norbinaltorphimine and Hypertension

Apelin receptors (APJ) cross-talk with other G-protein-coupled receptors. However, the role of APJ interaction with opioid receptors (OPR) on the cardiovascular effects of apelin in hypertension is not clear. Renovascular hypertension was induced by placing a Plexiglas clip on the left kidney of rats. After 16 weeks, F13A (an APJ antagonist), naloxone (a general OPR inhibitor), and nor-binaltorphimine dihydrochloride (nor-BNI; a selective inhibitor of KOR) were given prior to injections of apelin at doses of 40 and 60 μg/kg. The arterial systolic/diastolic blood pressure and left ventricular contractility responses were then evaluated. The arterial systolic/diastolic blood pressure in sham and 2K1C rats was 110/71 mm Hg and 171/124 mm Hg, respectively. The hypotensive effects of apelin at both doses were inhibited by F13A and naloxone. Nor-BNI completely inhibited the effects of apelin 40 on arterial pressure, and decreased the effects of 60 μg/kg. KOR inhibition also prevented the compensation for the decrease in the left ventricle +dp/dt max and -dp/dt max caused by apelin 60. The simultaneous inhibition of OPR and APJ reduced arterial pressure and increased cardiac contractility. Findings showed that the OPR, particularly KOR, mediate the inotropic, lusitropic, and depressor effects of apelin. The interaction of the OPR and APJ augments the inotropic and vasodepressor effects of apelin. This interaction may have potential clinical applications in cardiac failure since opioids are currently used in the treatment of myocardial infarction and stroke, and apelin has been introduced as a potential therapeutic agent in cardiovascular complications.

Topics: Animals; Apelin; Blood Pressure; Gene Expression Regulation; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Male; Myocardial Contraction; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Wistar; Receptors, Opioid

Previous research in our laboratory has established a restraining role of the hippocampal kappa-opioid receptor system in the neural control of blood pressure. Chronic or acute hippocampal administration of kappa-agonists has been shown to reduce blood pressure. Isolation of male Sprague-Dawley rats provokes an increase in blood pressure, which has been proposed as a valid model of mild emotionally induced hypertension. It was the purpose of this study to investigate the blood pressure effects of dorsal hippocampal administration of nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist; in conscious male Sprague-Dawley rats subjected to isolation-induced hypertension. Chronic bi-hippocampal microinjection of nor-BNI (10 nmol per side, twice a day for 13 days) caused increases in systolic blood pressure in grouped rats from a mean of 125 to 148 mmHg, and in isolated rats from a mean of 125 to 151 mmHg. This hypertension was similar in magnitude to the increase observed after rats were isolated for 7 days and treated with vehicle in a similar fashion (mean systolic blood pressure 144 mmHg). The increases in blood pressure were accompanied by bradycardia. No significant responses were seen in the blood pressure of grouped rats treated with vehicle. The hypotensive response to a single hippocampal microinjection of the kappa-agonist U62, 066E (10 or 20 nmol) was prevented in anesthetized rats treated previously with nor-BNI, indicating that in the nor-BNI treated rats there was effective blockade of dorsal hippocampal receptors. These data suggest that the rat hippocampal kappa-opioid receptor system and the endogenous neuropeptide dynorphin may be involved in the central neural regulation of blood pressure.

Topics: Anesthesia; Animals; Blood Pressure; Body Weight; Heart Rate; Hippocampus; Hypertension; Male; Microinjections; Naltrexone; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Social Isolation; Stress, Psychological

Previous studies in this laboratory have shown that dynorphins acting on hippocampal kappa opioid receptors in rat brain exert a restraining influence on arterial blood pressure and that a relative deficiency of their production in the spontaneously hypertensive rat (SHR) may be involved in SHR hypertension. Kappa receptor blockade should therefore exacerbate hypertension in SHR. We explored the latter possibility by chronic unilateral infusion of nor-binaltorphimine dihydrochloride (nor-BNI), a selective kappa receptor antagonist, into the right dorsal hippocampus of conscious SHR and normotensive Wistar-Kyoto (WKY) controls over a 14 day period. Additional controls consisted of similar hippocampal infusions of equivalent volumes of drug vehicle in both rat strains. Mean arterial pressure (MAP) and heart rates (HR) were determined in each animal once daily by the tail cuff method during this period. Nor-BNI induced a sustained increase in the basal high level of MAP in SHR from 132 +/- 8 to 150 +/- 10 mmHg throughout the 14 days and an increased HR from 427 +/- 17 to 477 +/- 30 on day 3 to 5 following the drug. By contrast, nor-BNI had no significant effects on either MAP or HR in WKY rats and control infusions of drug vehicle were similarly without effect in both strains. The results support our previous suggestion that the kappa opioid system of the hippocampus ordinarily restrains arterial blood pressure in SHR since prolonged hippocampal kappa receptor blockade results in augmented hypertension in this strain.

Topics: Animals; Blood Pressure; Heart Rate; Hippocampus; Hypertension; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid, kappa

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The possibility that the dynorphinergic system in the hippocampal formation (HF) may be implicated in the central regulation of peripheral circulatory activity was examined in chronically catheterized and conscious spontaneously hypertensive rats (SHR) and their normotensive control Wistar-Kyoto (WKY) rats. The ipsilateral microinjection of dynorphin-A(1-8) (DA1-8) at a dose of 10 nmol into the dorsal region of HF, where injection of control saline failed to affect peripheral cardiovascular activities, lowered mean blood pressure (MBP) by 19.2 +/- 1.2 mmHg in WKY and 25.9 +/- 3.2 mmHg in SHR. However, no significant alteration of heart rate (HR) was found in either WKY or SHR following the drug administration. The depressor response to intra-HF DA1-8 was dose-related (0.05 to 50.0 nmol) in the two strains of rats. Intra-HF injection of the kappa opioid receptor antagonist norbinaltorphimine at a dose of 2 nmol, which by itself produced only minimal fluctuations of basal MBP and HR, markedly reversed subsequent reduction of blood pressure induced by intra-HF injection of DA1-8 in both strains of rats. The results indicate that DA1-8 administered into the HF acts on kappa opioid receptors to produce a profound decrease in blood pressure, but not heart rate, in conscious hypertensive and normotensive rats.

Topics: Animals; Blood Pressure; Cardiovascular System; Dose-Response Relationship, Drug; Dynorphins; Hippocampus; Hypertension; Male; Microinjections; Naltrexone; Peptide Fragments; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We previously demonstrated centrally mediated hypotensive and bradycardic effects of dynorphin A(1-8) (DA1-8) on microinjection into various areas of the hippocampal formation (HF) of both anesthetized and conscious male normotensive and spontaneously hypertensive rats (SHR). The purpose of the present study was to determine whether other dynorphin fragments also had this activity. We microinjected DA1-8, dynorphin A(1-13), dynorphin A(1-17), dynorphin B (DB), and the nonpeptide kappa-opioid agonist U-50,488H into HF areas previously found to react to DA1-8, at doses ranging from 0.05 to 50 nmol. The subjects were male SHR and normotensive Wistar-Kyoto (WKY) rats in which arterial pressure and heart rate were monitored. Dose-related centrally mediated hypotension and bradycardia were found in both strains with all agents used, except for DB, which had no effects. Similarly injected drug vehicle was also without effect. In general, the responses were greater in SHR than in WKY rats. Preinjection of the active HF areas with 2 nmol of nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist, which itself had no blood pressure or heart rate effects, abolished both the decrease in blood pressure and heart rate of all dynorphins and U-50,488H. The results demonstrated the equivalent abilities of all the dynorphin fragments studied, except DB, to cause HF-mediated hypotension and bradycardia. The results with U-50,488H and nor-BNI strongly implicate kappa-opiate receptor activation of the HF in these effects.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amino Acid Sequence; Animals; Antihypertensive Agents; Blood Pressure; Dynorphins; Heart Rate; Hippocampus; Hypertension; Male; Molecular Sequence Data; Naltrexone; Peptide Fragments; Pyrrolidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values