Kinin B1 receptors: a review

Proline specific peptidases

The blood-brain barrier (BBB) helps to maintain a constant internal environment for the brain by regulating the passage of substances between the general circulation and the brain tissue. After considerable research into the location and properties of this barrier (for reviews see, e.g., Davson, 1976; Bradbury, 1984, 1986), it was finally established by electron microscopy that its principal site is the endothelial cell layer of blood capillaries supplying the brain (Reese and Karnovsky, 1967; Brightman and Reese, 1969; Reese et al., 197 1). These cells possess several unique features that serve this purpose; most importantly they have been shown to be joined by tight junctions forming zona occludens around each cell (Brightman and Reese, 1969). In contrast, systemic capillaries often have pores or slits between the endothelial cells through which water and solutes can pass freely by nonspecific, passive processes such as diffusion. Cerebral capillaries contain few, if any, such pores (Patlak and Paulson, 198 1). This continuous physical barrier prevents nonspecific intercellular transport, and pinocytosis is also severely limited (Reese and Karnovsky, 1967). Intracellular or transcellular transport, i.e., directly through the endothelial cell membrane, is the principal route into and out of the CNS, though the choroid plexuses are also involved in the transport of solutes from brain to CSF, and vice versa. As a result the BBB exhibits a low permeability to hydrophilic substances such as small ions and polar nonelectrolytes that do not have specific transport mechanisms. Hydrophobic substances, because of their high lipid solubility, can generally diffuse freely across the barrier. Other types of cells including pericytes, astroglia, and smooth muscle cells are closely associated with the cerebral microvasculature. Perhaps the most important of these, and certainly the most extensively studied, are the astroglial cells. Astrocytic processes completely engulf cerebral microvessels so that the membranes of the astrocyte and the capillary endothelial cell are closely apposed, separated only by a basement membrane and a thin layer of interstitial substance (Dempsey and Wislocki, 1955). Although astroglia probably have no actual physical role in the functioning of the BBB, Davson and Oldendorf (1967) have speculated that they might influence the structural and functional characteristics of the cerebral endothelium (see, e.g., Stewart and Wiley, 1981; Janzer and Raff, 1987). The intimate association of astroglia and the capillaries has important implications for experimental work on the BBB because preparations of brain microvessels may contain astrocytic end-feet still attached, which may lead to erroneous conclusions about the exact cellular localization of BBB-associated substances. For example, the surfaces of isolated intact microvessels have been shown to stain for the astrocytic marker, glial fibrillary acidic protein (GFAP) (White et al., 198 I), presumably because glial filaments remain trapped within astrocyte end-feet that have remained associated with the vessels. However, our own work with bovine microvessels suggests that GFAP may not always give an accurate indication of such contamination. Although a 40-fold enrichment of y-glutamyl transpeptidase (a marker enzyme for brain capillaries) is routinely achieved in these preparations, and no more than 4% of the total cortical glutamine synthetase activity (a glial marker) remains, the intensity of staining of GFAP on western blots of microvessel protein was found to be somewhat greater than that obtained from an equal amount of whole cerebral cortical protein (Brownlees and Williams, unpublished observations). This sug-

Peptidases, Peptides, and the Mammalian Blood–Brain Barrier

Differential processing of substance P and neurokinin A by plasma dipeptidyl(amino)peptidase IV, aminopeptidase M and angiotensin converting enzyme.

1
Bradykinin (BK) has been shown to exert cardioprotective effects which are potentiated by inhibitors of angiotensin I-converting enzyme (ACE). In order to clarify the significance of ACE within the whole spectrum of myocardial kininases we investigated BK degradation in the isolated rat heart.

2
Tritiated BK (3H-BK) or unlabelled BK was either repeatedly perfused through the heart, or applied as an intracoronary bolus allowing determination of its elution kinetics. BK metabolites were analysed by HPLC. Kininases were identified by ramiprilat, phosphoramidon, diprotin A and 2-mercaptoethanol or apstatin as specific inhibitors of ACE, neutral endopeptidase 24.11 (NEP), dipeptidylaminopeptidase IV and aminopeptidase P (APP), respectively.

3
In sequential perfusion passages, 3H-BK concentrations in the perfusate decreased by 39% during each passage. Ramiprilat reduced the rate of 3H-BK breakdown by 54% and nearly abolished [1-5]-BK generation. The ramiprilat-resistant kininase activity was for the most part inhibited by the selective APP inhibitor apstatin (IC50 0.9 μM). BK cleavage by APP yielded the intermediate product [2-9]-BK, which was rapidly metabolized to [4-9]-BK by dipeptidylaminopeptidase IV.

4
After bolus injection of 3H-BK, 10% of the applied radioactivity were protractedly eluted, indicating the distribution of this fraction into the myocardial interstitium. In samples of such interstitial perfusate fractions, 3H-BK was extensively (by 92%) degraded, essentially by ACE and APP. The ramiprilat- and mercaptoethanol-resistant fraction of interstitial kininase activity amounted to 14%, about half of which could be attributed to NEP. Only the product of NEP, [1–7]-BK, was continuously generated during the presence of 3H-BK in the interstitium.

5
ACE and APP are located at the endothelium and represent the predominant kininases of rat myocardium. Both enzymes form a metabolic barrier for the extravasated fraction of BK. Thus, only interstitial, but not intravascular concentrations of BK are increased by kininase inhibitors to the extent that a significant potentiation of BK effects could be explained. NEP contributes less than 5% to the total kininase activity, but is the only enzyme which is exclusively present in the interstitial space.





British Journal of Pharmacology (1997) 122, 1179–1187; doi:10.1038/sj.bjp.0701501

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0701501

Intravascular and interstitial degradation of bradykinin in isolated perfused rat heart.

Metabolism of bradykinin analogs by angiotensin I converting enzyme and carboxypeptidase N

Metabolism of bradykinin agonists and antagonists by plasma aminopeptidase P.

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Metabolism of bradykinin analogs by angiotensin I converting enzyme and carboxypeptidase N

Metabolism of bradykinin agonists and antagonists by plasma aminopeptidase P.