functions.
ACKNOWLEDGEMENTS
In summary, the present data suggests strongly that there is an anatomic topographic organization in
The authors gratefully acknowledge the superb technical assistance of Jane H. Ward. This research
the mesencephalon for control of separate vascular beds. Although this topographic organization seems
was supported by Grants HL26349, RR05431 and
to disappear in the marginal nucleus of the brachium
HL00837 to D . G . W . from the U n i t e d States Public
conjunctivum, further analysis of these data indicates
Health Service, National Institutes of Health.
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