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The Role of Substance P in Regulation of Blood Pressure and Hypertension JUAN CHEN, JIAN-PING GAO, CHENG-TAO XU, GUO-QING ZHU, AND YAN LIU Peking Union Medical College Beijing, China 100005 Substance P (SP) plays an important role in the central and peripheral nervous regulation of blood pressure. It has been demonstrated that the cell bodies of SP-containing neurons, which have direct projections to the intermediolateral cell column (IML) of the spinal cord, are located in the rostra1 ventrolateral medulla (RVM),’ a vasomotor center. The mechanism of SP in the regulation of blood pressure and hypertension was investigated in anesthetized Wistar rats, spontaneously hypertensive rats (SHR), and age-matched Wistar-Kyoto (WKY) rats. Our findings were as follows: First, stimulation of the RVM by application of 20 pg of physostigmine (PHY) or 5 pL of 40 mM/L kainic acid (KA) produced an increase in mean blood pressure (MAP) near 60 mmHg. This was accompanied by a release of SP from the spinal cord: the SP-like immunoreactivity (SPLI) of spinal perfusate rose by 0.76-fold as compared with control. Intrathecal injection of capsaicin (6.5, 12.5, 25,50 pg) to release SP from the spinal cord induced dose-dependent pressor responses. However, all of these pressor responses were blocked by 5-10 pg of the SP antagonist, ~-Pro*,~-phe’,D-Trp~-sP (D-SP), or by 10 pL of 1:5 SP antiserum given intrathecally. In addition, the pressor response of PHY was inhibited by application of 5 pg of atropine to the RVM. Second, a 3-fold increase in plasma noradrenaline (NA) and a 1.9-fold increase in adrenaline (AD) were observed at the peak of the pressor response evoked by application of KA to the RVM. The levels of plasma NA and AD were reversed, whereas the pressor response caused by KA was abolished completely by intrathecal administration of 10 pg of D-SP. Third, the SPLI of the RVM and IML in both SHR and renal artery hypertensive rats (induced by application of a constricting clip on the left renal artery) was elevated dramatically in comparison with the SPLI of WKY and sham-operated rats, respectively (TABLE1). The MAP was lowered to normal levels in both SHR and renal hypertensive rats (RHR) when 5 pg of D-SPwas given intrathecally. These results suggest that the excitation resulted either from PHY stimulating the muscarinic receptor indirectly and then activating the SP neurons or from KA directly by provoking the RVM to produce a release of SP from the spinal cord; that is, the pressor response evoked by activation of the RVM may be mediated by an SP-containing bulbospinal pathway, with SP transmitting excitatory information to the peripheral vasculature via the spinal sympathetic adrenal medulla system, which plays an important role in maintaining vasomotor tone. The unusual elevation of SP content of the RVM and IML in SHR and RHR rats might partly account for their high levels of sympathoadrenal activity and high blood pressure. In an additional series of experiments, the levels of plasma SPLI and catecholamine were measured in patients and rats with hypertension. The experimental data showed the following results: First, in patients with primary hypertension, the levels of plasma SPLI were significantly lower, but the concentrations of plasma NA and AD were higher than those in normotensive subjects (TABLE2). However, the levels 413
ANNALS NEW YORK ACADEMY OF SCIENCES
414
The Levels of MAP, Plasma NA, Plasma AD, and SPLI in Normotensive Subjects and Patients with Primary Hypertension (X k SE)
TABLE I.
Group MAP (mmHg) NA (pg/mL) AD (pg/mL) SPLI (pmol/mL) 94.2 f 1.6 222.5 f 12.4 normal subjects (n = 36) 498.4 +. 59.8 87.8 -C 8.1 hypertension (n = 27) 125.9 f 3.0" 459.4 f 49.8b 352.5 + 66.3" 223.2 28"
*
"p < 0.01 compared with normal subjects. "p < 0.05 compared with normal subjects.
The Levels of MAP and SPLI in the RVM and IML of Different Rat Strains (X ? SE)
TABLE 2.
SPLI (pmol/lO mg wet weight) Strains SHR WKY RHR sham-operated
MAP (mmHg)
RVM
IML
167.8 f 4.4" (n = 16) 91.6 f 2.7 (n = 18)
2.33 f 0.25'' (n = 4) 1.87 f 0.22 (n = 7)
1.37 f 0.15" ( n = 10) 0.64 f 0.05 (n = 10)
167.3 & 5.5' (n = 15) 73.6 f 3.0 (n = 19)
2.46
1.76 f 0.12' (n = 6) 1.18 5 0.22 (n = 7)
0.16' ( n = 5)
1.77 ? 0.30 (n = 8)
"p < 0.01 compared with WKY strains. "p < 0.05 compared with WKY strains. ' p < 0.05 compared with sham-operated strains. < 0.01 compared with sham-operated strains.
of plasma SPLI increased and the concentration of plasma catecholamine decreased after antihypertensive drug treatment. Moreover, the magnitude of plasma SPLI elevation in patients with hypertension was markedly related to the depressor efficiency. Second, in comparison with WKY rats, SHR rats had significantly lower plasma SPLI levels. It has been suggested that SP in plasma has not only a vasodilating effect, but also a suppressing effect on the synthesis and release of catecholamine from adrenal medulla.' Therefore, these data imply that plasma SP may be involved in the pathogenesis of hypertension. REFERENCES 1. HELKE,C. J., J. J. NEIL, V. J. MASSARI & A. D. LOEWY.1982. Substance P neurons project from the ventral medulla to the intermedio-lateral cell column and ventral horn in the rat. Brain Res. 243: 147-152. 2. ROLE,L. W., S. E. LEEMAN & R. L. PERLMAN. 1981. Somatostatin and substance P inhibit catecholamine secretion from isolated cells of guinea pig adrenal medulla. Neuroscience 6 1813-1821.
The Role of Substance P in Regulation of Blood Pressure and Hypertension JUAN CHEN, JIAN-PING GAO, CHENG-TAO XU, GUO-QING ZHU, AND YAN LIU Peking Union Medical College Beijing, China 100005 Substance P (SP) plays an important role in the central and peripheral nervous regulation of blood pressure. It has been demonstrated that the cell bodies of SP-containing neurons, which have direct projections to the intermediolateral cell column (IML) of the spinal cord, are located in the rostra1 ventrolateral medulla (RVM),’ a vasomotor center. The mechanism of SP in the regulation of blood pressure and hypertension was investigated in anesthetized Wistar rats, spontaneously hypertensive rats (SHR), and age-matched Wistar-Kyoto (WKY) rats. Our findings were as follows: First, stimulation of the RVM by application of 20 pg of physostigmine (PHY) or 5 pL of 40 mM/L kainic acid (KA) produced an increase in mean blood pressure (MAP) near 60 mmHg. This was accompanied by a release of SP from the spinal cord: the SP-like immunoreactivity (SPLI) of spinal perfusate rose by 0.76-fold as compared with control. Intrathecal injection of capsaicin (6.5, 12.5, 25,50 pg) to release SP from the spinal cord induced dose-dependent pressor responses. However, all of these pressor responses were blocked by 5-10 pg of the SP antagonist, ~-Pro*,~-phe’,D-Trp~-sP (D-SP), or by 10 pL of 1:5 SP antiserum given intrathecally. In addition, the pressor response of PHY was inhibited by application of 5 pg of atropine to the RVM. Second, a 3-fold increase in plasma noradrenaline (NA) and a 1.9-fold increase in adrenaline (AD) were observed at the peak of the pressor response evoked by application of KA to the RVM. The levels of plasma NA and AD were reversed, whereas the pressor response caused by KA was abolished completely by intrathecal administration of 10 pg of D-SP. Third, the SPLI of the RVM and IML in both SHR and renal artery hypertensive rats (induced by application of a constricting clip on the left renal artery) was elevated dramatically in comparison with the SPLI of WKY and sham-operated rats, respectively (TABLE1). The MAP was lowered to normal levels in both SHR and renal hypertensive rats (RHR) when 5 pg of D-SPwas given intrathecally. These results suggest that the excitation resulted either from PHY stimulating the muscarinic receptor indirectly and then activating the SP neurons or from KA directly by provoking the RVM to produce a release of SP from the spinal cord; that is, the pressor response evoked by activation of the RVM may be mediated by an SP-containing bulbospinal pathway, with SP transmitting excitatory information to the peripheral vasculature via the spinal sympathetic adrenal medulla system, which plays an important role in maintaining vasomotor tone. The unusual elevation of SP content of the RVM and IML in SHR and RHR rats might partly account for their high levels of sympathoadrenal activity and high blood pressure. In an additional series of experiments, the levels of plasma SPLI and catecholamine were measured in patients and rats with hypertension. The experimental data showed the following results: First, in patients with primary hypertension, the levels of plasma SPLI were significantly lower, but the concentrations of plasma NA and AD were higher than those in normotensive subjects (TABLE2). However, the levels 413
ANNALS NEW YORK ACADEMY OF SCIENCES
414
The Levels of MAP, Plasma NA, Plasma AD, and SPLI in Normotensive Subjects and Patients with Primary Hypertension (X k SE)
TABLE I.
Group MAP (mmHg) NA (pg/mL) AD (pg/mL) SPLI (pmol/mL) 94.2 f 1.6 222.5 f 12.4 normal subjects (n = 36) 498.4 +. 59.8 87.8 -C 8.1 hypertension (n = 27) 125.9 f 3.0" 459.4 f 49.8b 352.5 + 66.3" 223.2 28"
*
"p < 0.01 compared with normal subjects. "p < 0.05 compared with normal subjects.
The Levels of MAP and SPLI in the RVM and IML of Different Rat Strains (X ? SE)
TABLE 2.
SPLI (pmol/lO mg wet weight) Strains SHR WKY RHR sham-operated
MAP (mmHg)
RVM
IML
167.8 f 4.4" (n = 16) 91.6 f 2.7 (n = 18)
2.33 f 0.25'' (n = 4) 1.87 f 0.22 (n = 7)
1.37 f 0.15" ( n = 10) 0.64 f 0.05 (n = 10)
167.3 & 5.5' (n = 15) 73.6 f 3.0 (n = 19)
2.46
1.76 f 0.12' (n = 6) 1.18 5 0.22 (n = 7)
0.16' ( n = 5)
1.77 ? 0.30 (n = 8)
"p < 0.01 compared with WKY strains. "p < 0.05 compared with WKY strains. ' p < 0.05 compared with sham-operated strains. < 0.01 compared with sham-operated strains.
of plasma SPLI increased and the concentration of plasma catecholamine decreased after antihypertensive drug treatment. Moreover, the magnitude of plasma SPLI elevation in patients with hypertension was markedly related to the depressor efficiency. Second, in comparison with WKY rats, SHR rats had significantly lower plasma SPLI levels. It has been suggested that SP in plasma has not only a vasodilating effect, but also a suppressing effect on the synthesis and release of catecholamine from adrenal medulla.' Therefore, these data imply that plasma SP may be involved in the pathogenesis of hypertension. REFERENCES 1. HELKE,C. J., J. J. NEIL, V. J. MASSARI & A. D. LOEWY.1982. Substance P neurons project from the ventral medulla to the intermedio-lateral cell column and ventral horn in the rat. Brain Res. 243: 147-152. 2. ROLE,L. W., S. E. LEEMAN & R. L. PERLMAN. 1981. Somatostatin and substance P inhibit catecholamine secretion from isolated cells of guinea pig adrenal medulla. Neuroscience 6 1813-1821.
