icatibant and Shock

Topics: Adult; Angioedemas, Hereditary; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Diagnosis, Differential; Female; Humans; Hypovolemia; Kinins; Shock; Tomography, X-Ray Computed

Bradykinin (BK) is regarded as an important mediator of edema, shock, and inflammation during sepsis. In this study, we evaluated the contribution of BK in porcine sepsis by blocking BK and by measuring the stable BK metabolite, BK1-5, using anesthetized pigs. The effect of BK alone, the efficacy of icatibant to block this effect, and the recovery of BK measured as plasma BK1-5 were first investigated. Purified BK injected intravenously induced an abrupt fall in blood pressure, which was completely prevented by pretreatment with icatibant. BK1-5 was detected in plasma corresponding to the doses given. The effect of icatibant was then investigated in an established model of porcine gram-negative sepsis. Neisseria meningitidis was infused intravenously without any pretreatment (n = 8) or pretreated with icatibant (n = 8). Negative controls received saline only. Icatibant-treated pigs developed the same degree of severe sepsis as did the controls. Both groups had massive capillary leakage, leukopenia, and excessive cytokine release. The plasma level of BK1-5 was low or nondetectable in all pigs. The latter observation was confirmed in supplementary studies with pigs undergoing Escherichia coli or polymicrobial sepsis induced by cecal ligation and puncture. In conclusion, icatibant completely blocked the hemodynamic effects of BK but had no beneficial effects on N. meningitidis-induced edema, shock, and inflammation. This and the fact that plasma BK1-5 in all the septic pigs was virtually nondetectable question the role of BK as an important mediator of porcine sepsis. Thus, the data challenge the current view of the role of BK also in human sepsis.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Edema; Inflammation; Neisseria meningitidis; Sepsis; Shock; Swine

Footshocks increases mean arterial pressure and heart rate. Systemic or intracerebroventricular (IVT) administration of losartan, a specific angiotensin AT1 receptor antagonist, not only inhibited the pressor response to footshocks but resulted in vasodepression. Peripheral or IVT administration of PD 123319, a specific angiotensin AT2 receptor antagonist, did not alter the haemodynamic response to footshocks. However, simultaneous blockade of angiotensin AT1 and AT2 receptors by combined systemic or central administration of losartan and PD 12319, eliminated the vasodepressor response to footshocks unmasked in losartan pretreated rats. Our data suggest that activation of peripheral or brain angiotensin AT2 receptor mediated the vasodepressor response to footshocks in the presence of angiotensin AT1 receptor antagonist. We studied the role of kinins and nitric oxide in the vasodepressor response observed after footshocks. The decrease in mean arterial pressure observed after footshocks in losartan treated rats was blunted by systemic or IVT administration of icatibant (HOE 140) or N(G)-nitro-L-arginine-methyl ester, indicating that peripheral or brain kinins and nitric oxide are involved in the hypotensor response to footshocks during angiotensin AT1 receptor blockade. Our results suggest a role for angiotensin AT2 receptor in the regulation of arterial blood pressure, possibly through the release of vasodilator autacoids such as bradykinins and nitric oxide.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Drug Administration Routes; Enzyme Inhibitors; Hot Temperature; Hypertension; Hypotension; Imidazoles; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Shock; Vasodilation