Prevention of isolation-induced hypertension by intrahippocampal administration of a nonpeptide kappa-opioid receptor agonist.

Previous research in this laboratory showed that hypertension in the spontaneous hypertensive rat (SHR) appears to correlate to insufficient production of hippocampal dynorphins, and that blood pressure could be reduced by intrahippocampal administration of dynorphins and nonpeptide kappa agonists. The purpose of the present study was to investigate whether kappa agonists could prevent the development of hypertension in a different hypertensive model, i.e., the isolated male rat model of hypertension (IHR). Isolation of young male rats for 5-7 days in standard rat cages caused an increase in systolic blood pressure from a mean of 132 to 184 mmHg. The blood pressures of rats grouped 3 per cage remained stable. Rats received the nonpeptide kappa agonist U62, 066E, (Spiradoline, Upjohn), 10 nmoles/0.2 microl or drug vehicle bilaterally into the the hippocampus for 3 days prior to and during isolation or grouping. Animals treated with U62, 066E did not develop hypertension as compared to isolated animals treated with vehicle. The isolation procedure used in these studies appears to induce anxietal stress, as indicated by reduced time spent by the rats in the open arms of the elevated-plus maze. This time is increased by U62, 066E, suggesting that the drug possesses anxiolytic properties and may reduce hypertension in part, by blocking an anxiety/stress component. These data strengthen our previous findings that opioids in the hippocampus may be important in restraining increased blood pressure provoked by environmental stimuli such as isolation.

Chronic blockade of hippocampal kappa receptors increases arterial pressure in conscious spontaneously hypertensive rats but not in normotensive Wistar Kyoto rats.

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.

Hippocampal administration of kappa-opioid receptor antisense exacerbates isolation-induced hypertension.

Isolation of young male Sprague Dawley rats for 7 days provoked hypertension which was exacerbated by hippocampal administration of an antisense oligodeoxynucleotide targeted to the kappa-opioid receptor (1 microg/0.5 microL bilaterally, twice daily, during the isolation or grouping period). Systolic blood pressure rose from a mean of 134 to 162 mmHg in isolated rats treated with antisense and only 139 to 151 mmHg in grouped rats treated with antisense. In grouped rats treated with either vehicle or missense, isolation caused a mean increase in systolic blood pressure of only 16 and 14 mmHg respectively. Neither the missense oligodeoxynucleotide nor the vehicle had any significant effects upon systolic pressure in grouped rats, which had not been isolated. Pharmacological studies indicated that rats previously treated with the antisense had no significant depressor response to U62, 066E (a non-peptide kappa agonist known to reduce blood pressure acutely when administered into the hippocampus), however rats previously treated with vehicle or missense exhibited a significant hypotensive response to the drug. This implies that the antisense had reduced the density or activity of the kappa receptors within the hippocampal formation. These data are in accordance with our previous studies, i.e. in several rat models of hypertension, the increase in blood pressure may be modulated via hippocampal kappa opioid receptors.

Decreased dynorphin levels and increased kappa opioid receptor binding in male rats with isolation-induced hypertension.

The role of hippocampal dynorphin A (1-8) (Dyn A (1-8)) and kappa opioid receptors was investigated in the isolation-induced hypertensive rat (IHR). Male Sprague Dawley rats were either isolated (1 per cage) or grouped (3 per cage) for 7 days. Isolated rats exhibited increased blood pressure (systolic blood pressure 159.7 +/- 6.6 mmHg) whereas the grouped rats remained normotensive (systolic blood pressure 137 +/- 6.3 mmHg). Using radioligand binding techniques we observed a significant increase in kappa opioid receptor binding in the hippocampus of isolated rats (56% increase) and this further increased when the length of isolation was increased to 2 weeks (72% increase). Radioimmunoassay showed that isolation decreased the hippocampal content of Dyn A (1-8) from 12.7 +/- 0.4 to 11.6 +/- 0.2 pg Dyn A (1-8) per 10 mg tissue (rats weighing approximately 100 g) and from 13.3 +/- 0.8 to 9.7 +/- 1 pg Dyn A (1-8) per 10 mg tissue (approximately 200 g rats). These data suggest that functional alterations in the hippocampal dynorphin system may be involved in the maintenance of isolation induced hypertension.

Kappa-opioid receptor antisense oligonucleotide injected into rat hippocampus causes hypertension.

Bi-hippocampal microinjection treatment (1 microg per side, twice a day for 5 days) with an antisense phosphorothioate oligodeoxynucleotide antisense oligodeoxynucleotide to the rat kappa-opioid receptor, caused hypertension in normotensive Wistar Kyoto (WKY) rats and increased the blood pressure of spontaneously hypertensive rats (SHR). Systolic blood pressure in WKY rats increased from 121+/-4 to 153+/-6 mm Hg, and in SHR systolic blood pressure increased from 153+/-4 to 183+/-5 mm Hg. Similar results were observed with mean blood pressure, however, there were no changes in heart rate. No significant responses were seen with either vehicle or missense injections. Radioligand binding studies indicated that there was a significant decrease in apparent kappa-opioid receptor density due to antisense oligodeoxynucleotide treatment. The results are in accord with our earlier suggestions that the kappa-opioid system in the hippocampus may have a role in the neural control of blood pressure.

Comparison of cardiovascular responses to intra-hippocampal mu, delta and kappa opioid agonists in spontaneously hypertensive rats and isolation-induced hypertensive rats.

OBJECTIVE: To investigate the cardiovascular effects of microinjection into the hippocampus of selective mu, delta and kappa opioid receptor agonists in anesthetized spontaneously hypertensive rats, isolation-induced hypertensive rats and their normotensive Wistar-Kyoto and group-housed Sprague-Dawley controls. METHODS AND RESULTS: The microinjection of a selective kappa agonist, spiradoline mesylate, (+/-)-(5alpha, 7alpha, 8beta)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro++ +[4.5]dec-8-yl]-benzeneacetamide mesylate) (5 nmol) into the dorsal region of hippocampus, where injection of control saline failed to affect cardiovascular activities, induced centrally mediated decreases in mean blood pressure and heart rate in both hypertensive and normotensive rats. The effects were blocked by prior treatment of the hippocampus with nor-binaltorphimine dihydrochloride, a selective kappa opioid receptor antagonist The hypotensive and bradycardic effects were quantitatively similar between spontaneously hypertensive rats and Wistar-Kyoto rats and between isolated hypertensive rats and normotensive group-housed rats. The sequential administration of increasing doses (5, 10, 50 nmol) of the selective mu agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin and delta agonists [D-Ala2, D-Leu5]-enkephalin or [D-Pen2, D-Pen5]-enkephalin into the same areas of the hippocampus as used for the kappa agonist had no significant effects on mean blood pressure and heart rate in either hypertensive or normotensive rats. CONCLUSION: The present results extend our previous findings of a hippocampally mediated hypotensive effect of kappa agonists in the spontaneously hypertensive rat to the isolated rat model of hypertension and they establish that mu and delta opioid receptor agonists similarly applied are ineffective. Hippocampal kappa receptors may have a greater role in cardiovascular control than mu and delta receptors.

Practical considerations of the pharmacology of angiotensin receptor blockers.

A review of the drug class of angiotensin receptor blockers (ARBs) as well as the ARBs currently available by prescription in the United States is presented. The importance of angiotensin II production by non-angiotensin-converting enzyme (non-ACE) pathways, particularly human chymase, is discussed. Emphasis is placed on the mechanism of action of ARBs and the different binding kinetics of these agents. Although all ARBs, as a group, block the AT1 receptor, they may differ in the pharmacological characteristics of their binding and be classified as either surmountable or insurmountable antagonists. Mechanisms of surmountable and insurmountable antagonism as well as possible benefits of these blocking characteristics are discussed in relation to the various ARBs. The cardiovascular effects of activation of the two main subtypes of angiotensin receptors (AT1 and AT2) are presented. In addition to their treatment of hypertension, ACE inhibitors are recognized as being effective in the management of heart failure, left ventricular hypertrophy, recurrent myocardial infarctions, and renal disease. ARBs are currently indicated only for the treatment of hypertension; however, in vitro and in vivo pharmacological studies as well as preliminary clinical data suggest that ARBs, like ACE inhibitors, may also provide effective protection against end-organ damage in these conditions.

Depressor effect of kappa opioid agonist on hypertension induced by isolation in the rat.

Previous studies by us established that peripheral and hippocampal administration of kappa opioid receptor agonists lowered blood pressure (BP) in the spontaneously hypertensive rat (SHR). The object of the present study was to determine whether U62,066E, a non-peptide kappa agonist, would lower BP in another animal model of hypertension; that produced by isolation of young male rats. After 7 days of isolation had produced a sustained hypertension of approximately 40 mmHg, drug effects were determined in the isolated hypertensive animals and group-housed normotensive rats. Two drug-treated plus vehicle control groups were used as follows: (1) 2 mg/kg intraperitoneally twice daily for 3 days in conscious animals and (2) intrahippocampal injection of from 1 to 10 nmol in animals anesthetized with chloralose and pentobarbital. In group (1) the drug lowered both systolic BP (SBP) and mean BP (MBP) nearly to pre-isolation levels, while having no significant effect on these parameters in group-housed normotensive controls. Heart rate (HR) was not significantly affected by the drug in either sub-group. In group (2) SBP, MBP and HR were reduced in both the isolated hypertensive and group-housed normotensive animals when the drug was given intrahippocampally at 5.0 nmol. The depressor response to intrahippocampal U-62,066E was dose-related in both isolated and grouped rats at doses ranging from 1 to 10 nmol. The findings support our earlier suggestions that the hippocampal kappa opioid system may be somehow involved in cardiovascular regulation and that the non-peptide kappa agonists might make effective antihypertensive drugs.

Synergistic centrally mediated cardiovascular effects of a kappa opioid agonist and an alpha2-adrenoceptor agonist.

In this study, we determined possible additive and synergistic centrally mediated hypotensive and bradycardic effects of U-62,066E, a nonpeptide kappa opioid agonist acting on the hippocampal formation (HF), and guanabenz, an alpha2-adrenoceptor agonist acting on the rostral ventrolateral medulla (RVLM), the nucleus tractus solitarius (NTS), or the locus coeruleus (LC). The drugs were microinjected at various doses into these areas of alpha-chloralose-anesthetized Sprague-Dawley rats. There were synergistic hypotensive and bradycardic effects between low, noneffective doses of U-62,066E acting on the HF and guanabenz acting simultaneously on the RVLM. Higher doses of each agent, which themselves caused hypotension and bradycardia acting on each brain area alone, did not lead to synergistic effects when the drugs were injected simultaneously into those areas. There were no synergistic effects between U-62,066E acting on the HF and guanabenz acting on the NTS or the LC.

Kappa-opioid receptors behind the blood-brain barrier are involved in the anti-hypertensive effects of systemically administered kappa-agonists in the conscious spontaneously hypertensive rat.

We have shown previously that chronic intrahippocampal, intraperitoneal and subcutaneous administrations of non-peptide opioid receptor agonists induced depressor responses in the spontaneously hypertensive rat (SHR). However, it is not clear whether the hypotensive effect of systemic administration involves kappa receptors behind the blood-brain barrier. In this study, the relative roles of central vs peripheral kappa-opioid receptors in the hypotensive effect of kappa-agonists was examined in conscious SHRs following chronic subcutaneous administration of two selective kappa-agonists, BRL 52656 which freely penetrates the blood-brain barrier, and BRL 52974 which has only limited ability to do so. Initial studies determined the dose-response relationship for each of the two drugs given intraperitoneally twice a day, while monitoring systolic arterial pressure (SAP), mean arterial pressure (MAP) and heart rate (HR) measured by the tail-cuff method. Both drugs caused biphasic arterial pressure responses, with lower doses of BRL 52656 causing depressor effects and higher doses resulting in pressor effects. By contrast, lower doses of BRL 52974 caused pressor effects and higher doses depressor effects. The biphasic effects occurred with BRL 52656 from 0.01 to 3.0 mg kg(-1) and that for BRL 52974 from 0.1 to 30 mg kg(-1). In subsequent studies the drugs were infused chronically, subcutaneously via osmotic minipumps over a 14-day period, BRL 52656 at 0.2 or 0.5 mg kg(-1)/day and BRL 52974 at 0.2 mg kg(-1)/day. At lower doses, BRL 52656 decreased SAP, MAP and HR but at higher doses only bradycardia was observed. BRL 52974 given chronically subcutaneously over 14 days had no significant effects on arterial pressure and decreased heart rate only after seven days of treatment. Collectively, the results established that only the kappa-agonist, which gained access to the central nervous system, lowered arterial pressure and heart rate, whereas the compound with limited ability to cross the blood-brain barrier was ineffective at equivalent doses. The complex dose-response pattern found with both drugs suggests that kappa-agonists have central hypotensive and bradycardic actions at low doses but at higher doses a mixture of both central and peripheral actions leads to hypertension and tachycardia.

Effects of rat brain kappa 1- and kappa 2-opioid receptors after chronic treatment with non-peptide kappa-agonists.

Injection of kappa-agonist dynorphins and non-peptide kappa-agonists into the hippocampus induces a reduction in blood pressure. It has been postulated that kappa-opioid agonists and kappa-receptors are important in one mechanism of antihypertension and might have clinical potential for the treatment of hypertension. We have investigated whether chronic treatment with U-50488H and U-62066E, two non-peptide kappa-agonists, effects brain kappa 1- or kappa 2-receptor numbers or affinities in areas that might correlate with changes in blood pressure. kappa 1- and kappa 2-Opioid receptor affinities and densities were determined in cortex, hippocampus, hypothalamus, midbrain and pons after 14 days subcutaneous infusion of two non-peptide kappa-agonists, U-50488H and U-62066E, 9.6 mg kg day-1, by means of osmotic minipumps, to spontaneously hypertensive rats (SHR) and to Wistar-Kyoto (WKY) rats. This infusion significantly reduced blood pressure. Brains were removed within 48 h of the end of drug infusion and kappa-receptor binding studies were performed on homogenates from each brain area using [3H]U-69593 to assay kappa 1-receptors and [3H]bremazocine to assay kappa 2-receptors. U-62066E treatment seemed to cause a slight decrease in the number of [3H]bremazocine binding sites (kappa 2-receptors) from 98.2 +/- 9 to 74.9 +/- 8 fmol (mg protein)-1 in the hippocampus when compared with SHR controls. A small decrease in kappa 2-receptor density in the pons of WKY rats was also observed after U-50488H treatment (control, 51.2 +/- 5; U-50488H-treated, 24.3 +/- 9 fmol (mg protein)-1. Although SHR blood pressure values were consistently reduced by treatment with kappa-agonists, there was little if any significant change in apparent numbers of kappa 1- or kappa 2-receptors or their affinities in any of the brain regions examined. These data indicate that although chronic treatment with kappa-agonists reduces blood pressure in SHR, the treatment does not elicit major changes in brain kappa-receptors either in SHR or in WKY rats. The potential use of kappa-agonists for treating hypertension might not cause receptor changes in the brain and might, therefore, result in fewer side effects or negligible rebound hypertension.

Comparative hypotensive actions of three nonpeptide kappa opioid agonists on hippocampus of SHRs and normotensive WKY rats.

Comparative centrally mediated hypotensive effects of three nonpeptide kappa opioid agonist drugs (bremazocine, spiradoline, and U-50,488H) were evaluated in chloralose-anesthetized male spontaneously hypertensive rats (SHRs) and in normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. The drugs were administered unilaterally into previously established active hypotensive sites in the dorsal hippocampus at doses of 12, 24, and 48 nmol. Each drug produced dose-related decreases in mean arterial pressure, ranging from -5 to -40% of predrug control values, with bremazocine being somewhat more effective than spiradoline, which was in turn slightly more active than U-50,488H. The effects were only marginally greater in SHRs than in normotensive controls. Each drug caused a modest decrease in heart rate, but except for the highest dose of bremazocine, the effects were not statistically significant. The onset of hypotension after intrahippocampal injection of each agent was approximately 2 min and lasted approximately 30 min with U-50,488H and spiradoline and >60 min with bremazocine. The responses to all three drugs were completely blocked by prior injection of the active hippocampal sites with nor-binaltorphimine (nor-BNI), a selective kappa-receptor antagonist. Because bremazocine is more selective for kappa-2 opioid receptors, whereas U-50,488H and spiradoline favor the kappa-1 subtype, the results suggest that drugs active on each of these subtypes should be investigated as potential antihypertensives.

Sustained antihypertensive effects of chronic administration of two kappa-opioid agonists in spontaneously hypertensive rats.

The ability of two nonpeptide kappa-opioid receptor agonists, U-50, 488H and U-62,O66E (spiradoline), to lower arterial pressure on chronic administration to 12-week-old male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar Kyoto (WKY) rats was assessed. Each drug was infused subcutaneously at approximately 9.6 mg/kg/d, over a 14-day period with Alzet osmotic pumps in each strain of rat. Arterial pressures were determined daily in each rat by photoelectric tail-cuff plethysmography. Control rats received similar infusions of 0.9% NaCl. Body weights and water consumption were also recorded daily. Both drugs effected a 10% to 20% sustained lowering of arterial pressure beginning on the second day of infusion, until explantation of the pumps on day 14. Heart rates similarly were decreased by 10% to 15% in SHRs. By contrast, neither drug caused significant decrements in arterial pressure or heart rate in the normotensive WKY group. Control infusions of 0.9% NaCl had no significant effects on arterial pressure or heart rate in either SHRs or WKY rats. U-62,066E, but not U-50,488H, caused sustained increased water consumption in both SHRs and WKY rats, with a greater effect in the SHR strain. This likely was accompanied by a water diuresis. Body weight gains over the 14-day period were similar for both strains of rats treated with U-50,488H, compared with saline-treated controls, but rats of both strains infused with U-62,066E gained significantly less weight than saline controls over the 14-day period. The results are supportive of further experimental evaluations of the potential antihypertensive use of nonpeptide kappa-opioid agonist drugs.

Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats.

1. The central cardiovascular effects of several opioid receptor selective agonists and the nonselective opioid antagonist, naloxone, were studied in anesthetized normotensive control rats, in spontaneously hypertensive rats (SHR), and in foot-shock-stressed rats. 2. Receptor-selective agonists injected into the rostral ventrolateral medulla (RVLM), paraventricular nucleus (PVN), and dorsal hippocampus (dHip) were DAGO (mu), DADLE (delta), and U50,488H (kappa). 3. DAGO and DADLE (3 nM) decreased arterial pressure and heart rate in RVLM and PVN of all rat strains, while U-50,488H (9 nM) had only minimal effects in these areas. 4. In dHip, only DADLE (3 nM) had depressor and bradycardic effects, and then, only in SHR, with DAGO and U50,488H being ineffective in any strain, even at 9 nM. 5. Prior injection of naloxone (10 nM) into the RVLM, PVN and dHip blocked and postinjection reversed the cardiovascular effects of the agonists. Naloxone alone increased blood pressure and heart rate in all three areas, in all rat strains except SHR, suggesting a tonic depressor effect of endogenous opioids. 6. Lack of significant quantitative differences in opioid agonist and antagonist effects between normotensive and hypertensive or stressed rats argues against a role for endogenous brain opioids in experimental hypertension.

Survey results of POPS use in United States and Canadian schools of medicine and pharmacy.

Recent initiatives calling for changes in medical education, such as the General Professional Education of the Physician and Robert Wood Johnson Reports, have recommended alternative teaching approaches to the lecture format. The Patient-Oriented Problem-Solving (POPS) exercises, sponsored by the Upjohn Company (Kalamazoo, MI) and made available for pharmacology in 1985, offer one of many possible alternatives to lectures. The technique involves group interactions between four students in a working group, each of whom must, with the aid of their colleagues, arrive at mutual solutions to simulated cases in clinical pharmacology. The exercises are intended to complement and enhance the learning of concepts from lectures, and to help students apply these concepts practically. The system is used extensively by medical, pharmacy, and other health profession schools throughout the United States and also abroad, and many thousands of exercise booklets have been distributed free of charge by the Upjohn Company. Currently, a committee of the American Medical School Pharmacology (AMSP) group, working with Upjohn Company personnel, is responsible for overseeing the writing and educational testing of new and revised exercises. The purpose of this paper is to report the results of a survey of POPS use in medical and pharmacy schools in the United States, Canada, and Puerto Rico, completed in March 1993. The returns indicate continued strong interest in the approach, and the acquired data affirm its value in teaching principles of clinical pharmacology to students in basic pharmacology courses. Detailed data were obtained on patterns of use, and a number of advantages and disadvantages were identified. Priorities for the writing of new POPS exercises were expressed by the respondents. The information acquired will form the basis for planning new and revised POPS exercises in the future.

Influence of hypertension development on rat tail artery responses to opioid peptides.

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.

Receptors mediating depressor responses to intrahippocampal injection of L-glutamate and dynorphin-A(1-8) in conscious, spontaneously hypertensive and normotensive Wistar-Kyoto rats.

We previously demonstrated a centrally mediated hypotensive effect of dynorphin A(1-8) (Dyn) in conscious spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats, by intrahippocampal injection. The effect was due to kappa-opioid receptor activation. L-Glutamate (Glu) injected similarly in the same hippocampal sites also produced hypotension. The neural relation between Dyn and Glu responses was unclear. In the present study, using conscious SHR and WKY rats, we determined whether the selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) and the Glu NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (AP-5) had the ability to block the hypotensive effects of intrahippocampal Glu and Dyn, respectively. Block of the Glu response by nor-BNI or of the Dyn response by the N-methyl-D-aspartate (NMDA) receptor blocker might indicate that the Dyn- and Glu-releasing neurons are connected in series in hippocampus. A lack of cross-blocking activity might indicate that Dyn- and Glu-activated systems operate independently in cardiovascular control. The results demonstrated that intrahippocampal nor-BNI antagonized the depressor responses subsequent to Dyn but not those to Glu injected unilaterally in the same hippocampal areas. Similarly, the NMDA receptor blocker antagonized Glu but not Dyn hypotension. Neither Dyn nor Glu responses were blocked by a non-NMDA subclass receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Dentate granule cells as a central cardioregulatory site in the rat.

Dentate granule cells can be selectively destroyed by intrahippocampal injections of colchicine. This study evaluates the consequences of granule cell destruction on blood pressure regulation in the normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR). Bilateral destruction of dentate granule cells at 6 weeks of age produced a significant increase in blood pressure in the WKY that lasted for approximately 3 weeks, and a biphasic effect (increase then decrease) in the SHR that resulted in a significant hypotensive period that persisted for 6 weeks. Granule cell destruction at 11 weeks produced a maximal hypertension in the SHR that preceded age-matched controls by 4 weeks, but produced only a small transient increase in WKY blood pressure. Dentate granule cells are the exclusive source of prodynorphin-derived peptides in the hippocampal formation and their synthesis is regulated by glucocorticoids. Evidence suggests glucocorticoids may be involved in the regulation of blood pressure and hypertension. We determined that chronic high levels of corticosterone significantly reduced hippocampal dynorphin B levels in normotensive Sprague-Dawley rats. In addition, we confirmed that naive SHRs also contain significantly lower levels of hippocampal dynorphin B. These results suggest (i) that dentate granule cells represent a discrete neural site that may exert a tonic inhibitory influence on blood pressure, (ii) that dentate granule cells are not required for the full expression of hypertension in the SHR, and (iii) that chronic high levels of corticosterone can reduce dynorphin B levels in the dentate granule cells of normotensive rats.

A deficit in preprodynorphin mRNA expression in hippocampus of spontaneously hypertensive rats.

A significantly lower level of preprodynorphin mRNA hybridization signal was found in hippocampal dentate granule cells of spontaneously hypertensive rats at 4 and 16 weeks old, before and after hypertension development respectively, when compared with preprodynorphin (PPD) mRNA level in the hippocampus of age-matched Wistar-Kyoto rats. The possible implications of disturbed PPD mRNA and dynorphin expression in the hippocampus are discussed with regard to pathophysiology of hypertension and central control of cardiovascular function.

Cardiovascular responses to intra-hippocampal dynorphin A-(1-8) in spontaneously hypertensive rats.

Previous studies by us established that dynorphin A-(1-8) concentration in the hippocampal formation of spontaneously hypertensive rat (SHR) brain was much less than in the hippocampus of normotensive controls. The connection between low dynorphins and SHR hypertension was unclear. The object of the present study was to determine (1) whether microinjections of dynorphin A-(1-8) into the hippocampus of anesthetized SHR would produce centrally mediated effects on arterial pressure and heart rate and (2) whether these responses would differ qualitatively or quantitatively from those elicited in normotensive Wistar-Kyoto (WKY) or Sprague-Dawley rats. A statistically significant elevation of arterial pressure was observed in SHR at 8, 12 and 16 weeks compared to WKY and Sprague-Dawley controls at similar ages. There were no significant changes in heart rate of SHR compared to WKY and Sprague-Dawley rats. Intra-hippocampal dynorphin A-(1-8) caused a dose-dependent (0.05, 0.5, 5.0 and 50.0 nmol) hypotension and bradycardia in all strains, and ages but the responses were quantitatively larger in SHR than in the normotensive strains. Nor-binaltorphimine, a selective antagonist for kappa-opioid receptor, pretreated into the hippocampus caused a significant blockade of the dynorphin A-(1-8) responses in all strains. The results established that (1) intra-hippocampal dynorphin A-(1-8) lowered the arterial pressure and heart rate by a central mechanism, in all strains, at all ages tested and (2) the responses were quantitatively greater in SHR than in WKY and Sprague-Dawley strains. The responses appear to involve activation of a kappa receptor in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)