1 Five undeca-and six C-terminal heptapeptide substance P (SP) analogues were tested for their capacity to block the contractile effect of SP on the guinea-pig isolated taenia coli. They had one feature in common, namely substitutions in positions 7 and 9 in the SP molecule. In the majority of analogues D-tryptophan was used for these substitutions. 2 All analogues tested were found to be competitive antagonists to exogenous SP and to be capable of blocking the electrically induced non-cholinergic, non-adrenergic neuronal contraction of the taenia. (Spantide) had the highest pA2 value, 7.1 -7.2, and the lowest IC50 value, 10-6 M. The pA2 values of the heptapeptides were generally lower. 4 Three of the most potent antagonists were tested for specificity and found to block the smooth muscle contraction induced by SP, physalaemin, eledoisin and bombesin but not that induced by bradykinin, carbachol, 5-hydroxytryptamine, histamine, prostaglandins and vasopressin. 5 The SP antagonists were also tested for spasmogenic effect on the taenia and for their capacity to release histamine from rat isolated peritoneal mast cells. The spasmogenic activity displayed by most of the SP antagonists tested is likely to be related to their ability to release histamine since the contractile response was reduced by mepyramine, a histamine Hl-receptor antagonist.6 (D-Arg', D-Trp7 9, Leutt) SP was notable for combining a high antagonistic potency with a weak spasmogenic effect (and poor histamine releasing effect). IntroductionMethods
1. Homogenates of Propionibacterium freudenreichii transform riboflavin into 5,6-dimethylbenzimidazole. This process is stimulated by nicotinamide. Homogenates of Propionibacterium shermanii form only small amounts of 5,6-dimethylbenzimidazole from riboflavin in the absence of nicotinamide, but also form appreciable amounts in the presence of nicotinamide.2. The stimulation of the 5,6-dimethylbenzimidazole-forming system by nicotinamide shows a lag phase which is abolished by preincubation of the homogenate with nicotinamide. Since no lag phase is observed when nicotinamide is replaced by nicotinate, nicotinate seems to be the true stimulating agent. These observations are in agreement with the fact that nicotinamide is rapidly split to nicotinate in homogenates of P. jreudenreichii.3. The 5,6-dimethylbenzimidazole-forming homogenate system is only active at a high buffer concentration (0.3-0.5 M) and in the presence of oxygen. The system has a pronounced oxygen optimum .4. Flavin mononucleotide and flavin-adenine dinucleotide are better substrates for the 5,6-dimethylbenzimidazole-forming homogenate system than riboflavin. But with [l '-14C]riboflavin as substrate the specific radioactivity of 5,6-dimethylbenzimidazole is higher than the specific radioactivity of flavin -adenine dinucleotide and lower than the specific radioactivity of flavin mononucleotide. Therefore flavin mononucleotide is the immediate substrate for the formation of 5,6-dimethylbenzimidazole.5. A tentative reaction sequence for the transformation of flavin mononucleotide into 5,6-dimethylbenzimidazole is discussed.
Since the elucidation of the structure of substance P (Arg ‐ Pro ‐ Lys ‐ Pro ‐ Gin ‐ Gin ‐ Phe ‐ Phe ‐ Gly ‐ Leu ‐Met ‐ NH2) by Chang, Leeman & Niall (1971), many SP‐analogs have been described and have provided important information about the sequence‐activity relationships of SP. These studies have revealed the importance of chain length and of Phe7, Leu10 and Met11 for SP smooth muscle activity (Bergmann et al. 1974, Rosell et al. 1977). Thus, the smooth muscle stimulating activity is confined to the hexa‐peptide sequence at the C‐terminal. The (IIe7)‐SP analog showed little or no smooth muscle stimulating activity (Leban et al. 1979). Yamaguchi et al. (1979) synthesized (D‐Phe7)‐SP which was found to be a weak partial agonist on the guinea‐pig ileum. Likewise, (D‐Pro2)‐SP and (D‐Leu8, D‐Phe9)‐SP exerted some SP‐antagonism. A series of newly designed SP‐analogs has been tested for possible SP‐antagonism. We have found that (D‐Pro2, D‐Phe7, D‐Trp9)‐SP is an inhibitor of SP both on isolated organs and in vivo.
Indirect evidence has abundantly been presented to support the view that substance P (SP) is involved in the vasodilatation following activation of fine calibre pain fibres (Lembeck & Holzer 1979). In this respect, the dental pulp is interesting since it is richly supplied with SP‐immunoreactive nerves originating from the trigeminal system (Olgart et al. 1917b, Brodin et al. 1980). These nerves are in all probability related to nociception (Henry et al. 1980). Recent observations in the cat showing that electrical stimulation of the inferior alveolar nerve produces an atropine resistant vasodilatation (Gazelius & Olgart 1980), and a release of substance P‐like immunoreactivity in the pulp (Olgart et al. 1977a, Brodin et al. 1980) are in accord with the suggested role of SP. In the present study, the availability of an antagonist to SP has made possible the further elucidation of the role of SP as a mediator of antidromic vasodilatation in the dental pulp and in the oral mucosa of the cat. We have also determined whether (D‐Pro2, D‐Phe7, D‐Trp9)‐SP specifically blocks the vascular effects of SP.
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