The inactivation of bradykinin in the pulmonary circulation of isolated lungs

I The activity and pulmonary metabolism of two peptides, 7-homo Pro-bradykinin and 8-homo Phebradykinin were studied in isolated systems. 2 Both analogues were about 50-70 times less active than bradykinin on the guinea-pig ileum and 70-160 times less active on isolated strips of cat terminal ileum. 3 The action of both analogues on guinea-pig ileum was potentiated (2.5-3.0 fold) by a bradykinin potentiating peptide (BPP9a) but less so than the action of bradykinin (4-5 fold).4 Like bradykinin, the 8-homo Phe analogue was extensively inactivated (>90%) in a single passage through the pulmonary circulation of guinea-pig or rat isolated lungs and this inactivation was prevented by pre-treatment of the lungs with BPP9a. 5The 7-homo Pro analogue was inactivated to a lesser degree in guinea-pig lungs (58%) and in rat lungs (89%) and its inactivation was not affected by BPP9a.6 It is concluded that the 8-homo Phe analogue is a substrate for the dipeptidylcarboxypeptidase (angiotensin I converting enzyme) of lung, whereas the 7-homo Pro analogue is not a substrate. 7 There is about four times as much dipeptidylcarboxypeptidase activity in guinea-pig isolated lungs as there is in rat isolated lungs.

Section: Activity Ofbradykinin Analogues On Isolated Tissuesmentioning

confidence: 93%

Pulmonary Metabolism of Bradykinin Analogues and the Contribution of Angiotensin Converting Enzyme to Bradykinin Inactivation in Isolated Lungs

Bakhle

1977

“…The inhibition of bradykinin inactivation in perfused lungs by N-ethylmaleimide (Alabaster & Bakhle, 1972a) led us to try this compound as an inhibitor of the bradykininase activity in fraction P3. However, despite preincubation with the enzyme for up to 30 min and in concentrations up to 1 mm, N-ethylmaleimide did not affect the inactivation of bradykinin.…”

Section: Resultsmentioning

confidence: 99%

“…Bradykinin was measured on any one of four tissues; the isolated terminal ileum of the guinea-pig, the longitudinal muscle from this tissue (Rang, 1964), or strips of the cat or kitten terminal ileum (Alabaster & Bakhle, 1972a). The tissue was suspended in a 5 ml organ bath in Krebs bicarbonate solution, gassed with 95% oxygen and 5% carbon dioxide, maintained at 370 C, or superfused at a rate of 8-10 ml/min with gassed Krebs bicarbonate solution at 370 C. Hyoscine (100 ng/ml) was sometimes added to the Krebs solution to reduce spontaneous activity of the tissues.…”

Section: Methodsmentioning

confidence: 99%

“…There is a potent bradykininase activity in blood-free isolated lungs (Alabaster & Bakhle, 1972a) and we have studied this activity in homogenates of dog lung in greater detail. One of the aims of this study was to compare the characteristics of the bradykininase activity with those already established for angiotensin converting enzyme activity present in the cellfree extracts of dog lung (Bakhle, 1968;Huggins, Corcoran, Gordon, Henry & John, 1970), since it had been suggested by Ng & Vane (1968) that these two peptidase activities were identical.…”

Section: Introductionmentioning

confidence: 99%

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The bradykininase activities of extracts of dog lung

Alabaster

Bakhle

1973

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Summary Homogenates of dog lungs freed from blood inactivate bradykinin. The bradykininase activity is present in soluble and particulate subcellular fractions. The fraction with the highest relative specific activity is that sedimenting between 8,700 g and 78,000 g. This fraction has been studied in more detail. There is evidence for two bradykinin inactivating enzymes in this fraction with apparent Km values of 7·5 μm and 120 μm. The bradykininase activity is not dependent on the concentration of chloride ion. The bradykininase activity is inhibited by EDTA, 2:3‐dimercaptopropanol, nickel ions and some of the peptides from the venom of Bothrops jararaca and of Agkistrodon halys blomhoffii but not by 2‐mercaptoethanol or N‐ethylmaleimide. Angiotensin II in either 15 or 170 mm chloride ion is not an inhibitor of bradykininase activity but angiotensin I at either chloride concentration is an inhibitor. It is proposed that chloride is not necessary for binding of angiotensin I to converting enzyme but is necessary to ensure the correct orientation of substrate for hydrolysis to proceed.

“…During passage through the pulmonary circulation, bradykinin is inactivated by several peptidases (Ferreira & Vane, 1967b;Alabaster & Bakhle, 1972; Orawski et al, 1987). Agonistic analogues of bradykinin also have been shown to be broken down in the lung .…”

Section: Introductionmentioning

confidence: 99%

Effects of the bradykinin antagonist B4310 on smooth muscles and blood pressure in the rat, and its enzymatic degradation

Griesbacher

Lembeck

Saria

1989

Austria1 Six competitive bradykinin (Bk) antagonists were tested for their agonistic properties on the rat uterus. Five of these peptides showed agonistic effects only at concentrations at least two orders of magnitude higher than those of bradykinin. 2 The antagonistic potency of Lys-Lys-3-Hyp-5,8-Thi-7-DPhe-Bk (B4310) in the rat uterus (pA2 = 7.24) and in the rat duodenum (pA2 = 7.31) was very similar to that determined in an earlier study for the antagonism of the bradykinin-induced stimulation of the trigeminal nerve in the rabbit iris sphincter muscle preparation (pA2 = 7.59). 3 The fall in mean arterial blood pressure induced by i.a. injections of bradykinin was greatly reduced during an i.a. infusion of B4310, but not 10min thereafter, which indicates a rapid inactivation of B4310 in,vivo. Bacitracin possibly interferes with the enzymatic cleavage of B4310 but seems to have no effect on the degradation of bradykinin. 4 An i.a. infusion of captopril greatly enhanced the potency of bradykinin in inducing a fall in arterial blood pressure, confirming the important role of angiotensin converting enzyme in the cleavage of bradykinin. However, the design of this experiment did not allow conclusions about the effect of captopril on the degradation of B43 10. 5 B4310 incubated with rat lung tissue disappeared from the incubation medium within a few minutes, i.e. as fast as bradykinin, which explains its short duration of action in vivo. Captopril partially inhibited the cleavage of both bradykinin and B4310. 6 The present results show that the bradykinin antagonists available at present are useful tools for the investigation of the biological role of bradykinin. However, the susceptibility to enzymatic degradation may limit their usefulness in animal experiments or in clinical studies.