beta-funaltrexamine and Hypertension

To determine whether the peripheral opioid system participates in hypertension development we studied responses to various opioid receptor agonists in field-stimulated isolated tail artery segments taken from spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats at different ages. The mu-selective agonist (DAGO) and the delta-selective D-Ala2-D-Leu5-enkephalin (DADLE) both suppressed the electrically stimulated vasoconstriction (EIC), but only in SHR arteries. The mu-selective antagonist beta-funaltrexamine reversed the effects of both DAGO and DADLE. Since the delta-selective antagonist ICI-174864 did not block DADLE inhibition, it is likely that both DAGO and DADLE effects were mu-receptor-mediated. Effects of DAGO and DADLE were qualitatively and quantitatively similar at all ages of SHR tested, and were not temporally related to hypertension development. Dynorphin (1-13) (DYN), a kappa-agonist, increased basal tone and EIC in all three rat strains. These responses were not blocked by nor-binaltorphimine, a selective kappa-opioid antagonist, suggesting that they may not involve kappa-receptor activation. There was a greater sensitivity to DYN at younger ages in all three rat strains and the sensitivity decreased with age. At 16 weeks when SHR hypertension was fully developed, SHR tail artery became almost totally insensitive to DYN in contrast to the continued responsiveness of 16-week-old WKY and SD arteries. The diminished effects to DYN in 16-week-old SHR tail arteries is suggestive of a compensatory mechanism to the hypertensive state. Collectively, the results establish that opioid receptor responses in SHR tail artery differ from those of normotensive rats. The significance of these differences to hypertension development in SHR remains to be determined.

Topics: Age Factors; Animals; Dose-Response Relationship, Drug; Dynorphins; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Hypertension; In Vitro Techniques; Male; Naltrexone; Narcotic Antagonists; Phenylephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Opioid; Tail; Vasoconstriction

We have previously shown that prolonged low-frequency muscle stimulation, inducing contractions of the gastrocnemius muscle, in conscious spontaneously hypertensive rats leads to an opioid-mediated post-stimulatory reduction in blood pressure and analgesia. In the present study we investigated whether muscle stimulation would also induce a post-stimulatory reduction in behavioural activity in the spontaneously hypertensive rats. Selective opioid receptor antagonists were used to analyse the involvement of endogenous opioids. Muscle stimulation, lasting 60 min, induced a post-stimulatory sedation that outlasted the stimulation for hours. Sniffing, locomotor activity and total behavioural activity were significantly reduced. The post-stimulatory reduction in activity was reversed back to control levels by a high dose of naloxone (15 mg kg-1 i.v.). The selective mu-receptor antagonist beta-funaltrexamine, given intracerebroventricularly before stimulation, did not influence the development of the post-stimulatory drop in activity. The delta-receptor antagonist ICI 154,129 had no effect at all on the already developed sedation, whereas MR 2266 BS, a kappa-receptor antagonist (3 mg kg-1 i.v.), completely reversed the drop in activity. These results show that muscle stimulation gives rise to an opioid-mediated post-stimulatory reduction in activity in spontaneously hypertensive rats. The results also indicate the involvement of the opioid kappa-receptor in the behavioural response.

Topics: Animals; Benzomorphans; Electric Stimulation; Hypertension; Male; Motor Activity; Muscles; Naloxone; Naltrexone; Rats; Rats, Inbred SHR; Receptors, Opioid

Naloxone enantiomorphs were given intracerebroventricularly (i.c.v.) to rats socially deprived for a brief period of time (7-14 days) in order to ascertain the mediation of central opiate receptors in the reversal effect of opiate antagonists on the high systolic blood pressure induced by this type of stress. While the active enantiomorph ((-)-naloxone, 20 nmol per rat) lowered the elevated blood pressure, the (+)-enantiomorph (which shows a 10,000-fold lower affinity for opiate receptors) had no effect. Additionally, the antihypertensive effect induced by i.c.v. administration of an antagonist of the mu-opiate receptor (beta-funaltrexamine, 20 nmol per rat), but not of the delta-opiate receptor (ICI 174,864, 15 nmol per rat) pointed to the involvement of mu-opiate receptors as the endogenous component of the hypertensive response of rats to stress.

Topics: Animals; Blood Pressure; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Social Isolation; Stereoisomerism; Stress, Psychological

Effects of opiate receptor antagonists on centrally mediated cardiovascular responses to clonidine and beta-endorphin were studied in urethane-anesthetized spontaneously hypertensive Okamoto-Aoki rats (SHR), normotensive Sprague-Dawley rats, and Sprague-Dawley rats made hypertensive with deoxycorticosterone pivalate/salt. Microinjection of 270 pmol of naloxone into the nucleus tractus solitarii (NTS) significantly inhibited the hypotensive and bradycardic response to 5 nmol of similarly administered clonidine in both SHR and normotensive Sprague-Dawley rats. In SHR, a similar inhibition was observed after the delta-opiate receptor antagonist ICI 174864, but not after the mu-receptor antagonist beta-funaltrexamine (both at 270 pmol, intra-NTS), whereas in normotensive Sprague-Dawley rats, beta-funaltrexamine, but not ICI 174864, was an effective inhibitor. The same pattern of differential inhibition was seen when clonidine was given i.v. and the opiate antagonists were given intracisternally in SHR and Sprague-Dawley rats. Intra-NTS microinjection of 280 fmol of beta-endorphin caused hypotension and bradycardia, and these effects were similarly inhibited by ICI 174864 in SHR and by beta-funaltrexamine in Sprague-Dawley rats. In Sprague-Dawley rats made hypertensive by chronic administration of deoxycorticosterone pivalate and salt, the hypotensive and bradycardic effects of intra-NTS clonidine were inhibited by ICI 174864, but not by beta-funaltrexamine, a pattern similar to that in SHR, but different from that in normotensive Sprague-Dawley rats. These results support the hypothesis that beta-endorphin release and subsequent stimulation of opiate receptors in the NTS are involved in the cardiovascular effects of clonidine in rats. These results further suggest, however, that hypertension regulates the subtype of opiate receptors mediating these effects.

Topics: Animals; Blood Pressure; Clonidine; Endorphins; Enkephalin, Leucine; Heart Rate; Hypertension; Male; Naloxone; Naltrexone; Rats; Rats, Inbred SHR; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu