- Email: [email protected]
Cardiovascular responses induced by the spinal action of substance P in the conscious freely moving rat: Mechanism of action and neurokinin receptor characterization studies
82
CARDIOVASCULAR RESPONSES CONSCIOUS FREELY MOVING CHARACTERIZATION STUDIES H. HASSESSIAN
INDUCED BY THE SPINAL ACTION OF SUBSTANCE P IN THE RAT: MECHANISM OF ACTION AND NEUROKININ RECEPTOR
and R. COUTURE
Dept. of Physiology, Faculty Quebec, Canada, H3C 3J7
of
Medicine,
University
of Montreal,
Montreal,
Substance P (SP) may be a transmitter in the spinal cord, mediating the central regulation of the cardiovascular system (I). The present study was undertaken to characterize the neurokinin (NK) receptor which mediates the cardiovascular responses elicited by the iotrathecal (i.th.) administration of SP, and to investigate the sympatho-adrenal components that are activated. In addition to SP, neurokinin A (NKA), neuroklnin B (NKB) and SP fragments, five NK receptor subtype selective agonists: {Pro 9, Met(09)ll]sp, denoted A, [~-Ala 4, Sat 9, Met(02)II]sp (4-11), denoted B, [NIeI0]NKA ~4-I0), denoted C,--[B-Asp 4, MePhe7] NKB (4-10), denoted D and [Succinyl-Asp 6, MePhe8]Sp (6-11--), denoted E, were studied for their effects on mean arterial pressure (MAP) and heart rate (HR). Under pentobarbital anesthesia (65 mg/kg, i.p.), male Wistar rats (250-300 g) were instrumented with two catheters. A PE-50 catheter was inserted into the caudal artery, which served for the direct measurement of MAP and HR, and a PE-10 catheter was extended to the T8-TI0 vertebral level in the spinal subarachnoid space for the administration of peptides. A 24 h recuperation period was given before initiating experiments in the conscious freely moving rat. The three NK elicited a presslve effect with the following rank order of potency: SP > NKA = NKB. Only the response to SP was dose dependent (0.065-65 nmol). All NK elicited a dose dependent increase in HR with the following rank order of potency: SP > NKA > NKB. SP (6.5 nmol) produced cardiovascular responses markedly greater than an equivalent dose of its fragments, and the C-terminal sequences SP (4-II), [pGIuS]Sp (5-11), [pG]u6]Sp (6-11), and SP (7-11) as a group were slightly more potent than the N-terminal fragments SP (i-4), SP (i-7) and SP (i-9) which were almost inactive. The NK-I selective agonists (A and B) produced a maximal pressive and positive chronotropic effect greater in intensity than SP and the HR response they elicited lasted longer. The NK-2 (C) and NK-3 (D and E) selective agonists elicited MAP increases comparable to SP but produced a much weaker HR response• It is concluded that the cardiac and vascular responses elicited by the spinal action of SP are mediated by an NK-I receptor. These cardiovascular responses could be dissociated from nociceptlon as analgeslc doses of morphine (3-6 mg/kg, i.a. or I0 ~g, i.th.) failed to attenuate the cardiovascular effect elicited by 6.5 nmol of SP. The i.th. dose of morphine prolonged the HR response without affecting the MAP change. The systemic administration of 1 mg/kg of phentolamine blocked the pressive response and a depressor effect appeared, while i mg/kg propranolol blocked only the HR effect. Althoug h catecho]amines mediate the cardiovascular responses to SP, bilateral adrenalectomy of the rat 48 h prior to experimentation was inconsequential, indicating that adrenal medullary catecholamines are not essential for these responses. After transection of the spinal cord at the C3-C 4 level, the pressive response to SP was unaffected while the peak HR response was significantly reduced (P < 0.001). These results demonstrate that spinal activation of sympathetic fibers by SP can account for the pressive response and that admlnlstration of SP at the T8-TIo level activates ascending fibers which participate in the HR response• i. Couture R, Hass~ssian
H and Gupta A (1988) J Cardlov Pharmacol
II
270-283
We are indebted to Drs. D. Regoli and G. Drapeau of Sherbrooke University the synthesis and gift of NK receptor subtype selective agonists. Supported tion.
by the Medical
Research
Council
for
of Canada and the Quebec Heart Founda-
CARDIOVASCULAR RESPONSES CONSCIOUS FREELY MOVING CHARACTERIZATION STUDIES H. HASSESSIAN
INDUCED BY THE SPINAL ACTION OF SUBSTANCE P IN THE RAT: MECHANISM OF ACTION AND NEUROKININ RECEPTOR
and R. COUTURE
Dept. of Physiology, Faculty Quebec, Canada, H3C 3J7
of
Medicine,
University
of Montreal,
Montreal,
Substance P (SP) may be a transmitter in the spinal cord, mediating the central regulation of the cardiovascular system (I). The present study was undertaken to characterize the neurokinin (NK) receptor which mediates the cardiovascular responses elicited by the iotrathecal (i.th.) administration of SP, and to investigate the sympatho-adrenal components that are activated. In addition to SP, neurokinin A (NKA), neuroklnin B (NKB) and SP fragments, five NK receptor subtype selective agonists: {Pro 9, Met(09)ll]sp, denoted A, [~-Ala 4, Sat 9, Met(02)II]sp (4-11), denoted B, [NIeI0]NKA ~4-I0), denoted C,--[B-Asp 4, MePhe7] NKB (4-10), denoted D and [Succinyl-Asp 6, MePhe8]Sp (6-11--), denoted E, were studied for their effects on mean arterial pressure (MAP) and heart rate (HR). Under pentobarbital anesthesia (65 mg/kg, i.p.), male Wistar rats (250-300 g) were instrumented with two catheters. A PE-50 catheter was inserted into the caudal artery, which served for the direct measurement of MAP and HR, and a PE-10 catheter was extended to the T8-TI0 vertebral level in the spinal subarachnoid space for the administration of peptides. A 24 h recuperation period was given before initiating experiments in the conscious freely moving rat. The three NK elicited a presslve effect with the following rank order of potency: SP > NKA = NKB. Only the response to SP was dose dependent (0.065-65 nmol). All NK elicited a dose dependent increase in HR with the following rank order of potency: SP > NKA > NKB. SP (6.5 nmol) produced cardiovascular responses markedly greater than an equivalent dose of its fragments, and the C-terminal sequences SP (4-II), [pGIuS]Sp (5-11), [pG]u6]Sp (6-11), and SP (7-11) as a group were slightly more potent than the N-terminal fragments SP (i-4), SP (i-7) and SP (i-9) which were almost inactive. The NK-I selective agonists (A and B) produced a maximal pressive and positive chronotropic effect greater in intensity than SP and the HR response they elicited lasted longer. The NK-2 (C) and NK-3 (D and E) selective agonists elicited MAP increases comparable to SP but produced a much weaker HR response• It is concluded that the cardiac and vascular responses elicited by the spinal action of SP are mediated by an NK-I receptor. These cardiovascular responses could be dissociated from nociceptlon as analgeslc doses of morphine (3-6 mg/kg, i.a. or I0 ~g, i.th.) failed to attenuate the cardiovascular effect elicited by 6.5 nmol of SP. The i.th. dose of morphine prolonged the HR response without affecting the MAP change. The systemic administration of 1 mg/kg of phentolamine blocked the pressive response and a depressor effect appeared, while i mg/kg propranolol blocked only the HR effect. Althoug h catecho]amines mediate the cardiovascular responses to SP, bilateral adrenalectomy of the rat 48 h prior to experimentation was inconsequential, indicating that adrenal medullary catecholamines are not essential for these responses. After transection of the spinal cord at the C3-C 4 level, the pressive response to SP was unaffected while the peak HR response was significantly reduced (P < 0.001). These results demonstrate that spinal activation of sympathetic fibers by SP can account for the pressive response and that admlnlstration of SP at the T8-TIo level activates ascending fibers which participate in the HR response• i. Couture R, Hass~ssian
H and Gupta A (1988) J Cardlov Pharmacol
II
270-283
We are indebted to Drs. D. Regoli and G. Drapeau of Sherbrooke University the synthesis and gift of NK receptor subtype selective agonists. Supported tion.
by the Medical
Research
Council
for
of Canada and the Quebec Heart Founda-