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Effect of mono- and bilateral nephrectomy on efferent sympathetic nerve activity to the kidneys in the rat
POSTERS: Neural Mechanisms and Transmitters
E001 A FAMILY HISTORY OF OBESITY, A FAMILY HISTORY OF HYPERTENSION AND BLOOD PRESSURE LEVELS K. Masuo*, H. Mikami*, T. Ogihara*, and M.L. Tuck*. Osaka University Medical School, Suita City, Japan, and Sepulveda VA Medical Center, Sepulveda, CA We previously reported that family history (FH) of hypertension (HT) related with stimulated sympathetic activity and BP elevation in nonobese men over 10 years. In addition, it is probable the sympathetic nervous activation with weight gain is a major mechanism of blood pressure elevation. Hyperinsulinemia and hyperleptinemia may be ancillary factors, contributing to sympathetic nervous stimulation with weight. In the present study, we tried to delineate the effects of both family history of obesity (OBFH) and hypertension (HTFH) on BP levels in young men. A positive or a negative OBFH was defined as both parents were obese (BMI ⬎ 26.0 kg/m2) or lean (⬍ 22.0 kg/m2). A positive or a negative HTFH were defined as both parents were HT (⬎140/90 mmHg) or NT (⬉130/85 mmHg). The subjects were 21 lean OBFH⫺ & HTFH⫺, 7 lean OBFH⫺ & HTFH⫹, 8 lean OBFH⫹ & HTFH⫺, 5 lean OBFH⫹ & HTFH⫹, 9 obese OBFH⫺ & HTFH⫺, 5 obese OBFH⫺ & HTFH⫹, 16 obese OBFH⫹ & HTFH⫺, 17 obese OBFH⫹ & HTFH⫹. They were measured BMI, BP, pulse rate, plasma norepinephrine (NE), insulin, and leptin after overnight fast in supine position. The subjects were men and non-diabetic. Obese subjects had significantly higher levels in BP, NE and insulin than lean subjects regardless of OBFH or HTFH. In OBFH⫹ regardless of BMI, BP, NE, insulin, and leptin in HTFH⫹ were higher compared with HTFH⫺. On the other hand, in OBFH⫺, BP and NE in HTFH⫹ were higher than HTFH⫺, although plasma insulin and leptin in HTFH⫹ were similar to those in HTFH⫺. These results demonstrated that OBFH and HTFH contribute BP levels. Sympathetic activation with HTFH is a dominant mechanism in BP elevation, and hyperinsulinemia and hyperleptinemia may be ancillary factors with sympathetic activation in obese subjects and subjects with OBFH. Key Words: Sympathetic activity; leptin; obesity; family history of obesity; family history of hypertension E002 A NEW APPROACH IN THE TREATMENT OF DISABLING ORTHOSTATIC INTOLERANCE J. Freitas, R.M. Santos, E. Azevedo, O. Costa, M. Carvalho, and A. Falca˜o de Freitas. Centro de Estudos da Func¸a˜o Autono´mica—Hospital Sa˜o Joa˜o—Porto, Portugal Introduction: Orthostatic intolerance (OI) is a frequent misdiagnosis disabling condition. Objective: To evaluate the efficacy of drugs in the treatment of the autonomic/hemodynamic and clinical disturbance that characterizes OI patients. Material and Methods: 10 women, with a mean age 31 years (21 to 57 years), with orthostatic grade by symptoms ⱖ 3 © 2000 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
AJH
2000;13:164A–168A
(florid POTS), were evaluated before (b) and after treatment (a). Five received oral bisoprolol (B) therapy, 2 pts flurocortisone (F) and 3 pts association of B and F. The patients were study in basal and tilt position. HRV, SBPV and spontaneous baroreceptor gain were calculated by FFT and ␣ index. The hemodynamic data was assessed by modelflow-TNO® analysis. Results:
Basal (b) Basal (a) Tilt (b) Tilt (a)
SV
TPR
58.1 60.6 34.0 41.6
1409 1733 2284 2241
BR␣
HR
15.2 92.5 22.8 69.5 4.4 121.4 11.8 81.9
LFrr
HFrr
SBP
LFsb
41.3 40.1 55.8 51.1
45.8 50.9 18.0 35.1
115.5 101.2 136.1 110.6
2.4 3.5 23.1 7.4
Units: HR in bpm; SV in ml; HRV in nu; SBPV in mmHg2; BR in ms/mmHg; TPR in dyn.s.cm-5; SBP in mmHg.
Conclusion: 1–Bisoprolol and/or flurocortisone improve the clinical and autonomic/hemodynamic disturbance observed in POTS. 2–All medical personnel must be alert to the diagnosis of this disabling misdiagnosis syndrome with such an easy treatment and marked clinical improvement. Key Words: Orthostatic intolerance; sympathetic activity; beta-blockers E003 EFFECT OF MONO- AND BILATERAL NEPHRECTOMY ON EFFERENT SYMPATHETIC NERVE ACTIVITY TO THE KIDNEYS IN THE RAT G. Recordati, F. Zorzoli, and A. Zanchetti. Centro Fisiologia Clinica ed Ipertensione, Universita’ di Milano and Ospedale Maggiore, Milano, Italy The object of this study was to verify if the removal of one or of both normal kidneys is accompanied by alterations in the efferent sympathetic nerve activity to the kidneys (RSNA). RSNA, blood pressure (BP), heart rate (HR), rate of breathing (RB), and rectal temperature (T) were continuously monitored for five hours in three groups of pentobarbital anesthetized, spontaneously breathing Sprague-Dawley (250 – 300 g) rats: group 1 (n ⫽ 5), both kidneys intact; group 2 (n ⫽ 5) and 3 (n ⫽ 5), left kidney excised. In addition in group 3, after one hour of control recording, the right renal hylus was tied to produce a complete, reversible, ischemia of the right kidney (functional right nephrectomy: FRN). In group 3 the RSNA was recorded continuously for one hour before, during three hours of FRN and for one hour after. In group 1 and 2, while BP, HR and RB remained fairly constant, RSNA progressively increased from a control value of 22.3 ⫾ 2.1 and of 26.7 ⫾ 1.2 imp/sec at time 0 (mean ⫾ S.E.) to 122.9 ⫾ 13.6 and to 80.9 ⫾ 10.7 imp/sec at time 5 h respectively. In contrast in group 3 RSNA progressively declined during the three hours of FRN, from a control value of 39.1 ⫾ 3.1 at time 1 h (beginning of FRN), to 13.7 ⫾ 2.6 imp/sec at time 4 h (end of FRN period), while BP and HR did not exhibit any significant alterations. The reopening of the right renal hylus was followed by a hypertensive and tachycardic episode, (described in a separate 0895-7061/00/$20.00
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
POSTERS: Neural Mechanisms and Transmitters
165A
communication), and by short lasting complex alterations of RSNA. These data show that the removal of both kidneys is accompanied by a clear progressive reduction in the RSNA, thus suggesting that the normal kidneys exert a supportive and facilitatory role on efferent sympathetic activity directed back to the kidneys either through a reflex mechanism initiated by afferent renal nerves or substances released from the kidneys.
E005 DIFFERENTIAL DISTRIBUTION OF G-PROTEINCOUPLED RECEPTOR KINASE TYPES 2, 3, 4, 5, AND 6 IN HUMAN BRAIN: AN IMMUNOHISTOCHEMICAL ANALYSIS H. Watanabe, M.A. Stier, H. Sanada, P.A. Jose, and R.A. Felder*. The University of Virginia, Department of Pathology, Charlottesville, VA, 22908. Georgetown University Hospital, Department of Pediatrics, Washington, D.C. 20007
Key Words: Nephrectomy; sympathetic nerve activity; renin-angiotensin system; renal sensory innervation
G protein-coupled receptor kinases (GRKs) inhibit the signaling pathways of G-protein related receptors through protein phosphorylation. GRKs have been shown to be involved in various neuronal signaling pathways. However, a systematic localization of GRK isoforms has not been demonstrated in the human central nervous system. We show immunohistochemical localization of GRK type 2– 6 in 5 um slices of fresh postmortem human brain fixed with Histochoice. GRK6 immunoreactivity was identified in neuronal cytoplasm, and dense fiber tracks in the basal ganglia. Dense staining was also noted in the media of varying caliber arterial blood vessels. Extensive GRK4 staining was noted. Therefore, we examined various GRK4 isoforms for their anatomical immunoreactive distribution. GRK4 alpha-beta (antisera cannot differentiate between the alpha and beta isoforms) was positive in fibers of the pontine reticular formation, substantia nigra, and basal ganglia. Astrocytic cell processes also appear distinctly positive for GRK4 alpha-beta. GRK gamma-delta showed distinct reactivity in fibers near the amygdaloid complex, neurons and fibers in the hippocampus and pontine reticular formation, and in the adventitia of arterial blood vessels. GRK4 theta-epsilon was positive in cellular processes and neurons in the hippocampus, ependema, leptomeninges, and all layers of arterial blood vessels. In our hands, we could not demonstrate immunostaining for GRK 2, 3 and 5 in human brain. Our results suggest that GRKs may have differential roles in the modulation of the central nervous system due to the wide variation in their anatomical distribution.
E004 ABNORMAL CARDIOVASCULAR RESPONSES TO TILT TABLE TESTING IN YOUNG HEALTHY INDIVIDUALS WITH FAMILY HISTORY OF HYPERTENSION A. Babaev, N. Khamidov, and Kh. Rafiev. Tajik State Medical University, Dushanbe, Tajikistan The aim of the study was to evaluate the cardiovascular responses to head-upright tilt table test in young healthy subjects with and without family history of essential hypertension (HTN). We studied 56 young healthy males, who were divided into two groups: Group I–25 subjects with family history of HTN (one or both parents), and Group II–31 individuals without. Groups were comparable by age, blood pressure and body mass index (BMI) (Table 1). All subjects underwent 70 degrees head-upright tilt table testing of 10 minutes duration. Blood pressure and heart rate were constantly monitored during the test. All participants took no medications for at least 1 month, and no caffeinated beverages for 12 hours prior to the study.
Group I Group II P value
Age
BMI
SBP
DBP
HR
23 ⫾ 1.5 23 ⫾ 1.6 n.s.
23 ⫾ 1.5 23.3 ⫾ 1.6 n.s.
113 ⫾ 7.0 112 ⫾ 8.0 n.s.
72.9 ⫾ 6.2 71 ⫾ 6.3 n.s.
65 ⫾ 7 66 ⫾ 8 n.s.
There were no significant differences in systolic blood pressure and heart rate responses to head-upright tilt, but diastolic blood pressure rise was significantly greater in individuals with family history of hypertension (Table 2).
Group I Group II P value
⌬SBP mm Hg
⌬ DBP mm Hg
⌬ HR bpm
⫺2 ⫾ 4.9 ⫺.4 ⫾ 7.1 n.s.
4.2 ⫾ 4.1 11.4 ⫾ 3.9 P ⬍ 0.001
18.9 ⫾ 5.3 20 ⫾ 6.3 n.s.
Conclusion: Healthy young subjects with family history of hypertension have an exaggerated diastolic BP response to orthostasis. This finding is probably suggestive of hereditary abnormality in baroreflex mechanisms predisposing these individuals to the development of HTN. Key Words: Baroreflex; orthostasis
Key Words: G-protein related kinase; G-protein coupled receptor; human; brain; central nervous system E006 MORNING BLOOD PRESSURE SURGE DERIVES FROM CENTRAL SYMPATHETIC NERVE ACTIVITY BUT NOT FROM PARASYMPATHETIC ACTIVITY E. Miyajima, T. Shigemasa, Y. Kawano, T. Endo, and S. Umemura. Division of Cardiology, Yokohama City University, Medical Center, Yokohama, Japan Although cardiovascular events appears to be greatest in the early morning, blood pressure control in this period may not be sufficient by the first-line antihypertensive drugs. Since sympathetic nervous system may be responsible for this morning blood pressure surge, centrally acting ␣2 agonists may inhibit these responses. We examined ambulatory blood pressure (BP) and ECG for 24 hours in 101 hypertensive patients (54 ⫾ 1 y old; 68 men and 33 women). HF (0.15– 0.4 Hz) and LF/HF ratio of heart rate variability (HRV) were calculated by maximum entropy methods in each 2-min interval. The data used were 4 h before and 4 h
E001 A FAMILY HISTORY OF OBESITY, A FAMILY HISTORY OF HYPERTENSION AND BLOOD PRESSURE LEVELS K. Masuo*, H. Mikami*, T. Ogihara*, and M.L. Tuck*. Osaka University Medical School, Suita City, Japan, and Sepulveda VA Medical Center, Sepulveda, CA We previously reported that family history (FH) of hypertension (HT) related with stimulated sympathetic activity and BP elevation in nonobese men over 10 years. In addition, it is probable the sympathetic nervous activation with weight gain is a major mechanism of blood pressure elevation. Hyperinsulinemia and hyperleptinemia may be ancillary factors, contributing to sympathetic nervous stimulation with weight. In the present study, we tried to delineate the effects of both family history of obesity (OBFH) and hypertension (HTFH) on BP levels in young men. A positive or a negative OBFH was defined as both parents were obese (BMI ⬎ 26.0 kg/m2) or lean (⬍ 22.0 kg/m2). A positive or a negative HTFH were defined as both parents were HT (⬎140/90 mmHg) or NT (⬉130/85 mmHg). The subjects were 21 lean OBFH⫺ & HTFH⫺, 7 lean OBFH⫺ & HTFH⫹, 8 lean OBFH⫹ & HTFH⫺, 5 lean OBFH⫹ & HTFH⫹, 9 obese OBFH⫺ & HTFH⫺, 5 obese OBFH⫺ & HTFH⫹, 16 obese OBFH⫹ & HTFH⫺, 17 obese OBFH⫹ & HTFH⫹. They were measured BMI, BP, pulse rate, plasma norepinephrine (NE), insulin, and leptin after overnight fast in supine position. The subjects were men and non-diabetic. Obese subjects had significantly higher levels in BP, NE and insulin than lean subjects regardless of OBFH or HTFH. In OBFH⫹ regardless of BMI, BP, NE, insulin, and leptin in HTFH⫹ were higher compared with HTFH⫺. On the other hand, in OBFH⫺, BP and NE in HTFH⫹ were higher than HTFH⫺, although plasma insulin and leptin in HTFH⫹ were similar to those in HTFH⫺. These results demonstrated that OBFH and HTFH contribute BP levels. Sympathetic activation with HTFH is a dominant mechanism in BP elevation, and hyperinsulinemia and hyperleptinemia may be ancillary factors with sympathetic activation in obese subjects and subjects with OBFH. Key Words: Sympathetic activity; leptin; obesity; family history of obesity; family history of hypertension E002 A NEW APPROACH IN THE TREATMENT OF DISABLING ORTHOSTATIC INTOLERANCE J. Freitas, R.M. Santos, E. Azevedo, O. Costa, M. Carvalho, and A. Falca˜o de Freitas. Centro de Estudos da Func¸a˜o Autono´mica—Hospital Sa˜o Joa˜o—Porto, Portugal Introduction: Orthostatic intolerance (OI) is a frequent misdiagnosis disabling condition. Objective: To evaluate the efficacy of drugs in the treatment of the autonomic/hemodynamic and clinical disturbance that characterizes OI patients. Material and Methods: 10 women, with a mean age 31 years (21 to 57 years), with orthostatic grade by symptoms ⱖ 3 © 2000 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
AJH
2000;13:164A–168A
(florid POTS), were evaluated before (b) and after treatment (a). Five received oral bisoprolol (B) therapy, 2 pts flurocortisone (F) and 3 pts association of B and F. The patients were study in basal and tilt position. HRV, SBPV and spontaneous baroreceptor gain were calculated by FFT and ␣ index. The hemodynamic data was assessed by modelflow-TNO® analysis. Results:
Basal (b) Basal (a) Tilt (b) Tilt (a)
SV
TPR
58.1 60.6 34.0 41.6
1409 1733 2284 2241
BR␣
HR
15.2 92.5 22.8 69.5 4.4 121.4 11.8 81.9
LFrr
HFrr
SBP
LFsb
41.3 40.1 55.8 51.1
45.8 50.9 18.0 35.1
115.5 101.2 136.1 110.6
2.4 3.5 23.1 7.4
Units: HR in bpm; SV in ml; HRV in nu; SBPV in mmHg2; BR in ms/mmHg; TPR in dyn.s.cm-5; SBP in mmHg.
Conclusion: 1–Bisoprolol and/or flurocortisone improve the clinical and autonomic/hemodynamic disturbance observed in POTS. 2–All medical personnel must be alert to the diagnosis of this disabling misdiagnosis syndrome with such an easy treatment and marked clinical improvement. Key Words: Orthostatic intolerance; sympathetic activity; beta-blockers E003 EFFECT OF MONO- AND BILATERAL NEPHRECTOMY ON EFFERENT SYMPATHETIC NERVE ACTIVITY TO THE KIDNEYS IN THE RAT G. Recordati, F. Zorzoli, and A. Zanchetti. Centro Fisiologia Clinica ed Ipertensione, Universita’ di Milano and Ospedale Maggiore, Milano, Italy The object of this study was to verify if the removal of one or of both normal kidneys is accompanied by alterations in the efferent sympathetic nerve activity to the kidneys (RSNA). RSNA, blood pressure (BP), heart rate (HR), rate of breathing (RB), and rectal temperature (T) were continuously monitored for five hours in three groups of pentobarbital anesthetized, spontaneously breathing Sprague-Dawley (250 – 300 g) rats: group 1 (n ⫽ 5), both kidneys intact; group 2 (n ⫽ 5) and 3 (n ⫽ 5), left kidney excised. In addition in group 3, after one hour of control recording, the right renal hylus was tied to produce a complete, reversible, ischemia of the right kidney (functional right nephrectomy: FRN). In group 3 the RSNA was recorded continuously for one hour before, during three hours of FRN and for one hour after. In group 1 and 2, while BP, HR and RB remained fairly constant, RSNA progressively increased from a control value of 22.3 ⫾ 2.1 and of 26.7 ⫾ 1.2 imp/sec at time 0 (mean ⫾ S.E.) to 122.9 ⫾ 13.6 and to 80.9 ⫾ 10.7 imp/sec at time 5 h respectively. In contrast in group 3 RSNA progressively declined during the three hours of FRN, from a control value of 39.1 ⫾ 3.1 at time 1 h (beginning of FRN), to 13.7 ⫾ 2.6 imp/sec at time 4 h (end of FRN period), while BP and HR did not exhibit any significant alterations. The reopening of the right renal hylus was followed by a hypertensive and tachycardic episode, (described in a separate 0895-7061/00/$20.00
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
POSTERS: Neural Mechanisms and Transmitters
165A
communication), and by short lasting complex alterations of RSNA. These data show that the removal of both kidneys is accompanied by a clear progressive reduction in the RSNA, thus suggesting that the normal kidneys exert a supportive and facilitatory role on efferent sympathetic activity directed back to the kidneys either through a reflex mechanism initiated by afferent renal nerves or substances released from the kidneys.
E005 DIFFERENTIAL DISTRIBUTION OF G-PROTEINCOUPLED RECEPTOR KINASE TYPES 2, 3, 4, 5, AND 6 IN HUMAN BRAIN: AN IMMUNOHISTOCHEMICAL ANALYSIS H. Watanabe, M.A. Stier, H. Sanada, P.A. Jose, and R.A. Felder*. The University of Virginia, Department of Pathology, Charlottesville, VA, 22908. Georgetown University Hospital, Department of Pediatrics, Washington, D.C. 20007
Key Words: Nephrectomy; sympathetic nerve activity; renin-angiotensin system; renal sensory innervation
G protein-coupled receptor kinases (GRKs) inhibit the signaling pathways of G-protein related receptors through protein phosphorylation. GRKs have been shown to be involved in various neuronal signaling pathways. However, a systematic localization of GRK isoforms has not been demonstrated in the human central nervous system. We show immunohistochemical localization of GRK type 2– 6 in 5 um slices of fresh postmortem human brain fixed with Histochoice. GRK6 immunoreactivity was identified in neuronal cytoplasm, and dense fiber tracks in the basal ganglia. Dense staining was also noted in the media of varying caliber arterial blood vessels. Extensive GRK4 staining was noted. Therefore, we examined various GRK4 isoforms for their anatomical immunoreactive distribution. GRK4 alpha-beta (antisera cannot differentiate between the alpha and beta isoforms) was positive in fibers of the pontine reticular formation, substantia nigra, and basal ganglia. Astrocytic cell processes also appear distinctly positive for GRK4 alpha-beta. GRK gamma-delta showed distinct reactivity in fibers near the amygdaloid complex, neurons and fibers in the hippocampus and pontine reticular formation, and in the adventitia of arterial blood vessels. GRK4 theta-epsilon was positive in cellular processes and neurons in the hippocampus, ependema, leptomeninges, and all layers of arterial blood vessels. In our hands, we could not demonstrate immunostaining for GRK 2, 3 and 5 in human brain. Our results suggest that GRKs may have differential roles in the modulation of the central nervous system due to the wide variation in their anatomical distribution.
E004 ABNORMAL CARDIOVASCULAR RESPONSES TO TILT TABLE TESTING IN YOUNG HEALTHY INDIVIDUALS WITH FAMILY HISTORY OF HYPERTENSION A. Babaev, N. Khamidov, and Kh. Rafiev. Tajik State Medical University, Dushanbe, Tajikistan The aim of the study was to evaluate the cardiovascular responses to head-upright tilt table test in young healthy subjects with and without family history of essential hypertension (HTN). We studied 56 young healthy males, who were divided into two groups: Group I–25 subjects with family history of HTN (one or both parents), and Group II–31 individuals without. Groups were comparable by age, blood pressure and body mass index (BMI) (Table 1). All subjects underwent 70 degrees head-upright tilt table testing of 10 minutes duration. Blood pressure and heart rate were constantly monitored during the test. All participants took no medications for at least 1 month, and no caffeinated beverages for 12 hours prior to the study.
Group I Group II P value
Age
BMI
SBP
DBP
HR
23 ⫾ 1.5 23 ⫾ 1.6 n.s.
23 ⫾ 1.5 23.3 ⫾ 1.6 n.s.
113 ⫾ 7.0 112 ⫾ 8.0 n.s.
72.9 ⫾ 6.2 71 ⫾ 6.3 n.s.
65 ⫾ 7 66 ⫾ 8 n.s.
There were no significant differences in systolic blood pressure and heart rate responses to head-upright tilt, but diastolic blood pressure rise was significantly greater in individuals with family history of hypertension (Table 2).
Group I Group II P value
⌬SBP mm Hg
⌬ DBP mm Hg
⌬ HR bpm
⫺2 ⫾ 4.9 ⫺.4 ⫾ 7.1 n.s.
4.2 ⫾ 4.1 11.4 ⫾ 3.9 P ⬍ 0.001
18.9 ⫾ 5.3 20 ⫾ 6.3 n.s.
Conclusion: Healthy young subjects with family history of hypertension have an exaggerated diastolic BP response to orthostasis. This finding is probably suggestive of hereditary abnormality in baroreflex mechanisms predisposing these individuals to the development of HTN. Key Words: Baroreflex; orthostasis
Key Words: G-protein related kinase; G-protein coupled receptor; human; brain; central nervous system E006 MORNING BLOOD PRESSURE SURGE DERIVES FROM CENTRAL SYMPATHETIC NERVE ACTIVITY BUT NOT FROM PARASYMPATHETIC ACTIVITY E. Miyajima, T. Shigemasa, Y. Kawano, T. Endo, and S. Umemura. Division of Cardiology, Yokohama City University, Medical Center, Yokohama, Japan Although cardiovascular events appears to be greatest in the early morning, blood pressure control in this period may not be sufficient by the first-line antihypertensive drugs. Since sympathetic nervous system may be responsible for this morning blood pressure surge, centrally acting ␣2 agonists may inhibit these responses. We examined ambulatory blood pressure (BP) and ECG for 24 hours in 101 hypertensive patients (54 ⫾ 1 y old; 68 men and 33 women). HF (0.15– 0.4 Hz) and LF/HF ratio of heart rate variability (HRV) were calculated by maximum entropy methods in each 2-min interval. The data used were 4 h before and 4 h