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Arterial pressure and heart rate responses to microinjection of corticotropin releasing hormone in the intermediolateral nucleus of the anaesthetized rat
Heart,
Lung
and Circulation
48th Annual
2000; 9
LARGE ARTERY MECHANICAL PROPERTIES CORRELATE WITH SEVERITY OF CORONARY ARTERY DISEASE. TK Waddell*. TL
AM Dart. BA w. Alfred & Baker Medical Unit, Baker Medical Research Institute, Prabran, Victoria, Australia. Q&&es: Proximal aortic compliance has been shown to be lower in coronary artery disease (CAD) patients compared with healthy matched controls, The present study aimed to characterise large artery mechanical properties in relation to severity of CAD, as determined by the magnitude of the maximum coronary stenosis on angiography. M&Q&: Seventy-two males with CAD (mean * SD, 57 + 9 years) and forty age and gender matched healthy controls (54 f 10 years) were recruited. CAD pattents were classified as having a maxtmum stenosis of SO-79% (moderate CAD; n = 35) or 280% (severe CAD; n = 37) of at least one major coronary artery. Arterial mechanics were assessed by measuring systemic arterial compliance (SAC), aortic input impedance and pulse wave veloctty WV). J&&s: SAC was significantly lower in the severe CAD group (mean * SEM, 0.44 i 0.04 arbitrary comphance units, ACU) compared to moderate CAD (0.55 * 0.04 ACU; p = 0.05) and connols (0.62 + 0.04 ACU, p = 0.001). Furthermore, aorttc input impedance was significantly higher in severe CAD (2.59 f 0.23 mmHg.s.cm”) compared to moderate CAD (2.06 f 0.17 mmHg.s.cm-‘; p = 0.04) and controls (1.75 f 0.12 mmHg.s.cm”; p = 0.001). A similar trend was also evident for carotid-femoral PWV (severe CAD: 11.34 It 0.71 ms-I versus moderate CAD: 9.55 f 0.49 mi’; p = 0.02; and controls: 9.30 & 0.29 mP’; p = O.OOS), however there was no difference in femoral-dorsalis pedis PWV between the three groups. Resting carotid pulse pressure was significantly greater in the severe CAD group (54 + 4 mmBg) compared to moderate CAD (45 * 3 mmHg; p = 0.05) and controls (39 f 2 mmBg; p = O.OOl), but there was no difference in brachial systolic, diastolic, mean arterial pressure or heart rate between the three groups. Conclusions: These findings suggest that there is a correlation between the severity of aortic and coronary atherosclerosis, and that large artery mechanical properttes represent a surrogate marker of disease severity in CAD patients.
CARDIOVASCULAR MICROINJFXTION ANAESTHETIZED
of Medicine,
RESPONSES IN
THE
TO
CRH
NTS
OF
RATS. m, Flinders Medical Centre, Bedford Park SA
OR DLH URETHANE Department
Corticotropin releasing hormone (CRH) is widely distributed in the central nervous system (CNS) and is present in areas in the forebrain, brainstem and spinal cord that are involved in cardiovascular homeostasis and physiological responses to stress. Microinjection of CRH in the nucleus tractus solitarius (NTS), the site of termination of cardiovascular afferent fibres projecting to the CNS, lowers arterial pressure (AP) and heart rate (HR, 1). To investigate the distribution of CRH-responsive sites in the NTS, and to determine whether the AP and HR responses to CRH are similar to the responses elicited by microinjection of the excitatory amino acid dl-homocysteic acid (DLH), CRH (10e4 M) and DLH (0.15 M) were microinjected (15 nL) throughout the rostrocaudal extent of the NTS of urethane anaesthetized (1.4 g/kg ip) rats. DLH elicited small decreases in AP (5.2kl.7 mmHg) when microinjected from 0 to +0.6 mm from the obex and decreased HR (-13.4k4.2 bpm) Ram 0.3 mm caudal to 1.5 mm rostra1 to the obex. In contrast, microinjection of CRH only changed AP (-7.5k2.1 mmHg) and HR (-10.7k2.1 bpm) when microinjected 0.6 mm rostra1 to the obex. Localization of the AP and HR responses at this site revealed that responses were largest 0.6 - 0.9 mm ventral to the medulla surface, that AP responses predominated on the right side and HR responses were most reliably elicited on the left. Histological analysis indicated that the responsive site was within the dorsal motor nucleus of the vagus (DMV), not the NTS. The results support a suggestion that a CRH projection from Barrington’s nucleus to the DMV may may be involved in autonomic aspects of stress responses (2). (1. T.Milner, D.Reis, V.Pickel et al., J. Comp. Neurol. 333: 151167, 1993. 2. R.Valentino, L.Pavcovitch, H.Hirata, J. Comp. Neurol. 363: 402-422, 1995.).
Scientific
Meeting
of CSANZ
A155
ARTERIAL PRESSURE AND HEART RATE RESPONSES TO CORTICOTROPIN RELEASING MICROINJECTION OF HORMONE IN THE INTERMEDIOLATERAL NUCLEUS OF THE . ANAESTHETIZED RAT. D.J.d L.F. AnmId& Cardiology
Department,
Flinders Medical Centre, Bedford Park, SA.
Corticotropin releasing hormone (CRH) controls the release of adrenocorticotropin and 3-endorphin from the anterior pituitaty and intracerebrovenhicular injection of CRH has been shown to elicit autonomic responses similar to those seen after exposure to stressful stimuli. CRH has been identified in a number of areas noted for their role in the control of the sympathetic nervous system, including the rostra1 ventrolateral medulla (RVLM) and intermediolateral nucleus of the spinal cord (IML). Moreover, microinjection of CRH in the RVLM has been shown to elicit increases in arterial pressure (AP; J. Comp. Neural., 333(2), 151, 1993). As CRH immunoreactivity has been identified in the IML, the present study was done to determine the effects on AP and heart rate (HR) of CRH in the right Tz IML of anaesthetized rats and to compare responses to CRH with the responses to glutamate (GLU). Both CRH and GLU elicited increases in AP and HR that were significantly greater than control microinjections of phosphate buffered saline (PBS) into cardiovascular sites in the IML (n
ALTERED REGULATORY PROTEINS OF CELL CYCLE PROGRESSION AND APOPTOSIS IN GENETIC HYPERTENSION. J. Shen*, A. Zulli. B. F. Buxton. and J, J. LiG Austin and Repatriation Medical Center, Heidelberg, VIC, Objective: A key pathological change in genetic hypertension is cardiovascular remodelling, which is mainly determined by cell overgrowth and cell death. Regulatory proteins for cell growth and cell death are common targets of various hormones and drugs. Studies on these final common pathways could provide highly efficient therapeutic strategy for treatment of the disease. Using spontaneously hypertensive rats (SHR) as a chronic disease model, we have studied the regulatory proteins of cell cycle entry: cyclindependent kinases (Cdk’s) and proliferating cell nuclear antigen (PCNA), and the regulatory proteins of apoptosis: Bcl-2 (antianoototic) and Bax (ore-anontotic). We have also snalvsed the effect 0; iamiphl, an ang~oten&convkrting enzyme inhibitor, on these regulatory proteins. Methods: an objectively quantitative immunohistochemical method was used to quantify the protein contents in coronarv arteries. hearts, and kidnevs of SHR and WKY. Results: (1) the expression of Cdkl and PCNA in the coronary arteries, the hearts and the kidneys was significantly higher in SHR than in normotensive rats (WKY); (2) the expression of Bc12 was significantly lower in SHR than in WKY, while that of Bax was significantly higher in SHR than in WKY(the ratio of Bcl2/Bax was sharply reduced); and (3) ramipril effectively reduced the expression of Cdkl and PCNA and increased the ratio of Bcl-2/Bax in SHR. Conclusion: these studies demonstrate that the regulatory proteins of cell cycle progression and apoptosis are altered in genetic hypertension, which could be one of the explanations for increased cell turnover and restructuring of the tissues in the disease. The studies also suggest that one of the mechanisms for ACE inhibitors to prevent cardiovascular remodelling could occur through their impact on these regulatory proteins.
Lung
and Circulation
48th Annual
2000; 9
LARGE ARTERY MECHANICAL PROPERTIES CORRELATE WITH SEVERITY OF CORONARY ARTERY DISEASE. TK Waddell*. TL
AM Dart. BA w. Alfred & Baker Medical Unit, Baker Medical Research Institute, Prabran, Victoria, Australia. Q&&es: Proximal aortic compliance has been shown to be lower in coronary artery disease (CAD) patients compared with healthy matched controls, The present study aimed to characterise large artery mechanical properties in relation to severity of CAD, as determined by the magnitude of the maximum coronary stenosis on angiography. M&Q&: Seventy-two males with CAD (mean * SD, 57 + 9 years) and forty age and gender matched healthy controls (54 f 10 years) were recruited. CAD pattents were classified as having a maxtmum stenosis of SO-79% (moderate CAD; n = 35) or 280% (severe CAD; n = 37) of at least one major coronary artery. Arterial mechanics were assessed by measuring systemic arterial compliance (SAC), aortic input impedance and pulse wave veloctty WV). J&&s: SAC was significantly lower in the severe CAD group (mean * SEM, 0.44 i 0.04 arbitrary comphance units, ACU) compared to moderate CAD (0.55 * 0.04 ACU; p = 0.05) and connols (0.62 + 0.04 ACU, p = 0.001). Furthermore, aorttc input impedance was significantly higher in severe CAD (2.59 f 0.23 mmHg.s.cm”) compared to moderate CAD (2.06 f 0.17 mmHg.s.cm-‘; p = 0.04) and controls (1.75 f 0.12 mmHg.s.cm”; p = 0.001). A similar trend was also evident for carotid-femoral PWV (severe CAD: 11.34 It 0.71 ms-I versus moderate CAD: 9.55 f 0.49 mi’; p = 0.02; and controls: 9.30 & 0.29 mP’; p = O.OOS), however there was no difference in femoral-dorsalis pedis PWV between the three groups. Resting carotid pulse pressure was significantly greater in the severe CAD group (54 + 4 mmBg) compared to moderate CAD (45 * 3 mmHg; p = 0.05) and controls (39 f 2 mmBg; p = O.OOl), but there was no difference in brachial systolic, diastolic, mean arterial pressure or heart rate between the three groups. Conclusions: These findings suggest that there is a correlation between the severity of aortic and coronary atherosclerosis, and that large artery mechanical properttes represent a surrogate marker of disease severity in CAD patients.
CARDIOVASCULAR MICROINJFXTION ANAESTHETIZED
of Medicine,
RESPONSES IN
THE
TO
CRH
NTS
OF
RATS. m, Flinders Medical Centre, Bedford Park SA
OR DLH URETHANE Department
Corticotropin releasing hormone (CRH) is widely distributed in the central nervous system (CNS) and is present in areas in the forebrain, brainstem and spinal cord that are involved in cardiovascular homeostasis and physiological responses to stress. Microinjection of CRH in the nucleus tractus solitarius (NTS), the site of termination of cardiovascular afferent fibres projecting to the CNS, lowers arterial pressure (AP) and heart rate (HR, 1). To investigate the distribution of CRH-responsive sites in the NTS, and to determine whether the AP and HR responses to CRH are similar to the responses elicited by microinjection of the excitatory amino acid dl-homocysteic acid (DLH), CRH (10e4 M) and DLH (0.15 M) were microinjected (15 nL) throughout the rostrocaudal extent of the NTS of urethane anaesthetized (1.4 g/kg ip) rats. DLH elicited small decreases in AP (5.2kl.7 mmHg) when microinjected from 0 to +0.6 mm from the obex and decreased HR (-13.4k4.2 bpm) Ram 0.3 mm caudal to 1.5 mm rostra1 to the obex. In contrast, microinjection of CRH only changed AP (-7.5k2.1 mmHg) and HR (-10.7k2.1 bpm) when microinjected 0.6 mm rostra1 to the obex. Localization of the AP and HR responses at this site revealed that responses were largest 0.6 - 0.9 mm ventral to the medulla surface, that AP responses predominated on the right side and HR responses were most reliably elicited on the left. Histological analysis indicated that the responsive site was within the dorsal motor nucleus of the vagus (DMV), not the NTS. The results support a suggestion that a CRH projection from Barrington’s nucleus to the DMV may may be involved in autonomic aspects of stress responses (2). (1. T.Milner, D.Reis, V.Pickel et al., J. Comp. Neurol. 333: 151167, 1993. 2. R.Valentino, L.Pavcovitch, H.Hirata, J. Comp. Neurol. 363: 402-422, 1995.).
Scientific
Meeting
of CSANZ
A155
ARTERIAL PRESSURE AND HEART RATE RESPONSES TO CORTICOTROPIN RELEASING MICROINJECTION OF HORMONE IN THE INTERMEDIOLATERAL NUCLEUS OF THE . ANAESTHETIZED RAT. D.J.d L.F. AnmId& Cardiology
Department,
Flinders Medical Centre, Bedford Park, SA.
Corticotropin releasing hormone (CRH) controls the release of adrenocorticotropin and 3-endorphin from the anterior pituitaty and intracerebrovenhicular injection of CRH has been shown to elicit autonomic responses similar to those seen after exposure to stressful stimuli. CRH has been identified in a number of areas noted for their role in the control of the sympathetic nervous system, including the rostra1 ventrolateral medulla (RVLM) and intermediolateral nucleus of the spinal cord (IML). Moreover, microinjection of CRH in the RVLM has been shown to elicit increases in arterial pressure (AP; J. Comp. Neural., 333(2), 151, 1993). As CRH immunoreactivity has been identified in the IML, the present study was done to determine the effects on AP and heart rate (HR) of CRH in the right Tz IML of anaesthetized rats and to compare responses to CRH with the responses to glutamate (GLU). Both CRH and GLU elicited increases in AP and HR that were significantly greater than control microinjections of phosphate buffered saline (PBS) into cardiovascular sites in the IML (n
ALTERED REGULATORY PROTEINS OF CELL CYCLE PROGRESSION AND APOPTOSIS IN GENETIC HYPERTENSION. J. Shen*, A. Zulli. B. F. Buxton. and J, J. LiG Austin and Repatriation Medical Center, Heidelberg, VIC, Objective: A key pathological change in genetic hypertension is cardiovascular remodelling, which is mainly determined by cell overgrowth and cell death. Regulatory proteins for cell growth and cell death are common targets of various hormones and drugs. Studies on these final common pathways could provide highly efficient therapeutic strategy for treatment of the disease. Using spontaneously hypertensive rats (SHR) as a chronic disease model, we have studied the regulatory proteins of cell cycle entry: cyclindependent kinases (Cdk’s) and proliferating cell nuclear antigen (PCNA), and the regulatory proteins of apoptosis: Bcl-2 (antianoototic) and Bax (ore-anontotic). We have also snalvsed the effect 0; iamiphl, an ang~oten&convkrting enzyme inhibitor, on these regulatory proteins. Methods: an objectively quantitative immunohistochemical method was used to quantify the protein contents in coronarv arteries. hearts, and kidnevs of SHR and WKY. Results: (1) the expression of Cdkl and PCNA in the coronary arteries, the hearts and the kidneys was significantly higher in SHR than in normotensive rats (WKY); (2) the expression of Bc12 was significantly lower in SHR than in WKY, while that of Bax was significantly higher in SHR than in WKY(the ratio of Bcl2/Bax was sharply reduced); and (3) ramipril effectively reduced the expression of Cdkl and PCNA and increased the ratio of Bcl-2/Bax in SHR. Conclusion: these studies demonstrate that the regulatory proteins of cell cycle progression and apoptosis are altered in genetic hypertension, which could be one of the explanations for increased cell turnover and restructuring of the tissues in the disease. The studies also suggest that one of the mechanisms for ACE inhibitors to prevent cardiovascular remodelling could occur through their impact on these regulatory proteins.