RPEP-00052 · 1987Dynorphin A accumulated in injured brain regions after fluid-percussion brain injury in cats. These same regions showed significant decreases in cerebral blood flow. Enkephalin did not accumulate.
The opioid antagonist Win-(-), given 15 minutes after injury, significantly improved multiple outcomes: mean arterial blood pressure increased, EEG amplitude (brain wave activity) improved, regional cerebral blood flow recovered, and both the severity and incidence of brain hemorrhage decreased. Survival after injury was significantly better.
The control was elegant: Win-(+), the mirror-image version of the same drug that cannot bind opioid receptors, had no effect. Neither did saline. This confirmed the benefits came specifically from blocking opioid receptors.
McIntosh, T K; Hayes, R L; DeWitt, D S; Agura, V; Faden, A I · Animal Study
RPEP-00064 · 1988After middle cerebral artery occlusion (a stroke model) in rats, the opioid antagonist WIN at doses of 0.4 to 400 micrograms/kg produced several benefits.
All WIN doses significantly increased mean arterial blood pressure compared to saline controls. At the optimal dose of 40 micrograms/kg, rats showed significantly greater EEG (brain wave) recovery and higher neurological scores at 24 hours compared to controls.
Neurological outcome correlated with brain wave recovery on the injured side, confirming the measures tracked together.
However, 24-hour mortality and infarct (dead tissue) size were not significantly different from controls. The drug improved functional recovery without reducing the actual area of brain death.
At 1 hour after stroke, there were no significant changes in dynorphin, enkephalin, or endorphin levels in the injured vs. uninjured brain hemisphere. This was unexpected given the changes seen in trauma models.
Andrews, B T; McIntosh, T K; Gonzales, M F; Weinstein, P R; Faden, A I · Animal Study
RPEP-00065 · 1988Beta-endorphin was 49% higher in the pituitary of hypertensive rats (SHR) but dramatically lower in peripheral organs: 92% lower in heart, 48% lower in adrenals, and 57% lower in kidneys compared to normal rats (WKY). In the brain, beta-endorphin was 71% lower in the striatum of SHR rats.
Dynorphin was 38% lower in the pituitary, 55% lower in the striatum, and 46% lower in the heart of SHR rats, but 33% higher in the hypothalamus.
Met-enkephalin showed the opposite pattern in some areas: 268% higher in adrenals, 40% higher in cortex, and 33% higher in pons/medulla of SHR rats, but 40% lower in the pituitary.
The changes were not uniform. Each opioid peptide had its own distinct pattern of increases and decreases across brain regions and organs.
Bhargava, H N; Matwyshyn, G A; Hanissian, S; Tejwani, G A · Animal Study
RPEP-00068 · 1988Morphine injected into the brain (intracerebroventricular) was 10 times more potent than intravenous morphine at increasing plasma ANP (atrial natriuretic peptide), a hormone released by the heart that lowers blood pressure and promotes sodium excretion.
Leu-enkephalin decreased plasma ANP concentrations, the opposite effect of morphine.
Dynorphin and beta-endorphin (given either into the brain or into the vein) did not change ANP levels at all.
All four opioids increased plasma norepinephrine and epinephrine (stress hormones), but morphine caused increases 10 to 50 times greater than the others.
Ganglionic blockade (cutting the nerve connection from the brain to the heart) significantly reduced morphine's ability to increase ANP, confirming the effect requires an intact autonomic nervous system.
Crum, R L; Brown, M R · Animal Study
RPEP-00070 · 1988The three families of opioid peptides (dynorphins, endorphins, and enkephalins) all have cardiovascular effects. Dynorphins prefer kappa receptors, enkephalins prefer delta and mu receptors, and beta-endorphin prefers mu and delta receptors.
The review focused on mu-opioid receptors in the hypothalamus, a brain region that controls many body functions including blood pressure. While the opioid system's role in normal blood pressure regulation was not well understood, cardiovascular stress clearly activates the opioid system.
The review covered both normal cardiovascular regulation and pathological states like hypertension, hemorrhagic shock, and heart failure, where opioid system changes had been documented.
Feuerstein, G; Sirén, A L · Review
RPEP-00073 · 1988In rabbit ear and saphenous (leg) arteries, both delta-selective opioid agonists (leu-enkephalin and met-enkephalin) and kappa-selective agonists (dynorphin-(1-13) and ethylketocyclazocine) inhibited nerve-stimulation-evoked contractions.
Delta agonists showed a vessel-specific difference: their maximum inhibitory effect was significantly less in the saphenous artery than in the ear artery. Kappa agonists worked similarly in both vessels.
Yohimbine (an alpha-2 adrenergic blocker) did not enhance opioid inhibitory effects at any stimulation frequency in either vessel. This disproved the hypothesis that opioid receptors work by boosting alpha-2 receptor inhibition of noradrenaline release.
Gan, E A; Duckles, S P · In Vitro
RPEP-00125 · 198942% of enkephalin terminal targets in the blood pressure control region were catecholamine neurons. Some neurons co-contained both enkephalin and tyrosine hydroxylase.
Milner, T A; Pickel, V M; Reis, D J · Animal Study
RPEP-00140 · 1989Alpha-methyldopa's hypotensive effect requires opioid receptor activation in the NTS, specifically through beta-endorphin and not through enkephalins or dynorphin.
Van Giersbergen, P L; Roording, P; de Lang, H; de Jong, W · Animal Study
RPEP-00141 · 1989Both beta-endorphin(1-31) and dynorphin(1-13), but not met-enkephalin, mediate alpha-methyldopa's central hypotensive effect. The opioid peptides must be released early in the drug's mechanism.
van Giersbergen, P L; Wiegant, V M; de Jong, W · Animal Study
RPEP-00142 · 1989Clonidine's central hypotensive mechanism involves beta-endorphin and dynorphin only in spontaneously hypertensive rats, not in normotensive Wistar-Kyoto rats.
van Giersbergen, P L; Tierney, S A; Wiegant, V M; de Jong, W · Animal Study
RPEP-00144 · 1989All three opioid peptide families selectively blocked the exercise pressor reflex (ergoreceptor) without affecting the baroreceptor reflex, suggesting a specific opioid-catecholamine pathway for exercise blood pressure responses.
Williams, C A · Animal Study
RPEP-00145 · 1990Opioid peptides have differential effects on neonatal cerebral vasculature: enkephalins dilate, beta-endorphin constricts, and dynorphin switches depending on blood pressure status. All effects are prostaglandin-dependent.
Armstead, W M; Mirro, R; Busija, D W; Leffler, C W · Animal Study
RPEP-00174 · 1990Spinal dynorphin A raises blood pressure through kappa opioid receptors independently from vasopressin. Chain length of at least 13 amino acids is required for the cardiovascular effect.
Thornhill, J A; Pittman, Q J · Animal Study
RPEP-00182 · 1991Hemorrhagic hypotension raised brain fluid opioid levels and caused pial artery dilation in newborn pigs. Blood pressure dropped from 63 to 33 mmHg.
Armstead, W M; Mirro, R; Busija, D W; Desiderio, D M; Leffler, C W · Animal Study
RPEP-00192 · 1991Naloxone injection into the caudal ventrolateral medulla caused dose-dependent blood pressure drops. Delta and kappa receptor antagonists reproduced this effect; mu antagonist did not.
Drolet, G; Morilak, D A; Chalmers, J · Animal Study
RPEP-00216 · 1991Central and peripheral naloxone increased bleeding volumes before pressure dropped. Brain antibodies against beta-endorphin, alpha-endorphin, and dynorphin A also improved hemorrhage tolerance.
van den Berg, M H; van Giersbergen, P L; Cox-van Put, J; de Jong, W · Animal Study
RPEP-00217 · 1991Full beta-endorphin caused naltrexone-reversible hypotension and bradycardia. N-terminally modified fragments were inactive. Beta-endorphin(1-27) induced both hypertensive and hypotensive responses.
van Giersbergen, P L; de Lang, H; de Jong, W · Animal Study
RPEP-00222 · 1992Topical dynorphin(1-13) dilated pial arteries during normotension but constricted them during hypotension. It increased CSF vasopressin concentration in both states.
Armstead, W M; Crofton, J T; Share, L; Mirro, R; Zuckerman, S L; Leffler, C W · Animal Study
RPEP-00223 · 1992Transient plasma beta-endorphin elevation in painful AMI (Group II, n=16) that normalized when pain ceased. No changes in painless AMI (Group I, n=12). Met-enkephalin and dynorphin unchanged in both.
Bernardi, P; Fontana, F; Pich, E M; Spampinato, S; Canossa, M · Cross Sectional
RPEP-00241 · 1992SHR rats had distinct age-dependent opioid peptide profiles in brain regions linked to blood pressure control. Antihypertensive drugs partially normalized these changes.
Li, S J; Wong, S C; Hong, J S; Ingenito, A J · Animal Study
RPEP-00247 · 1992NEP inhibitor SQ 28,603 markedly potentiated BNP-32 responses in SHR and monkeys. BNP was more resistant to NEP degradation than ANP. Cyclic GMP responses also potentiated.
Seymour, A A; Asaad, M M; Abboa-Offei, B E; Rovnyak, P L; Fennell, S; Rogers, W L · Animal Study
RPEP-00262 · 1993Rat heart has a non-opioid dynorphin A(1-13) binding site: Kd 285 nM, Bmax 215 pmol/mg protein. Trypsin-sensitive. Inhibited by Zn2+ and Mg2+. Standard opioid ligands do not compete.
Dumont, M; Lemaire, S · In Vitro
RPEP-00263 · 1993ANF, beta-endorphin, met-enkephalin, dynorphin, and noradrenaline were all elevated in acute CHF. Higher levels correlated with greater severity.
Fontana, F; Bernardi, P; Pich, E M; Capelli, M; Bortoluzzi, L; Spampinato, S; Canossa, M · Cross Sectional
RPEP-00283 · 1993Leu-enkephalin at 0.2 micromolar increased spontaneous beating rate in SHR atria but not in normal rat atria, across ages 4 to 16 weeks.
Wong, S C; Ingenito, A J · Animal Study
RPEP-00290 · 1994Normotensive offspring of hypertensive parents showed altered opioid-ANF interactions during exercise, suggesting early neurohumoral changes before hypertension onset.
Fontana, F; Bernardi, P; Merlo Pich, E; Boschi, S; De Iasio, R; Capelli, M; Carboni, L; Spampinato, S · Cross Sectional
RPEP-00291 · 1994Orally active dual ACE/NEP inhibitors lowered blood pressure in hypertensive rats through combined angiotensin blockade and natriuretic peptide protection.
Fournié-Zaluski, M C; Coric, P; Turcaud, S; Rousselet, N; Gonzalez, W; Barbe, B; Pham, I; Jullian, N; Michel, J B; Roques, B P · Animal Study
RPEP-00341 · 1995SQ 28603 potentiated both ANP effects in monkeys (increased plasma ANP, sodium excretion) and BNP effects in hypertensive rats (blood pressure lowering, renal responses).
Seymour, A A; Abboa-Offei, B E; Smith, P L; Mathers, P D; Asaad, M M; Rogers, W L · Animal Study
RPEP-00346 · 1995Phorbol ester induced a concentration- and time-dependent increase in prodynorphin mRNA in cardiac myocytes, peaking at 4 hours and mediated through protein kinase C.
Ventura, C; Pintus, G; Vaona, I; Bennardini, F; Pinna, G; Tadolini, B · In Vitro
RPEP-00355 · 1996Endogenous opioid peptides in cerebral perivascular nerves and CSF actively regulate cerebral blood flow through opiate receptors, with concentrations changing in response to perfusion pressure and oxygen tension.
Benyó, Z; Wahl, M · Review
RPEP-00361 · 1996ANP, BNP, and cGMP were compared as screening markers for asymptomatic and symptomatic left ventricular dysfunction, with potential utility for early detection.
Friedl, W; Mair, J; Thomas, S; Pichler, M; Puschendorf, B · Cross Sectional
RPEP-00364 · 1996Plasma adrenomedullin concentrations were extremely elevated in septic ICU patients compared to healthy controls, correlating with disease severity.
Hirata, Y; Mitaka, C; Sato, K; Nagura, T; Tsunoda, Y; Amaha, K; Marumo, F · Cross Sectional
RPEP-00372 · 1996NPY mediates analgesia and hyperalgesia through distinct receptor subtypes, alongside established roles in blood pressure regulation and anxiety modulation.
Munglani, R; Hudspith, M J; Hunt, S P · Review
RPEP-00374 · 1996Mu, delta, and kappa opioid receptors in cardiac sarcolemma activate pertussis toxin-sensitive G proteins and inhibit adenylyl cyclase, confirming a complete opioid signaling pathway in the heart.
Niroomand, F; Mura, R A; Piacentini, L; Kübler, W · In Vitro
RPEP-00375 · 1996Plasma BNP may increase proportionally more than ANP after acute myocardial infarction and chronic heart failure, potentially offering superior diagnostic and prognostic value.
Omland, T; Aakvaag, A; Bonarjee, V V; Caidahl, K; Lie, R T; Nilsen, D W; Sundsfjord, J A; Dickstein, K · Cohort
RPEP-00388 · 1996Approximately 40% of cardiac ganglion cells contained dynorphin A immunoreactivity, and opioid peptides were found in parasympathetic, sympathetic, and sensory cardiac nerves.
Steele, P A; Aromataris, E C; Riederer, B M · Animal Study
RPEP-00392 · 1996NEP inhibition with thiorphan significantly potentiated the blood pressure-lowering, hormonal, and renal effects of all three natriuretic peptides (ANP, BNP, CNP) in hypertensive transgenic rats.
Wegner, M; Ganten, D; Stasch, J P · Animal Study
RPEP-00393 · 1996NEP activity is increased in volume-overload heart failure, potentially accelerating the breakdown of protective natriuretic peptides even as the heart produces more of them.
Wegner, M; Hirth-Dietrich, C; Stasch, J P · Animal Study
RPEP-00396 · 1996BNP was superior to both C-terminal ANP and N-terminal ANP for detecting left ventricular systolic dysfunction, diastolic dysfunction, and ventricular hypertrophy.
Yamamoto, K; Burnett, J C; Jougasaki, M; Nishimura, R A; Bailey, K R; Saito, Y; Nakao, K; Redfield, M M · Cross Sectional
RPEP-00403 · 1997Simultaneous comparison of six peptide biomarkers in heart failure patients identified the best early CHF indicators across NYHA classes I through IV.
Daggubati, S; Parks, J R; Overton, R M; Cintron, G; Schocken, D D; Vesely, D L · Cross Sectional
RPEP-00407 · 1997Low blood pressure responders to mental stress had significantly higher beta-endorphin release than high responders, suggesting endogenous opioids buffer the cardiovascular stress response.
Fontana, F; Bernardi, P; Pich, E M; Boschi, S; De Iasio, R; Spampinato, S; Grossi, G · Clinical Trial
RPEP-00408 · 1997Beta-endorphin, met-enkephalin, and dynorphin B levels changed significantly during acute blood pressure increases in hypertensive patients, alongside ANF and endothelin-1 alterations.
Fontana, F; Bernardi, P; Spampinato, S; Boschi, S; De Iasio, R; Grossi, G · Clinical Trial
RPEP-00421 · 1997Endurance training and hypobaric hypoxia independently and combinedly alter ANP and BNP gene expression in rat atrial and ventricular tissue.
Perhonen, M; Takala, T E; Vuolteenaho, O; Mäntymaa, P; Leppäluoto, J; Ruskoaho, H · Animal Study
RPEP-00431 · 1997BPC-157 counteracted both L-NAME (NO blocker) and L-arginine (NO donor) effects on gastric mucosa and blood pressure, confirming its role as an NO system modulator.
Sikirić, P; Seiwerth, S; Grabarević, Z; Rucman, R; Petek, M; Jagić, V; Turković, B; Rotkvić, I; Mise, S; Zoricić, I; Konjevoda, P; Perović, D; Jurina, L; Separović, J; Hanzevacki, M; Artuković, B; Bratulić, M; Tisljar, M; Gjurasin, M; Miklić, P; Stancić-Rokotov, D; Slobodnjak, Z; Jelovac, N; Marović, A · Animal Study
RPEP-00432 · 1997Spontaneously hypertensive rats had significantly lower dynorphin A and B levels in the hypothalamus and pituitary compared to normotensive rats.
Tan-No, K; Terenius, L; Silberring, J; Nylander, I · Animal Study
RPEP-00435 · 1997Plasma BNP concentration provided superior prognostic value compared to plasma ANP and other established variables in chronic symptomatic left ventricular dysfunction.
Tsutamoto, T; Wada, A; Maeda, K; Hisanaga, T; Maeda, Y; Fukai, D; Ohnishi, M; Sugimoto, Y; Kinoshita, M · Cohort
RPEP-00438 · 1997Dynorphin B induces dose-dependent autocrine stimulation of its own gene expression in cardiac myocytes, creating a self-amplifying loop that is exaggerated in cardiomyopathy.
Ventura, C; Pintus, G · In Vitro
RPEP-00454 · 1998BNP showed prolonged stability at room temperature in blood samples, significantly outlasting ANP stability, making BNP the preferred clinical biomarker for cardiac function assessment.
Buckley, M G; Marcus, N J; Yacoub, M H; Singer, D R · In Vitro
RPEP-00459 · 1998NYHA class III heart failure patients had elevated resting beta-endorphin and neurohormone levels, with naloxone-modifiable stress responses, confirming active opioid system involvement in cardiovascular stress regulation.
Fontana, F; Bernardi, P; Pich, E M; Boschi, S; De Iasio, R; Spampinato, S · Clinical Trial
RPEP-00460 · 1998Asymptomatic dilated cardiomyopathy patients had normal resting opioid peptide levels but showed altered opioid peptide responses to mental stress, alongside elevated ANF levels.
Fontana, F; Bernardi, P; Merlo Pich, E; Tartuferi, L; Boschi, S; De Iasio, R; Spampinato, S · Clinical Trial
RPEP-00471 · 1998BNP showed the most dramatic increase in ventricular tissue during heart failure progression and correlated most strongly with cardiac dysfunction severity, supporting its use as a heart failure biomarker.
Klinge, R; Hystad, M; Kjekshus, J; Karlberg, B E; Djøseland, O; Aakvaag, A; Hall, C · Animal Study