Cardiovascular effects of peptide kinin B2 receptor antagonists in rats

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 B-2 receptor antagonist, namely icatibant (0.1-1 mumol/kg as a bolus) and MEN11270 (0.1-1 mumol/kg as a bolus or 1 mumol/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 mumol/kg did not change BP but at 0.1 mumol/kg increased HR at 30 min from administration. MEN11270 at 0.1 or 0.3 mumol/kg induced a dose-related increase in BP and a concomitant bradycardia (significant at 0.3 mumol/kg) lasting for 5 or 30 min, respectively. Icatibant at 1 mumol/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). MEN11270 at 1 mumol/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 MEN11270 (1 mumol/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 MEN11270 (0.1 mumol/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 MEN11270 was more rapid than that of icatibant. These results indicate that kinin B-2 receptor antagonists can induce acute cardiovascular effects, and the reason for the different haemodynamic profile between icatibant and MEN11270 could be putatively attributed to kinetic characteristics.