Pharmacological characterization of the cardiovascular responses elicited by kinin B(1) and B(2) receptor agonists in the spinal cord of streptozotocin-diabetic rats

Abstract

Kinin receptor agonists and antagonists at the B(1) and B(2) receptors were injected intrathecally (i.t., at T-9 spinal cord level) to conscious unrestrained rats and their effects on mean arterial pressure (MAP) and heart rate (HR) were compared in streptozotocin (STZ)-diabetic rats (65 mg kg(-1) STZ, i.p. 3 weeks earlier) and aged-matched control rats. The B(1) receptor agonist, des-Arg(9)-Bradykinin (BK) (3.2 - 32.5 nmol), evoked dose-dependent increases in MAP and tachycardia during the first 10 min post-injection in STZ-diabetic rats only. The cardiovascular response to 6.5 nmol des-Arg(9)-BK was reversibly blocked by the prior i.t. injection of antagonists for the B(1) receptor ([des-Arg(10)]-Hoe 140, 650 pmol or [Leu(8)]-des-Arg(9)-BK, 65 nmol) and B(2) receptor (Hoe 140, 81 pmol or FR173657, 81 pmol) or by indomethacin (5 mg kg(-1), i.a.). The i.t. injection of BK (8.1 - 810 pmol) induced dose-dependent increases in MAP which were accompanied either by tachycardiac (STZ-diabetic rats) or bradycardiac (control rats) responses. The pressor response to BK was significantly greater in STZ-diabetic rats. The cardiovascular response to 81 pmol BK was reversibly blocked by 81 pmol Hoe 140 or 81 pmol FR173657 but not by B(1) receptor antagonists nor by indomethacin in STZ-diabetic rats. The data suggest that the activation of kinin B(1) receptor in the spinal cord of STZ-diabetic rats leads to cardiovascular changes through a prostaglandin mediated mechanism. Thus, this study affords an accessible model for studying the expression, the pharmacology and physiopathology of the B(1) receptor in the central nervous system.

Figure 1

Time-course effects on changes in mean arterial pressure (Δ MAP) and heart rate (Δ HR) for a period of 15 min induced by increasing doses of BK injected to the T-9 spinal cord level of conscious STZ-diabetic rats (a) and age-matched control rats (b). Each point represents the means±s.e.mean of (n) rats.

Figure 2

Time-course effects on changes in mean arterial pressure (Δ MAP) and heart rate (Δ HR) for a period of 15 min induced by increasing doses of des-Arg⁹-BK injected to the T-9 spinal cord level of conscious STZ-diabetic rats (a) and age-matched control rats (b). Each point represents the means±s.e.mean of (n) rats.

Figure 3

Time-course effects on changes in mean arterial pressure (Δ MAP) and heart rate (Δ HR) induced by 6.5 nmol des-Arg⁹-BK (a) and 81 pmol BK (b) injected to the T-9 spinal cord level of conscious STZ-diabetic rats with or without [Leu⁸]-des-Arg⁹-BK. Basal values were: MAP: 91.5±8 mmHg; HR: 256±14 beats min⁻¹ in (a) and MAP: 97±9 mmHg; HR: 244±17 beats min⁻¹ in (b). Data are means±s.e.mean of (n) rats. Statistical comparison to vehicle values (^*) or to the agonist without [Leu⁸]-des-Arg⁹-BK (†) is indicated by ^*,† P<0.05; ^**,†† P<0.01; ^***,††† P<0.001.

Figure 4

Time-course effects on changes in mean arterial pressure (Δ MAP) and heart rate (Δ HR) induced by 6.5 nmol des-Arg⁹-BK (a) and 81 pmol BK (b) injected to the T-9 spinal cord level of conscious STZ-diabetic rats with or without [des-Arg¹⁰]-Hoe 140. Basal values were: MAP: 93±10 mmHg; HR: 250±18 beats min⁻¹ in (a) and MAP: 97±13 mmHg; HR: 283±24 beats min⁻¹ in (b). Data are means±s.e.mean of (n) rats. Statistical comparison to vehicle values (^*) or to the agonist without [des-Arg¹⁰]-Hoe 140 (†) is indicated by ^*,† P<0.05; ^**,†† P<0.01.

Figure 5

Time-course effects on changes in mean arterial pressure (Δ MAP) and heart rate (Δ HR) induced by 6.5 nmol of des-Arg⁹-BK (a) and 81 pmol BK (b) injected to the T-9 spinal cord level of conscious STZ-diabetic rats with or without Hoe 140. Basal values were: MAP: 107±10 mmHg; HR: 216±14 beats min⁻¹ in (a) and MAP: 105±8.3 mmHg; HR: 233±18 beats min⁻¹ in (b). Data are means±s.e.mean of (n) rats. Statistical comparison to vehicle values (^*) or to the agonist without Hoe 140 (†) is indicated by ^*,† P<0.05; ^**,†† P<0.01; ^***,††† P<0.001.

Figure 6

Time-course effects on changes in mean arterial pressure (Δ MAP) and heart rate (Δ HR) induced by 6.5 nmol of des-Arg⁹-BK (a) and 81 pmol BK (b) injected to the T-9 spinal cord level of conscious STZ-diabetic rats with or without FR173657. Basal values were: MAP: 102±5 mmHg; HR: 233±5.6 beats min⁻¹ in (a) and MAP: 102±6 mmHg; HR: 228±7 beats min⁻¹ in (b). Data are means±s.e.mean of (n) rats. Statistical comparison to vehicle values (^*) or to the agonist without FR173657 (†) is indicated by ^*,† P<0.05; ^**,††P<0.01; ^***,††† P<0.001.

Figure 7

Time-course effects on changes in mean arterial pressure (Δ MAP) and heart rate (Δ HR) induced by 6.5 nmol des-Arg⁹-BK (a) and 81 pmol BK (b) injected to the T-9 spinal cord level of conscious STZ-diabetic rats with or without indomethacin. Basal values were: MAP: 96±5 mmHg; HR: 233±7 beats min⁻¹ in (a) and MAP: 103±6 mmHg; HR: 224±12 beats min⁻¹ in (b). Data are means±s.e.mean of (n) rats. Statistical comparison to vehicle values (^*) or to the agonist without indomethacin (†) is indicated by ^*,† P<0.05; ^**,†† P<0.01; ^***,††† P<0.001.