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Sympathoexcitation during nitric oxide-deficient hypertension: direct evidence from sympathetic nerve recording in conscious rats
AJH–April 2001–VOL. 14, NO. 4, PART 2
P-551 SYMPATHOEXCITATION DURING NITRIC OXIDEDEFICIENT HYPERTENSION: DIRECT EVIDENCE FROM SYMPATHETIC NERVE RECORDING IN CONSCIOUS RATS Weiguo Zhang, Ronald G. Victor. 1Internal Medicine/Hypertension, The University of Texas Southwestern Medical Center, Dallas, TX, United States An increasing body of experimental literature implicates a major sympathetic neural component to certain forms of nitric oxide (NO)-deficient hypertension. However, this hypothesis remains controversial and all the existing evidence is indirect, based largely on the ability of sympathectomy or adrenergic blockade to attenuate the hypertensive response to pharmacological inhibitors of NO synthase. In an attempt to provide direct evidence for sympathetic activation during NO-deficient hypertension, we recorded renal sympathetic nerve activity (SNA) and blood pressure in conscious unrestrained female Sprague-Dawley rats (n⫽6) before, during, and after intravenous infusion of N-Nitro-L-Arginine Methyl Ester (L-NAME, 2.5 mg/kg), a potent NO synthase inhibitor. We extended the observation period to more than 2 hours because our previous work suggested that sympathetic activation is involved mainly in the maintenance but not in initiation of L-NAME-induced hypertension. The major new finding is that L-NAME-induced hypertension is accompanied by a biphasic response in renal SNA: transient sympathetic inhibition followed by progressive sympathetic activation. During the first hour after L-NAME, mean arterial pressure (MAP) increased rapidly (to a value that was 21⫾4 mmHg above baseline), triggering baroreflex activation and causing renal SNA to decrease to a value that was 14⫾7 % of baseline. During the second hour, however, MAP remained elevated (21⫾3 mmHg above baseline) while SNA gradually returned to a value that was 69⫾22 % of baseline (p⬍0.05, 2nd vs. 1st hour). This delayed increase in SNA is specific for NO synthase inhibition, because SNA remained suppressed for more than 2 hours, with no evidence of a delayed increase, when we mimicked the L-NAME-induced elevation in blood pressure with intravenous infusion of ␣ adrenergic agonist phenylephrine (n⫽5). Blood pressure and SNA were unaffected by intravenous infusion of D-NAME, the inactive enantiomer (n⫽4). In conclusion, these experimental data provide the first direct evidence for sympathetic activation during L-NAME-induced hypertension. Activation of the sympathetic nervous system may contribute to certain forms of clinical hypertension that are caused by endogenous nitric oxide deficiency. Key Words: nitric oxide, hypertension, sympathetic nerve activity
P-552 GREATLY EXAGGERATED BLOOD PRESSURE RESPONSES TO TILT TABLE TESTING IN HYPERTENSIVES WITH NEUROCARDIOGENIC SYNCOPE Anvar A. Babaev, Shun Kohsaka, Jonathan S. Steinberg. 1Cardiology, St Luke’s-Roosevelt, New York, NY, United States Patients with hypertension (HTN) have abnormal cardiovascular responses to orthostatic stress. We tested the hypothesis that HTN patients with neurocardiogenic syncope have more pronounced abnormal cardiovascular responses to upright tilt table test (TTT) than normotensives (NTN) with syncope. We studied 155 consecutive patients referred for TTT for syncope of unknown origin, divided into 2 groups: HTN (n⫽54; age, 68.8⫾13.8 years) and NTN (n⫽101; age, 40.4⫾18.6 years). Mean baseline systolic blood pressure (SBP) in HTN patients was 154.9⫾20.6 mm Hg vs. 118.4⫾14.2 mm Hg (p⬍0.05) in NTN, and diastolic blood pressure (DBP) was 88.7⫾13.4 mm HG (p⫽ns), respectively. Patients with diabetes, CAD, structural heart disease and prior arrhythmia were excluded.
POSTERS: Neural Mechanisms and Transmitters
215A
Patients were off antihypertensive medications and underwent 80 degrees TTT for 45 minutes, or until syncope developed. Table demonstrates the BP (mm Hg) responses to TTT in studied groups, and in subgroups with induced syncope during test. An exaggerated BP reduction was observed in HTN compared to normotensives. There were no significant differnces in heart rate responses in studied groups. During TTT, 42% of HTN patients and 36% of NTN had syncope (p⫽ns). In those who did not develop syncope, HTN also had a significantly greater (p⬍0.01) reduction of SBP (15.2⫾22.5 mm Hg) compared to NTN (3.1⫾14.1 mm Hg). BP reduction during TTT was independent of age in all groups. Conclusion: Patients with HTN and neurocardiogenic syncope had more profound BP reduction and a predominantly vasodepressor type of syncope during TTT. Impairment of baroreflex mechanisms in HTN may explain these observations.
HTN NTN P Value
All Patients ⌬SBP
All Patients ⌬DBP
Syncope induced ⌬SBP
Syncope induced ⌬SBP
42.5 ⫾ 42.9 20.6 ⫾ 28.7 ⬍0.01
23.1 ⫾ 30.2 9.9 ⫾ 21.9 ⬍0.01
82.4 ⫾ 33.1 52.3 ⫾ 19.7 ⬍0.01
50.7 ⫾ 25.9 33.4 ⫾ 16.1 ⬍0.05
Key Words: Syncope, Tilt-testing, Baroreflex
P-553 DEVELOPMENTAL CHANGES OF TRANSCRIPTION FACTORS IN ADRENAL MEDULLA OF SPONTANEOUSLY HYPERTENSIVE RATS Toshio Kumai, Naoki Matsumoto, Shinichi Kobayashi. 1Pharmacology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan, 2Pharmacology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan, 3 Pharmacology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan We have previously reported that tyrosine hydroxylase (TH) mRNA contribute to hypertension of spontaneously hypertensive rats (SHR). Some investigators suggested that transcription factors (cAMP responsive element binding protein (CREB), activator protein-1 (AP-1), glucocorticoid receptor and Sp1) were related to TH gene transcription. To evaluate the role of these transcription factors in sympathetic nervous system on hypertension of SHR, we studied the changes of transcription factors in adrenal medulla at the development stage of hypertension in SHR. Male SHR and Wistar Kyoto rats (WKY)(5,6,7,10 weeks old) were used. Systolic blood pressure (SBP) was measured by tail cuff methods. Catecholamine and TH activity were measured by HPLC-ECD. TH mRNA was measured by Dot blot analysis. Transcription factors were measured by electrophoretic mobility-shift assay. SBP of SHR was significantly higher from 6 weeks of age than that of WKY. Epinephrine, norepinephrine levels, tyrosine hydroxylase (TH) activity and TH mRNA expression in adrenal medulla of SHR were increased from 6 weeks of age consistent with the changes of SBP. These parameters of SHR were significantly higher from 6 weeks of age than that of WKY. CREB and AP-1 binding activity in adrenal medulla of SHR were also increased from 6 weeks of age consistent with the changes of SBP and catecholamine synthetic pathway. Glucocorticoid receptor and Sp1 were no significant different between SHR and WKY. It is known well that CREB and AP-1 increases TH mRNA transcription. These results suggest that CREB and AP-1 in adrenal medulla may be contributing to establishment of hypertension in SHR through increase of catecholamine synthetic pathway. Key Words: SHR, tyrosine hydroxylase ,transcription factor
P-551 SYMPATHOEXCITATION DURING NITRIC OXIDEDEFICIENT HYPERTENSION: DIRECT EVIDENCE FROM SYMPATHETIC NERVE RECORDING IN CONSCIOUS RATS Weiguo Zhang, Ronald G. Victor. 1Internal Medicine/Hypertension, The University of Texas Southwestern Medical Center, Dallas, TX, United States An increasing body of experimental literature implicates a major sympathetic neural component to certain forms of nitric oxide (NO)-deficient hypertension. However, this hypothesis remains controversial and all the existing evidence is indirect, based largely on the ability of sympathectomy or adrenergic blockade to attenuate the hypertensive response to pharmacological inhibitors of NO synthase. In an attempt to provide direct evidence for sympathetic activation during NO-deficient hypertension, we recorded renal sympathetic nerve activity (SNA) and blood pressure in conscious unrestrained female Sprague-Dawley rats (n⫽6) before, during, and after intravenous infusion of N-Nitro-L-Arginine Methyl Ester (L-NAME, 2.5 mg/kg), a potent NO synthase inhibitor. We extended the observation period to more than 2 hours because our previous work suggested that sympathetic activation is involved mainly in the maintenance but not in initiation of L-NAME-induced hypertension. The major new finding is that L-NAME-induced hypertension is accompanied by a biphasic response in renal SNA: transient sympathetic inhibition followed by progressive sympathetic activation. During the first hour after L-NAME, mean arterial pressure (MAP) increased rapidly (to a value that was 21⫾4 mmHg above baseline), triggering baroreflex activation and causing renal SNA to decrease to a value that was 14⫾7 % of baseline. During the second hour, however, MAP remained elevated (21⫾3 mmHg above baseline) while SNA gradually returned to a value that was 69⫾22 % of baseline (p⬍0.05, 2nd vs. 1st hour). This delayed increase in SNA is specific for NO synthase inhibition, because SNA remained suppressed for more than 2 hours, with no evidence of a delayed increase, when we mimicked the L-NAME-induced elevation in blood pressure with intravenous infusion of ␣ adrenergic agonist phenylephrine (n⫽5). Blood pressure and SNA were unaffected by intravenous infusion of D-NAME, the inactive enantiomer (n⫽4). In conclusion, these experimental data provide the first direct evidence for sympathetic activation during L-NAME-induced hypertension. Activation of the sympathetic nervous system may contribute to certain forms of clinical hypertension that are caused by endogenous nitric oxide deficiency. Key Words: nitric oxide, hypertension, sympathetic nerve activity
P-552 GREATLY EXAGGERATED BLOOD PRESSURE RESPONSES TO TILT TABLE TESTING IN HYPERTENSIVES WITH NEUROCARDIOGENIC SYNCOPE Anvar A. Babaev, Shun Kohsaka, Jonathan S. Steinberg. 1Cardiology, St Luke’s-Roosevelt, New York, NY, United States Patients with hypertension (HTN) have abnormal cardiovascular responses to orthostatic stress. We tested the hypothesis that HTN patients with neurocardiogenic syncope have more pronounced abnormal cardiovascular responses to upright tilt table test (TTT) than normotensives (NTN) with syncope. We studied 155 consecutive patients referred for TTT for syncope of unknown origin, divided into 2 groups: HTN (n⫽54; age, 68.8⫾13.8 years) and NTN (n⫽101; age, 40.4⫾18.6 years). Mean baseline systolic blood pressure (SBP) in HTN patients was 154.9⫾20.6 mm Hg vs. 118.4⫾14.2 mm Hg (p⬍0.05) in NTN, and diastolic blood pressure (DBP) was 88.7⫾13.4 mm HG (p⫽ns), respectively. Patients with diabetes, CAD, structural heart disease and prior arrhythmia were excluded.
POSTERS: Neural Mechanisms and Transmitters
215A
Patients were off antihypertensive medications and underwent 80 degrees TTT for 45 minutes, or until syncope developed. Table demonstrates the BP (mm Hg) responses to TTT in studied groups, and in subgroups with induced syncope during test. An exaggerated BP reduction was observed in HTN compared to normotensives. There were no significant differnces in heart rate responses in studied groups. During TTT, 42% of HTN patients and 36% of NTN had syncope (p⫽ns). In those who did not develop syncope, HTN also had a significantly greater (p⬍0.01) reduction of SBP (15.2⫾22.5 mm Hg) compared to NTN (3.1⫾14.1 mm Hg). BP reduction during TTT was independent of age in all groups. Conclusion: Patients with HTN and neurocardiogenic syncope had more profound BP reduction and a predominantly vasodepressor type of syncope during TTT. Impairment of baroreflex mechanisms in HTN may explain these observations.
HTN NTN P Value
All Patients ⌬SBP
All Patients ⌬DBP
Syncope induced ⌬SBP
Syncope induced ⌬SBP
42.5 ⫾ 42.9 20.6 ⫾ 28.7 ⬍0.01
23.1 ⫾ 30.2 9.9 ⫾ 21.9 ⬍0.01
82.4 ⫾ 33.1 52.3 ⫾ 19.7 ⬍0.01
50.7 ⫾ 25.9 33.4 ⫾ 16.1 ⬍0.05
Key Words: Syncope, Tilt-testing, Baroreflex
P-553 DEVELOPMENTAL CHANGES OF TRANSCRIPTION FACTORS IN ADRENAL MEDULLA OF SPONTANEOUSLY HYPERTENSIVE RATS Toshio Kumai, Naoki Matsumoto, Shinichi Kobayashi. 1Pharmacology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan, 2Pharmacology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan, 3 Pharmacology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan We have previously reported that tyrosine hydroxylase (TH) mRNA contribute to hypertension of spontaneously hypertensive rats (SHR). Some investigators suggested that transcription factors (cAMP responsive element binding protein (CREB), activator protein-1 (AP-1), glucocorticoid receptor and Sp1) were related to TH gene transcription. To evaluate the role of these transcription factors in sympathetic nervous system on hypertension of SHR, we studied the changes of transcription factors in adrenal medulla at the development stage of hypertension in SHR. Male SHR and Wistar Kyoto rats (WKY)(5,6,7,10 weeks old) were used. Systolic blood pressure (SBP) was measured by tail cuff methods. Catecholamine and TH activity were measured by HPLC-ECD. TH mRNA was measured by Dot blot analysis. Transcription factors were measured by electrophoretic mobility-shift assay. SBP of SHR was significantly higher from 6 weeks of age than that of WKY. Epinephrine, norepinephrine levels, tyrosine hydroxylase (TH) activity and TH mRNA expression in adrenal medulla of SHR were increased from 6 weeks of age consistent with the changes of SBP. These parameters of SHR were significantly higher from 6 weeks of age than that of WKY. CREB and AP-1 binding activity in adrenal medulla of SHR were also increased from 6 weeks of age consistent with the changes of SBP and catecholamine synthetic pathway. Glucocorticoid receptor and Sp1 were no significant different between SHR and WKY. It is known well that CREB and AP-1 increases TH mRNA transcription. These results suggest that CREB and AP-1 in adrenal medulla may be contributing to establishment of hypertension in SHR through increase of catecholamine synthetic pathway. Key Words: SHR, tyrosine hydroxylase ,transcription factor