A non-peptide NK1-receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically.

1. The non-peptide neurokinin NK1-receptor antagonist, RP 67580 (3aR, 7aR), a perhydroisoindolone derivative, powerfully reduced plasma extravasation in rat hind paw skin induced by local application of xylene (ID50 = 0.03 mg kg-1, i.v.) or capsaicin (ID50 = 0.06 mg kg-1, i.v.), or by i.v. injection of exogenous substance P (SP) or septide ([pGlu6,Pro9]SP(6-11)) (ID50 = 0.04-0.05 mg kg-1, i.v.). RP 67580 (1 mg kg-1, i.v.) also abolished capsaicin-induced nasal fluid hypersecretion (by 82 +/- 5%). These effects were found to be stereospecific, the enantiomer, RP 68651 (3aS, 7aS), being inactive at 1 mg kg-1, i.v. 2. In rats neonatally treated with capsaicin (50 mg kg-1, s.c.), plasma extravasation induced by SP was significantly increased (by 43 +/- 7%). RP 67580 (1 mg kg-1, i.v.) completely inhibited the SP-induced plasma extravasation in capsaicin neonatally treated-animals, as it did in control animals. This result suggests that RP 67580 acts at the postsynaptic level for the inhibition of plasma extravasation. 3. Opioid receptor agonists, mu-(morphine) and kappa-(PD-117302) at 10 mg kg-1, s.c., in contrast to NK1-receptor antagonists, did not inhibit plasma extravasation induced by exogenous SP. They were, however, partially effective against plasma extravasation induced by electrical nerve stimulation (74 +/- 4% and 48 +/- 9% inhibition at 10 mg kg-1, s.c. of morphine and PD-117302, respectively, compared to 90 +/- 3% inhibition obtained with RP 67580, 3 mg kg-1, s.c.). These results indicate the presynaptic action of opioid receptor agonists, in contrast to the postsynaptic action of NK1-receptor antagonists for the inhibition of plasma extravasation.4. Ligature of the saphenous nerve distal to the point of electrical stimulation, local application of lignocaine to the saphenous nerve, neonatal capsaicin pretreatment, and colchicine at very low doses(120 microg kg-1 day-1 given for 3 days) were found to prevent plasma extravasation elicited by electrical nerve stimulation.5. The foregoing results demonstrate that the non-peptide NK1-receptor antagonist, RP67580, is a potent inhibitor of plasma extravasation induced in skin by NK1-receptor agonists, by local application of chemical irritants (capsaicin or xylene) or by electrical nerve stimulation. Moreover, opioid receptor agonists and colchicine inhibit plasma extravasation induced by electrical nerve stimulation but not that elicited by exogenous SP. Therefore, it is possible to inhibit neurogenic inflammation either at the presynaptic level with opioid receptor agonists and colchicine, or at the postsynaptic level withNK1-receptor antagonists, and that the new non-peptide NK1-receptor antagonists may have a great potential for alleviation of inflammation in various pathological syndromes in man.

Antagonism of substance P and related peptides by RP 67580 and CP-96,345, at tachykinin NK1 receptor sites, in the rat urinary bladder.

Tonic contraction of rat urinary bladder was elicited in vitro and in vivo by substance P, two selective NK1 receptor agonists, septide ([pGlu6,Pro9]substance P-(6-11)) and [Sar9,Met(O2)11]substance P, and an NK2 agonist, [Lys5,MeLeu9,Nle10]neurokinin A-(4-10), but not by senktide (succinyl[Asp6,MePhe8]substance P-(6-11)), an NK3 agonist. Substance P only stimulated the NK1 receptors of smooth muscle. The non-peptide selective NK1 receptor antagonists, RP 67580 and CP-96,345, both inhibited substance P-induced contraction (pKB values 6.7 and 5.7; ED50 = 1.4 and 5.0 mg/kg i.v., respectively) and septide-induced contraction (pKB values 7.5 and 6.5; ED50 = 0.076 and 0.250 mg/kg i.v., respectively). Both antagonists, at lower doses, also inhibited substance P- and septide-induced plasma extravasation. That both antagonists blocked the effects of septide much more than the effects of substance P suggests the existence of an NK1 receptor subtype or isoform. Selective NK1 receptor antagonists, by blocking both spasm and plasma extravasation in the urinary bladder, would be useful for treating substance P-related motor disorders and cystitis.

Increase in plasma renin activity evoked by fenoldopam in dogs is directly mediated by dopamine1 receptor stimulation.

In anesthetized dogs, a 15-min intravenous (i.v.) infusion of fenoldopam (2.0 micrograms/kg/min) produced a decrease in mean aortic blood pressure (MAP) and an increase in renal blood flow (RBF) and plasma renin activity (PRA). The hypotensive effect attained a maximum within 5 min and then waned by approximately 30% at the end of fenoldopam administration. The development of this "tolerance" phenomenon was prevented by enalapril or saralasin. The hypotension and the increase in PRA were not modified by either propranolol or chlorisondamine but were inhibited by SCH 23390, a DA1 antagonist. Fenoldopam (0.1 microgram/kg/min for 15 min) infused into the left renal artery (i.a.) in intact or ganglion-blocked dogs did not change MAP but increased PRA. This effect was antagonized by SCH 23390. In ganglion-blocked preparations in which an apparently maximal renal vasodilatation had been achieved by an i.a. acetylcholine, i.a. fenoldopam produced an increase in PRA which was again blocked by SCH 23390. In uninephrectomized dogs, blockade of alpha- and beta-adrenoceptors or inhibition of renal baroreceptor and macula densa mechanisms of renin release failed to prevent the fenoldopam-induced increase in PRA. In conclusion, the release of renin by fenoldopam is responsible for the development of tolerance to the hypotensive effects of fenoldopam. Furthermore, because the increase in PRA was blocked by SCH 23390 and occurred in the absence of either operational systemic or intrarenal regulatory mechanisms, we propose that it is mediated by stimulation of specific dopamine (DA1) receptors on the juxtaglomerular (JG) cells.

Effects of the K+ channel activators, RP 52891, cromakalim and diazoxide, on the plasma insulin level, plasma renin activity and blood pressure in rats.

In normo- or hyperglycemic (i.v. infusion of 50 mg/kg/min glucose over 30 min) pithed rats, diazoxide (1 mg/kg/min i.v. over 20 min) significantly reduced plasma insulin content. By contrast, cromakalim, nicorandil or RP 52891 even at doses 40-fold higher than those producing the same hypotensive effect as diazoxide in intact anesthetized normotensive rats, failed to change insulin plasma levels. Glibenclamide (0.01-0.3 mg/kg i.v.) pretreatment antagonized dose-dependently the hypoinsulinemic activity of diazoxide with an i.v. ED50 value of 49 +/- 1 microgram/kg. In pithed rats, diazoxide increased markedly plasma renin activity. This effect was almost inhibited completely by 20 mg/kg i.v., but not at all by a 1-mg/kg i.v. dose of glibenclamide. In pentobarbital-anesthetized rats, diazoxide (0.5-2 mg/kg/min i.v. over 20 min) produced decreases in mean carotid artery blood pressure which were antagonized dose-dependently by glibenclamide (5-20 mg/kg i.v.). This sulfonylurea (20 mg/kg i.v.) also prevented the hypotensive effects of several i.v. administered K+ channel activators (cromakalim, RP 52891 and nicorandil) but not those of numerous hypotensive agents such as acetylcholine, adenosine, bradykinin, clonidine, histamine, salbutamol, dihydralazine, papaverine, platelet aggregating factor, nitroglycerin, nitroprusside, nitrendipine and diltiazem. Although glibenclamide lowered plasma glucose levels, its blocking activity vis-à-vis the hypotension evoked by cromakalim was not affected when its hypoglycemic effects were reversed with an i.v. injection of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)