Cardiovascular effects of peptide kinin B₂ receptor antagonists in rats

Abstract

Bradykinin (BK) is a vasoactive peptide reputed to play an important role in cardiovascular homeostasis. In this study, we describe the cardiovascular changes (mean blood pressure (BP) and heart rate (HR)) induced by the i.v. administration (left jugular vein) of two selective kinin B2 receptor antagonist, namely icatibant (0.1-1 micromol/kg as a bolus) and MEN1 1270 (0.1-1 micromol/kg as a bolus or 1 micromol/kg infused in 15 or 60 min), in urethane-anaesthetized or conscious rats with an indwelling catheter implanted in the right carotid artery for BP measurements. In conscious rats, icatibant at 0.1 or 0.3 micromol/kg did not change BP but at 0.1 micromol/kg increased HR at 30 min from administration. MEN1 1270 at 0.1 or 0.3 micromol/kg induced a dose-related increase in BP and a concomitant bradycardia (significant at 0.3 micromol/kg) lasting for 5 or 30 min, respectively. Icatibant at 1 micromol/kg induced a slight (P < 0.05) increase in BP that resolved in 5 min and a biphasic tachycardia (peaks at 30 and 90 min from administration). MEN1 1270 at 1 micromol/kg induced a triphasic change in HR (tachycardia in the first 5 min, bradycardia at 30 min, and tachycardia at 90 and 120 min) and a biphasic change in BP (hypotension at 15 min and hypertension at 30 min). The i.v. infusion of MEN1 1270 (1 micromol/kg in 15 or 60 min) produced hypertension, whereas HR was increased only following the 15-min infusion. In urethane-anaesthetized rats, both icatibant and MEN1 1270 (0.1 micromol/kg as a bolus) increased BP and the onset for this effect was correlated with the time course of the antagonism of BK-induced hypotension, where the effect of MEN1 1270 was more rapid than that of icatibant. These results indicate that kinin B2 receptor antagonists can induce acute cardiovascular effects, and the reason for the different haemodynamic profile between icatibant and MEN1 1270 could be putatively attributed to kinetic characteristics.

Bradykinin B2 Receptor Does Not Contribute to Blood Pressure Lowering during AT1 Receptor Blockade

“…Genetic disruption of the B 2 receptor has been reported to increase heart rate in some studies (Emanueli et al, 1999) but not in others (Milia et al, 2001). As in the present study in humans, HOE-140 has been reported to increase heart rate in both a rat model (Carini et al, 2002) and in captopriltreated, sodium-depleted marmosets (Panzenbeck et al, 1995). Further studies are needed to address the mechanism through which endogenous bradykinin modulates the heart rate response to vasodilation during chronic AT 1 receptor blockade.…”

Activated plasma coagulation β-Factor XII-induced vasoconstriction in rats

“…BK also acts directly on the sino-atrial node, via the BK B 2 receptor, to lower HR [37]. In BK B 2 receptor knockout mice basal HR is elevated compared with littermate controls [38], and pharmacological blockade by the BK B 2 receptor antagonist HOE 140 increases HR in both rats [39] and humans [40]. A second potential explanation for the slower HR observed in rats with intact adrenal glands is that β-FXIIa induced increases in PACAP [13], which lowers HR by liberating acetylcholine from postganglionic parasympathetic nerves [41].…”

Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 1. Synthesis and SAR of α,α-Dimethylglycine Sulfonamides

“…On the basis of these findings, a potential therapeutic role for kinin B 2 receptor antagonists has been hypothesized in the treatment of airway inflammatory pathologies associated with hyper-responsiveness to BK, such as chronic bronchial asthma, or with the release of BK, such as perennial and seasonal allergic rhinitis . On the other hand, kinins also exert effects on the cardiovascular system: several studies suggest that BK contributes to the antihypertensive and cardioprotective effects of ACE inhibitors, and acute changes in cardiovascular parameters produced by kinin B 2 receptor antagonists have been observed . This indicates that in targeting airway inflammatory pathologies it is important to avoid interfering at the cardiovascular level.…”

“…11 On the other hand, kinins also exert effects on the cardiovascular system: several studies suggest that BK contributes to the antihypertensive and cardioprotective effects of ACE inhibitors, 12 and acute changes in cardiovascular parameters produced by kinin B 2 receptor antagonists have been observed. 13 This indicates that in targeting airway inflammatory pathologies it is important to avoid interfering at the cardiovascular level.…”