Opiate receptors and the endorphin-mediated cardiovascular effects of clonidine in rats: evidence for hypertension-induced mu-subtype to delta-subtype changes.
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.
Mosqueda-Garcia
R
R
Department of Pharmacology and Therapeutics, McGill University, Montreal, PQ, Canada.
Kunos
G
G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004723:Endorphins / Q000502:physiology*; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
D004723:Endorphins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009270:Naloxone; D004743:Enkephalin, Leucine; D009271:Naltrexone; C024524:beta-funaltrexamine; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine; D003000:Clonidine