The effects of N-(cyclopropylmethyl)-19-isopentylnororvinol (M320), a potent agonist at kappa- and mu-opiate receptors, on urine excretion of rats

Abstract

The effects of N-(cyclopropylmethyl)-19-isopentylnororvinol hydrochloride (M320) on urine excretion by rats were investigated. Further studies, using rabbit isolated vas deferens, investigated its interactions with kappa-opiate receptors. The output of urine for a 2 h period after M320, administered subcutaneously to normally hydrated Long Evans rats, showed a bell-shaped dose-response relationship, the maximum effect occurring after 10 micrograms kg-1. Urinary retention contributed to but did not fully account for the weaker diuresis after high doses. Attenuation of the ascending portion of the dose-response curve to M320 occurred after 1 and 10 mg kg-1 but not 0.1 mg kg-1 of naltrexone intraperitoneally. M320 in low doses (3-10 micrograms kg-1) caused a small but significant increase in sodium excretion. M320 (30 micrograms kg-1) reduced both sodium and potassium excretion. M320 (10 micrograms kg-1 s.c.) did not increase the volume of urine voided in 2 h by Brattleboro rats showing diabetes insipidus, even when urine excretion was reduced to normal by 1 week of vasopressin replacement. The volume of urine voided in 4 h by Brattleboro rats was progressively reduced to zero by M320 (10-100 micrograms kg-1 s.c.). Urinary retention contributed to but did not account for this reduction. Plasma levels of immunoreactive arginine vasopressin (ir-AVP) were reduced in both normal and dehydrated Long Evans rats after doses greater than 1 microgram kg-1 M320 s.c. In vitro, M320 caused persistent inhibition of twitches of the electrically stimulated rabbit vas deferens (IC50 1.7 nM). 8 These data suggest that M320 has potent opioid agonist activity at K-receptors and at higher concentrations stimulates mu- receptors. In the rat, its activity on K-receptors is associated with diuresis and suppression of plasma vasopressin levels. The antidiuresis seen after high doses may be due to its activity on mu-receptors, possibly at a central site.