dynorphins and Hypertension

After hyperventilation, systolic and diastolic blood pressure (BP) significantly decreased in 14 hypertensive patients (group 1), did not change in 9 (group 2) and increased in 8 (group 3). Basal BP, norepinephrine and dynorphin B levels were higher in group 1 than in groups 2 and 3. The decrease in BP after hyperventilation was associated with a decrease in plasma norepinephrine, Met-enkephalin and dynorphin B and an increase in beta-endorphin. Naloxone abolished the hyperventilation-induced BP and norepinephrine decreases. Our findings indicate that hyperventilation may select hypertensive patients with different sympatho-adrenergic activity and that the increase in beta-endorphin reduces BP response to hyperventilation in patients with high sympatho-adrenergic tone.

Topics: Aged; beta-Endorphin; Blood Pressure; Cross-Over Studies; Dynorphins; Enkephalin, Methionine; Female; Heart Rate; Humans; Hypertension; Hyperventilation; Male; Middle Aged; Naloxone; Norepinephrine; Time Factors

To investigate the effects of the endogenous opioid system on plasma atrial natriuretic factor (ANF) levels during sympathetic hyperactivity.. We studied the young normotensive offspring of parents who both had essential hypertension, who are characterized by a hyperactive sympathetic nervous system.. We assessed plasma beta-endorphin, met-enkephalin, dynorphin B, ANF and noradrenaline levels, blood pressure and heart rate values in eight normotensive offspring and in 10 young normotensive subjects with no family history of hypertension (controls) at rest and during two exercise tests: the first test performed with the infusion of placebo (1.5 ml/min saline) and the second test with the infusion of an opioid antagonist (9.5 micrograms/kg per min naloxone hydrochloride). ANF and opioids were radioimmunoassayed after chromatographic pre-extraction.. At rest plasma met-enkephalin, dynorphin B, ANF and noradrenaline values in the normotensive offspring were significantly higher than in the controls. Exercise with placebo significantly raised all hormonal and haemodynamic parameters in the two groups. This increase was significantly higher in the normotensive offspring than in the controls. Naloxone did not modify any parameter in either group at rest, but it enhanced further the rise in plasma noradrenaline levels induced by exercise in both groups. A similar effect of naloxone during exercise was observed for plasma ANF levels in the normotensive offspring.. Our findings show that plasma met-enkephalin, dynorphin B, ANF and noradrenaline levels at rest and during exercise are higher in normotensive offspring than in controls. The effects of naloxone indicate that in normotensive offspring at rest the opioid system does not affect ANF release, whereas during exercise it attenuates ANF hypersecretion, possibly by reducing noradrenaline release.

Topics: Adult; Atrial Natriuretic Factor; beta-Endorphin; Disease Susceptibility; Dynorphins; Endorphins; Enkephalin, Methionine; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Male; Naloxone; Norepinephrine; Opioid Peptides; Physical Exertion; Radioimmunoassay

Opioids/opiates are commonly administered to alleviate pain, unload the heart, or decrease breathlessness in patients with advanced heart failure. As such, it is important to evaluate whether the myocardial opioidergic system is altered in cardiac disease. A hamster model of spontaneous hypertension was investigated before the development of hypertension (1 mo of age) and in the hypertensive state (10 mo of age) to evaluate the effect of prolonged hypertension on myocardial opioidergic activity. Plasma beta-endorphin was decreased before the development of hypertension and in the hypertensive state (P < 0.05). There was no change in cardiac beta-endorphin content at either time point. No differences were detected in cardiac or plasma dynorphin A, Met-enkephalin, or Leu-enkephalin, or in cardiac peptide expression of kappa- or delta-opioid receptors. mu-Opioid receptor was not detected in either model. To determine how hypertension affects myocardial opioid signaling, the ex vivo work-performing heart was used to assess the cardiac response to opioid administration in healthy hearts and those subjected to chronic hypertension. Agonists selective for the kappa- and delta-opioid receptors, but not mu-opioid receptors, induced a concentration-dependent decrease in cardiac function. The decrease in left ventricular systolic pressure on administration of the kappa-opioid receptor-selective agonist, U50488H, was attenuated in hearts from hamsters subjected to chronic, untreated hypertension (P < 0.05) compared with control. These results show that peripheral and myocardial opioid expression and signaling are altered in hypertension.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Benzamides; beta-Endorphin; Blood Pressure; Cricetinae; Cyclic AMP; Disease Models, Animal; Dynorphins; Enkephalin, Leucine; Enkephalin, Methionine; Hypertension; Hypertrophy, Left Ventricular; Myocardial Contraction; Myocardium; Piperazines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Systole; Ventricular Remodeling

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.

Topics: Animals; Blood Pressure; Dynorphins; Heart Rate; Hippocampus; Hypertension; Injections; Male; Microinjections; Mutation, Missense; Oligodeoxyribonucleotides, Antisense; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; RNA, Messenger; Social Isolation; Stress, Psychological

The binding parameters of [3H]nociceptin were examined in membrane preparations of rat heart and compared with those of [3H]dynorphin A-(1-13) ([3H]Dyn A-(1-13)). Scatchard analysis of [3H]nociceptin binding revealed the presence of two distinct sites: a high affinity (Kd: 583 nM) low capacity (Bmax: 132 pmol/mg protein) site and a low affinity (Kd: 10,316 nM) high capacity (1552 pmol/mg protein) site. Dyn A and related peptides were potent competitors of the binding to the high affinity site with the following rank order of potency: alpha-neo-endorphin > Dyn A-(2-13) = Dyn A-(3-13) > Dyn A-(5-13) > Dyn A-(1-13) > Dyn A > Dyn B > Dyn A-(6-10) >> Dyn A-(1-8). Nociceptin was 6.7 times less potent than Dyn A with a Ki of 4.8 microM as compared with 0.72 microM for Dyn A. The order of potency of the various peptides in inhibiting [3H]nociceptin binding correlated well (r = 0.93) with their ability to complete with the binding of [3H]Dyn A-(1-13) (Dumont and Lemaire, 1993). In addition, the high affinity [3H]nociceptin and non-opioid [3H]Dyn A-(1-13) sites were both sensitive to NaCl (120 mM) and the phospholipase C (PLC) inhibitors, U-73122 and neomycin (100 microM). The binding activities were less affected by the weak PLC inhibitor, U-73343, and no effect was observed with the non-hydrolysable GTP analogs. Gpp(NH)p and GTP-gamma-S. Nociceptin (1-50 microM) was also shown to inhibit the uptake of [3H]noradrenaline ([3H]NA) by cardiac synaptosomal preparations. In spontaneously hypertensive rats (SHR), the potency of nociceptin in inhibiting [3H]NA uptake was increased by 1.6-fold as compared with Wistar Kyoto (WKY) control rats and such effect was accompanied by comparable increased levels of cardiac ORL1 mRNA and [3H]nociceptin high affinity sites. These changes correlated well with the previously observed increased levels of non-opioid cardiac [3H]Dyn A-(1-13) sites in SHR (1.3 times as compared with WKY) and increased potency of Dyn A-(1-13) in inhibiting [3H]NA uptake by cardiac synaptosomes in SHR (2.2-fold as compared with WKY) (Dumont and Lemaire, 1995). The results demonstrate that in rat heart the characteristics of the high affinity, low capacity [3H]nociceptin binding site are similar to those of the non-opioid Dyn binding site. The stimulation of this site by nociceptin, Dyn A or related peptides is more likely to produce a modulation of PLC activity and [3H]NA uptake and may participate to the pathophysiology of hypertension.

Topics: Animals; Binding Sites; Dose-Response Relationship, Drug; Dynorphins; Estrenes; Guanosine 5'-O-(3-Thiotriphosphate); Guanylyl Imidodiphosphate; Heart; Hypertension; Male; Myocardium; Neomycin; Nociceptin; Opioid Peptides; Pyrrolidinones; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; Synaptosomes; Time Factors

To investigate the involvement of endogenous opioids in acute increases in blood pressure and their functional relationship with atrial natriuretic factor and endothelin-1, we assessed plasma levels of beta-endorphin, met-enkephalin, dynorphin B, catecholamines, atrial natriuretic factor, and endothelin-1 before and after administration of the opioid antagonist naloxone hydrochloride (8 mg i.v.) in 28 hypertensive patients with a stress-induced acute increase in blood pressure. Ten patients with established mild or moderate essential hypertension and 10 normotensive subjects served as control groups. Opioids, atrial natriuretic factor, and endothelin-I were radioimmunoassayed after chromatographic preextraction; catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Patients with an acute increase in blood pressure (systolic, 203.2 +/- 2.2 mm Hg; diastolic, 108.4 +/- 1.3) had plasma opioid, catecholamine, and atrial natriuretic factor levels significantly (P < .01) higher than hypertensive control patients (systolic pressure, 176.4 +/- 1.0 mm Hg; diastolic, 100.0 +/- 1.4), who had a hormonal pattern similar to that of normotensive subjects (systolic pressure, 123.2 +/- 1.5 mm Hg; diastolic, 75.0 +/- 2.0). Endothelin-1 did not differ in any group. In patients with an acute increase in blood pressure, naloxone significantly (P < .01) reduced blood pressure, heart rate, opioids, catecholamines, and atrial natriuretic factor 10 minutes after administration. Naloxone effects on blood pressure, heart rate, opioids, and catecholamines wore off within 20 minutes. In control groups, naloxone failed to modify any of the considered parameters. Our findings suggest that pressor effects of opioid peptides mediated by the autonomic nervous system during stress-induced acute episodes of blood pressure increase in hypertensive patients.

Topics: Atrial Natriuretic Factor; beta-Endorphin; Blood Pressure; Dynorphins; Endorphins; Endothelin-1; Enkephalin, Methionine; Female; Heart Rate; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Naloxone; Narcotic Antagonists; Norepinephrine; Opioid Peptides; Stress, Physiological; Stress, Psychological

The levels of dynorphin A-like immunoreactivity (Dyn A-LI) and dynorphin B-like immunoreactivity (Dyn B-LI) were determined in various regions of brain, spinal cord and pituitary gland in spontaneously hypertensive rats (SHRs) as compared with the normotensive Wistar-Kyoto rats (WKYs). SHRs had significantly lower levels of Dyn A-LI and Dyn B-LI in the neurointermediate pituitary lobe and in the hippocampus. Conversely, the levels of Dyn A-LI and Dyn B-LI were higher in the hypothalamus, striatum and periaqueductal gray of the SHRs.

Topics: Animals; Biomarkers; Brain; Dynorphins; Endorphins; Enkephalins; Hypertension; Immunohistochemistry; Lumbosacral Region; Male; Pituitary Gland; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spinal Cord

To compare the expressions of prepropiomelanocortin (POMC) mRNA and preprodynorphin (PPD) mRNA between 16-wk-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY).. The expression of POMC mRNA and PPD mRNA were detected with nonradioactive in situ hybridization by digoxigenin-labeled RNA probe.. POMC mRNA mainly was expressed in arcuate nucleus, compared with WKY, SHR had higher level of POMC mRNA (542). PPD mRNA was found in hippocampus, hypothalamus, central gray, nucleus of the solitary tract (NTS), and thoracic spinal cord (T4-T6). Compared with WKY, PPD mRNA level of SHR decreased in dentate gyrus (2342), NTS (381), and medial preoptic area (467); no difference was observed in arcuate nucleus (263), thoracic spinal cord (750-1800) and CA1, CA2, CA3 of hippocampus (1674, 2014, 2626).. Increase of POMC mRNA in arcuate nucleus and decrease of PPD mRNA in dentate gyrus of SHR may be associated with the genesis of spontaneous hypertension.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain; Dentate Gyrus; Dynorphins; Hypertension; Male; Pro-Opiomelanocortin; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger

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

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.

Topics: Aging; Animals; Blood Pressure; Colchicine; Corticosterone; Dynorphins; Endorphins; Hippocampus; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley

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

To appreciate the role of some neuropeptides in the antihypertensive mechanism of clonidine, 17 patients with essential hypertension were given po clonidine 150 micrograms tid for 3 d. Plasma atrial natriuretic factor (ANF), vasopressin (Vas), and dynorphin A (Dyn A) were measured by radioimmunoassay. After the treatment, mean blood pressure (MBP), heart rate and 24 h urine norepinephrine, epinephrine were decreased, but no change was found in plasma Dyn A. The magnitudes of increased ANF and decreased Vas were correlated with the decreased MBP (r = -0.57 and 0.53, respectively, P < 0.05). These results suggest that both ANF and Vas are involved in the antihypertensive mechanism of clonidine.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Clonidine; Dynorphins; Female; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Vasopressins

The relationship of age-dependent changes in concentrations of various opioid peptides in the brain and pituitary to the development of hypertension was studied in the spontaneously hypertensive rat (SHR). Normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats served as controls. Opioids determined were dynorphin A (1-8) [DN-A(1-8)], beta-endorphin (BE) and Met-enkephalin (ME). Three approaches were used: (1) temporal correlations of opioid concentrations with the onset of hypertension in 4-, 8-, 12- and 16-week-old rats; (2) study of opioid changes when hypertension development was prevented with antihypertensive drugs and (3) determination of possible opioid peptide changes in another rat model of hypertension, the deoxycorticosterone acetate (DOCA) + salt model. Opioid peptide concentration differences (SHR/WKY) found were as follows. There were much lower DN-A(1-8) levels in the SHR hippocampus and hypothalamus at all ages studied. At 12 and 16 weeks, coincidently with the onset of hypertension, lower levels of BE were found in the anterior lobe of the pituitary, but there were higher BE and ME levels found in the neurointermediate lobe (NIL). Prevention of hypertension in SHR by 8 weeks of oral therapy with guanethidine and hydralazine reversed the BE and ME changes in the NIL but not in the anterior lobe. There were no brain or pituitary changes in opioid peptide concentrations associated with DOCA-salt hypertension. The results are interpreted as supporting a role for altered concentrations of brain and pituitary opioids in the genesis of SHR hypertension.

Topics: Aging; Animals; beta-Endorphin; Brain; Desoxycorticosterone; Dynorphins; Endorphins; Enkephalin, Methionine; Guanethidine; Hydralazine; Hypertension; Male; Pituitary Gland; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

Dynorphin receptor binding sites in hippocampal membrane preparations were assessed in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats at 4, 8, 12 and 16 weeks of age. At 4 weeks of age, before hypertension is manifested, SHRs had significantly more hippocampal dynorphin receptor binding sites than WKY controls. At 8, 12 and 16 weeks of age, however, when hypertension is seen, SHRs showed significantly fewer hippocampal binding sites than WKY rats. No receptor affinity changes for dynorphin were seen between the two strains of rats at any age. These results suggest that hippocampal receptor changes involving the opioid system may play a role in the central component of blood pressure control.

Topics: Age Factors; Animals; Binding Sites; Blood Pressure; Dynorphins; Etorphine; Hippocampus; Hypertension; Kinetics; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Opioid

Topics: Adrenal Glands; Age Factors; Animals; Dynorphins; Enkephalin, Leucine; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

In order to investigate the pathophysiological role of heart dynorphin-A (Dyn-A) in genetic hypertension, immunoreactive (ir)-Dyn-A was measured in heart extracts of spontaneously hypertensive rats (SHR) and compared with that of age matched Wistar (WR) and Wistar Kyoto (WKY) rats. Heart ir-Dyn-A contents in 8 week-old WK (84 fmol/g tissue) were not significantly different from those of age matched WKY (109 fmol/g tissue). In control WKY, the levels of ir-Dyn-A did not significantly vary with the age (from 109 to 117 fmol/g) except in 16 week-old animals which displayed a significant increase (238 fmol/g tissue) compared to younger animals. In SHR, the heart content of ir-Dyn-A displayed a 6.5 fold increase at 8 weeks compared to age matched WKY. Older SHR showed a return of their heart ir-Dyn-A content to control (12 week-old) or below control values (16 week-old; 121 compared with 238 fmol/g tissue in WKY). Heart ir-Dyn-A in WKY and SHR eluted as a single peak on mu-Bondapak HPLC, corresponding with the retention time of synthetic Dyn-A. A local function for cardiac ir-Dyn-A is suggested by the presence in heart membrane preparations of a high affinity binding site for the kappa selective opioid ligand, [3H]U-69593, with KD of 6.4 (WKY) and 8.5 (SHR) nM and Bmax of 3.7 (WKY) and 3.6 (SHR) pmol/g protein. The alterations in the levels of cardiac ir-Dyn-A during the development of hypertension in SHR were analyzed in regard with the reported effects of Dyn-related peptides on heart natriuretic and sympathetic functions.

Topics: Animals; Atrial Natriuretic Factor; Chromatography, High Pressure Liquid; Dynorphins; Hypertension; Male; Myocardium; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Opioid

In this study the possible role of hippocampal dynorphin in the development of hypertension in spontaneously hypertensive rats (SHR) was investigated by determining dynorphin A (1-8) (DN A (1-8] levels in hippocampus in 16 week old SRH, Wistar Kyoto (WKY) controls and SHR treated with antihypertensive drugs as well as DOCA-salt hypertensive Sprague Dawley (SD) rats, using radioimmunoassay (RIA). We found that DN A (1-8) was decreased significantly in both dorsal (-68%) and ventral (-58%) hippocampus in SHR compared with WKY rats. Treatment with hydralazine and guanethidine (25 mg/kg/24 hr of each drug in drinking water) for 8 weeks to prevent the development of hypertension in young SHR had no effect on this low hippocampal dynorphin level. We failed to find significant changes in hippocampal DN A (1-8) level in DOCA-salt hypertensive rats. The low level of hippocampal dynorphin existed before the development of hypertension in 6 day neonatal SHR (-73%). Hippocampal Met-enkephalin was unchanged in all experimental groups except for a slight decrease in neonatal SHR. The results establish a genetic difference in the hippocampal dynorphin system of SHR compared with WKY, the significance of which, for the development of hypertension, remains to be investigated.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Desoxycorticosterone; Disease Models, Animal; Dynorphins; Enkephalin, Methionine; Hippocampus; Hypertension; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Sodium Chloride

Dynorphin A (1-8)-like immunoreactivity (DN-LI A(1-8] was determined by radioimmunoassay in the brains of age matched spontaneously hypertensive rats (SHR) and two normotensive control groups consisting of Wistar-Kyoto (WKY) and Sprague-Dawley (SD) strain rats. A significantly lower DN-LI A(1-8) was found in the hippocampus and hypothalamus of the SHR compared with the WKY groups. DN-LI A(1-8) was 24% of control WKY levels in hippocampus and 79% of that in WKY hypothalamus at 16 weeks. Similar lower levels of DN-LI A(1-8) were also observed in SHR at 4, 8, and 12 weeks during the development of hypertension when compared with both WKY and SD groups. We failed to find significant differences in brain stem DN levels between the groups. The relationship between the low hippocampal dynorphin levels in SHR and the hypertension is problematical because the differences were present before (4 wks), during (8 and 12 wks) and after (16 wks) its development.

Topics: Aging; Animals; Brain Chemistry; Dynorphins; Hippocampus; Hypertension; Hypothalamus; Male; Peptide Fragments; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

The concentration of dynorphin (1-8) immunoreactivity [ir-dyn(1-8)] was measured in 10 hypothalamic and 11 brainstem nuclei of Sprague-Dawley (SD) and 6- and 14-week old Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The highest concentrations of ir-dyn(1-8) were found in the lateral preoptic and lateral hypothalamic areas of the hypothalamus and the solitary tract nucleus of the brainstem. Levels of the peptide were low in other brainstem nuclei compared to hypothalamic areas. There was a significant reduction in ir-dyn(1-8) concentrations at 14 weeks of age compared to 6 weeks of age in all 9 nuclei examined in SH and WKY rats. However, there were no differences between the strains at either age. These changes may be related to the increase in blood pressure that occurs in both SH and WKY rats over this age range although other factors must also be involved to produce the higher blood pressure levels of the SH rat.

Topics: Age Factors; Animals; Brain Stem; Dynorphins; Hypertension; Hypothalamus; Male; Peptide Fragments; Preoptic Area; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Tissue Distribution

We determined by radioimmunoassay concentration of dynorphin-(1-13)-like immunoreactivity in the central nervous system and pituitary gland of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). Compared to WKYs, SHRs had significantly lower levels of dynorphin-(1-13)-like immunoreactivity in the hypothalamus and pituitary gland. However, such immunoreactivity in the cerebral cortex, caudate nucleus, diencephalon, brainstem and spinal cord of SHRs and WKYs were similar.

Topics: Animals; Antigens; Central Nervous System; Dynorphins; Endorphins; Hypertension; Male; Peptide Fragments; Pituitary Gland; Radioimmunoassay; Rats