Part of the beneficial effects of angiotensin I-converting enzyme (ACE) inhibitors are due to augmenting the actions of bradykinin (BK). We studied this effect of enalaprilat on the binding of [3H]BK to Chinese hamster ovary (CHO) cells stably transfected to express the human BK B2 receptor alone (CHO-3B) or in combination with ACE (CHO-15AB). In CHO-15AB cells, enalaprilat (1 mumol/L) increased the total number of low-affinity [3H]BK binding sites on the cells at 37 degrees C, but not at 4 degrees C, from 18.4 +/- 4.3 to 40.3 +/- 11.9 fmol/10(6) cells (P < .05; Kd, 2.3 +/- 0.8 and 5.9 +/- 1.3 nmol/L; n = 4). Enalaprilat preserved a portion of the receptors in high-affinity conformation (Kd, 0.17 +/- 0.08 nmol/L; 8.1 +/- 0.9 fmol/10(6) cells). Enalaprilat decreased the IC50 of [Hyp3-Tyr(Me)8]BK, the BK analogue more resistant to ACE, from 3.2 +/- 0.8 to 0.41 +/- 0.16 nmol/L (P < .05, n = 3). The biphasic displacement curve of the binding of [3H]BK also suggested the presence of high-affinity BK binding sites. Enalaprilat (5 nmol to 1 mumol/L) potentiated the release of [3H]arachidonic acid and the liberation of inositol 1,4,5-trisphosphate (IP3) induced by BK and [Hyp3-Tyr(Me)8]BK. Moreover, enalaprilat (1 mumol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 mumol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140. Finally, enalaprilat, but not the prodrug enalapril, decreased internalization of the receptor from 70 +/- 9% to 45 +/- 9% (P < .05, n = 7). In CHO-3B cells, enalaprilat was ineffective. ACE inhibitors in the presence of both the B2 receptor and ACE enhance BK binding, protect high-affinity receptors, block receptor desensitization, and decrease internalization, thereby potentiating BK beyond blocking its hydrolysis.

Postoperative itching is an important problem in the postoperative care unit. Pruritus after surgery may be drug induced (including intrathecal opioids) or secondary to a preexisting systemic disease. Mechanisms of itching are complex and not completely understood. The purpose of this review is to highlight new discoveries in pathways and mechanisms of pruritus and to summarize up-to-date knowledge about treatment of itching after surgery. More basic and clinical studies are needed to address the effects of drugs on specific receptors and improve the treatment of postoperative pruritus.

We investigated the effects of the angiotensin-converting enzyme inhibitor captopril on neurologic outcome in a rat model of incomplete cerebral ischemia. Twenty male SpragueDawley rats were anesthetized with 70% nitrous oxide in oxygen and fentanyl (10/igxkg" 1 i.v. bolus, 25 /*gxkg~'xhr~1 i.v. continuous infusion). Animals in group 1 (n=10) received no angiotensin-converting enzyme inhibitor while animals in group 2 (n=10) were given 10 mgxkg" 1 i.v. captopril 30 minutes prior to the ischemic period. Ischemia was produced by unilateral carotid artery ligation and hemorrhagic hypotension to 35 mm Hg for 30 minutes. Body temperature, arterial blood gases, and arterial pH were maintained constant Neurologic outcome was evaluated every 24 hours for 3 days using a graded deficit score (0, normal; 18, stroke-related death). On the third day after ischemia, captopril significantly improved neurologic outcome (median deficit score=4) compared with controls (median deficit score=18) (p<0.05). These results suggest that reduced angjotensin II levels or increased tissue kinin concentrations may decrease ischemic brain injury. (Stroke 1991;22:910-914) C ontroversy exists on the influence of the brain renin-angiotensin system 12 in the modulation of cerebral ischemia. Studies in strokeprone spontaneously hypertensive rats and gerbils suggest that the administration of angiotensin-converting enzyme inhibitors reduce stroke-related mortality and neurologic symptoms. 34 In contrast, experiments on unilateral brain ischemia in gerbils demonstrate a reduction of stroke-related mortality in the presence of angiotensin II. 5 The protective effect of angiotensin II could be reversed using angiotensin-converting enzyme inhibitors or angiotensin II antagonists. 6 These results may be due in part to the cardiovascular effects of the drugs. The hypotensive effect of angiotensin-converting enzyme inhibitors may improve outcome from hypertensive stroke while angiotensin II may increase blood pressure and enhance cerebral perfusion during focal ischemia. We investigated the effect of the angiotensin-converting enzyme inhibitor captopril on neurologic outcome in a model of incomplete cerebral ischemia in rats.

Specific [125I-Tyr8]bradykinin (BK) binding was observed on myocardial membranes from adult guinea pigs, dogs, rats, and rabbits that was displaced by unlabeled BK with an IC50 between 0.1 and 30 nmol/L. In the adult guinea pig ventricular myocardium, which displays both high- and low-affinity binding, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S; 100 mumol/L) eliminated high-affinity binding and reduced total specific [2,3-prolyl-3,4-3H(N)]BK ([3H]BK) binding by > 60%. Agonist competition binding to rat myocardial membranes was characterized as being of one affinity for BK in the nanomolar range, and it was not altered by GTP gamma S. Saturation binding studies with [125I-Tyr8]BK and [3H]BK, performed on cultured neonatal rat cardiac myocytes, revealed a single class of BK binding sites with a Kd and Bmax of 0.24 +/- 0.04 nmol/L and 18.4 +/- 1.1 fmol/mg protein, respectively (approximately 1500 receptors per cell). In competitive binding assays, unlabeled BK, Hoe 140 (a specific BK B2 receptor antagonist), and des-Arg9,[Leu8]BK (a BK B1 receptor antagonist) displaced [125I-Tyr8]BK with an IC50 of 4.3, 0.041, and 307 nmol/L, respectively. In the presence of 100 mumol/L GTP gamma S, [3H]BK binding to myocyte membranes was reduced by 40%, but the IC50 did not change. Cardiac fibroblasts, evaluated in parallel to the myocytes, contain a single class of [3H]BK binding sites (248 +/- 72 fmol/mg) with a 130-fold lower relative affinity (32.4 +/- 11.3 nmol/L) than that determined in rat cardiomyocytes.(ABSTRACT TRUNCATED AT 250 WORDS)