The inhibitory effects of opioid peptides such as [Met5]-enkephalin and [Met5]-enkephalin-Arg6 on the electrically-evoked contractions of guinea-pig ileum, mouse vas deferens and rat vas deferens were enhanced by aminopeptidase inhibitors such as amastatin and bestatin, a peptidyl dipeptidase A inhibitor like captopril, and endopeptidase-24.11 inhibitors such as phosphoramidon and thiorphan. The magnitude of the enhancement by each peptidase inhibitor depended on both the preparation and opioid peptide employed. Additionally, enkephalin had been shown to be almost exclusively hydrolyzed at least in the ileal and striatal guinea pig membrane preparation by 3 kinds of enzymes, amastatin-sensitive aminopeptidase(s), captopril-sensitive peptidyl dipeptidase A and phosphoramidon-sensitive endopeptidase-24.11, which were indicated to be located very close to opioid receptors.
It is well known that the kallikrein-kinin system expresses potent biological activities through its final product, bradykinin. However, bradykinin has an extremely short half life in biological fluids, so that it is difficult to quantitate the amount of bradykinin released in relevant pathological samples. Therefore investigators have attempted to prove its involvement or importance by measuring the precursor proteins, such as prekallikrein, kininogens, and glandular kallikreins. In this review, I would like to focus the discussion on a study of the kallikrein-kinin system in B/N Katholiek rats, a strain that has a congenital deficiency in plasma high molecular weight and low molecular weight kininogens. When experimental inflammation induced in the mutant deficient rats are compared to that induced in the normal rats (B/N-Kitasato), there was a significant difference; i.e., the deficient rats showed less swelling in the carrageenin-induced paw edema and less exudate accumulation in carrageenin-induced rat pleurisy. These results indicate that bradykinin may be released from kininogens and it may cause exudate formation in above inflammation. Furthermore, when experimental hypertension was induced by DOCA-salt loading, the blood pressure of the deficient rats rose faster than that of the normal rats. From the above findings, it is concluded that the plasma kallikrein-kinin system could be an important regulatory system in body defense mechanisms such as inflammation and blood pressure control.
Membrane ionic currents were recorded using whole cell and patch clamp techniques in smooth muscle cells isolated from various organs to clarify the mechanisms underlying the diversity of membrane excitability. Components of inward and outward currents upon depolarization were resolved from one another kinetically or pharmacologically and were analyzed and compared in these cells under the same conditions. Cells were isolated from the ureter (UT), urinary bladder (UB), vas deferens (VD), aorta (AT), pulmonary artery (PA), taenia caeci (TC) and ileum (IL) of the guinea pig; the femoral artery (FA), portal vein (PV) and iris sphincter (IS) of the rabbit; the stomach fundus (SF) of the rat; the trachea (TR) of the dog and the coronary artery (CA) of the pig. Action potentials were elicited by depolarization in cells from UT, UB, VD, TC, IL, SF and PV, but not in those from AT, PA, FA, IS, TR and CA. Currents identified included Ca2+ currents, Na+ current, Ca2+-dependent K+ current, two kinds of delayed rectifier K+ currents which were pharmacologically distinguished by sensitivity to 4-aminopyridine, and Ca2+-independent A-type transient K+ current. The membrane excitabitiy including the action potential configuration in each cell type can be roughly explained by a combination of these currents, taking their amplitude and features into consideration.