dynorphins and Hemorrhage

Opioid receptors are activated during severe hemorrhage, resulting in sympathoinhibition and a profound fall in blood pressure. This study examined the location and subtypes of opioid receptors that might contribute to hypotension after hemorrhage. Intrathecal naloxone methiodide (100 nmol) abolished the fall in blood pressure after hemorrhage (1.5% of body wt; mean arterial pressure 122 +/- 8 mmHg after naloxone methiodide vs. 46 +/- 5 mmHg in controls, P < 0. 001). Intracisternal naloxone methiodide was less effective than intrathecal naloxone methiodide, whereas intravenous naloxone methiodide, which does not cross the blood-brain barrier, did not alter the fall in blood pressure after hemorrhage. These results demonstrate that spinal opioid receptors contribute to hypotension after hemorrhage but do not exclude supraspinal effects. In separate experiments, the subtype-specific opioid antagonists ICI-174864 (delta-antagonist), norbinaltorphimine (nor-BNI; kappa-antagonist), and H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; mu-antagonist) were each administered intrathecally to determine the minimum dose that would attenuate hypotension during severe hemorrhage. These antagonists were effective at similar doses (3 nmol for CTOP, 6 nmol for ICI-174864, and 10 nmol for nor-BNI), although the binding affinities of these three different agents for their target receptors varied >1600-fold. Comparisons of the minimum effective doses of these antagonists in relation to their binding affinities provides strong evidence for the participation of delta-receptors in mediating hypotension after hemorrhage. In contrast, the dose at which nor-BNI was effective suggests an effect at delta-receptors but not kappa-receptors. The efficacy of CTOP, albeit at a high dose, also suggests an effect at mu-receptors.

Topics: Animals; Blood Pressure; Consciousness; Dynorphins; Endorphins; Enkephalin, Leucine; Heart Rate; Hemorrhage; Hypotension; Male; Naloxone; Narcotic Antagonists; Neural Inhibition; Rats; Rats, Inbred WKY; Receptors, Opioid, kappa; Receptors, Opioid, mu; Somatostatin; Spinal Cord; Sympathetic Nervous System

We studied the effect of dynorphin A-(1-13), dynorphin A-(1-17), des-tyr dynorphin A-(2-17) (inactive at opioid receptor) or normal saline (NS) microinjected into the paraventricular nucleus (PVN) (n = 9/treatment) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), and left ventricular stroke work (LVSW) during fixed-volume hemorrhage in conscious rats. Microinjection of dynorphin A-(1-13) (6 nmol) into PVN at 15 min following the termination of fixed volume hemorrhage (8 ml/300 g) significantly decreased MAP from 50 min to 2 hr postinjection (P < 0.05 compared to animals receiving NS), while dynorphin A-(1-17) (6 nmol) significantly decreased MAP from 30 min up to 2 hr postinjection (P < 0.05). Microinjection of des-tyr dynorphin A-(2-17) (6 nmol) into the PVN did not significantly affect MAP following hemorrhage. Recovery of MAP in the dynorphin A-(1-13) and dynorphin A-(1-17) groups following hemorrhage was found to be significantly attenuated compared to the NS group (P < 0.05 and P < 0.01, respectively). Dynorphin A-(1-13) increased heart rate at 20 min and decreased stroke volume at 60 min after microinjection directly into the PVN following hemorrhage when compared with the NS group (P < 0.05). Both dynorphin A-(1-13) and dynorphin A-(1-17) significantly decreased LVSW after PVN injection following hemorrhage compared to NS group (both P < 0.05). No significant effects were observed on CO following microinjection of active or inactive opioid peptides into the PVN following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cardiovascular System; Dynorphins; Hemodynamics; Hemorrhage; Male; Microinjections; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Sprague-Dawley; Reference Values

The region surrounding the anteroventral part of the third ventricle (AV3V) is important for the regulation of cardiovascular homeostasis. In the present study we investigated the effect of the kappa-opioid receptor agonists dynorphin A-(1-17) and dynorphin A-(1-13) microinjected into the AV3V region on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), and left ventricular stroke work (LVSW) during fixed-volume hemorrhage in conscious rats. During fixed-volume hemorrhage (8 ml/300 g), dynorphin A-(1-17) (6 nmol), microinjected into the AV3V, significantly decreased MAP up to 30 min postinjection (P < 0.05). Recovery of MAP, SV, and LVSW in the dynorphin A-(1-17) group following hemorrhage was found to be significantly attenuated compared to that in animals receiving microinjection of normal saline (NS) vehicle into the AV3V (P < 0.05). Hypothalamic microinjection of dynorphin A-(1-13) (6 nmol) also attenuated the recovery of SV following hemorrhage compared with the NS group (P < 0.05). No significant effects were observed on HR or CO following microinjection of dynorphin into the AV3V region. The results of this study suggest that activation of the kappa-opiate receptor system in the AV3V region of the hypothalamus can attenuate the compensatory cardiovascular responses to hemorrhage.

Topics: Animals; Blood Pressure; Cardiac Output; Dynorphins; Heart Rate; Hemodynamics; Hemorrhage; Hypothalamus; Male; Microinjections; Rats; Rats, Sprague-Dawley; Stroke Volume

This study was designed to determine if opioids were detectable in cerebrospinal fluid (CSF) and if these concentrations were altered by hemorrhagic hypotension. This study was further designed to determine the effects of topically administered opioids on pial arteriolar diameter during normotension and hypotension. Closed cranial windows were used to determine pial arteriolar diameter. Periarachnoid cortical and cisterna magna CSF was collected from piglets during normotension and hypotension (systemic arterial pressure decreased from 63 +/- 1 to 33 +/- 1 mm Hg). Opioid profiles were assessed qualitatively by radioreceptor assay, and individual opioids were measured quantitatively by radioimmunoassay. Periarachnoid cortical and cisterna magna CSF methionine enkephalin-, leucine enkephalin-, dynorphin-, and beta-endorphin-like receptor active values all were increased by hypotension. When quantified by radioimmunoassay, periarachnoid cortical CSF values for methionine enkephalin-like immunoreactivity were 1,167 +/- 58 and 2,975 +/- 139 pg/ml for normotension and hypotension, respectively. Periarachnoid cortical CSF radioimmunoassay values for dynorphin-like immunoreactivity were 15 +/- 2 and 28 +/- 2 pg/ml for normotension and hypotension, respectively. When applied topically to the cortical surface, synthetic methionine enkephalin increased pial arteriolar diameter (134 +/- 4, 158 +/- 4, and 163 +/- 4 microns for control, 574 pg/ml [10(-10) M], and 5,740 pg/ml [10(-9) M], respectively). Similarly, topical synthetic leucine enkephalin and dynorphin elicited pial arteriolar dilation. However, beta-endorphin produced arteriolar constriction. Hypotension attenuated methionine and leucine enkephalin-induced dilation and reversed dynorphin-induced dilation to concentration-dependent constriction. beta-Endorphin-induced constriction was not changed by hypotension. Therefore, opioids could contribute to the control of the cerebral circulation during hypotension.

Topics: Animals; Animals, Newborn; beta-Endorphin; Cerebral Arteries; Dynorphins; Endorphins; Enkephalin, Leucine; Enkephalin, Methionine; Hemorrhage; Hypotension; Muscle, Smooth, Vascular; Radioimmunoassay; Radioligand Assay; Reference Values; Swine; Vasodilation

In the present study, the role of the endogenous opioid peptide systems in the regulation of blood pressure during standardized, stepwise hemorrhagic hypotension was investigated in anesthetized rats. Central as well as peripheral administration of naloxone resulted in an increase in the bleeding volumes required to reduce blood pressure. Bleeding volumes also increased after the peripheral injection of naloxone methobromide, an analog of naloxone that does not readily cross the blood-brain barrier. Following central administration of antisera against beta- and alpha-endorphin and dynorphin A(1-13), the amount of blood that had to be withdrawn to induce hypotension was elevated. In rats treated with an antiserum against [Met5] enkephalin or gamma-endorphin, bleeding volumes did not differ from those of rats treated with control serum. These data indicate that activation of central and possibly also of peripheral opiate receptors plays a role in the control of blood pressure during blood loss. Dynorphin A(1-13), beta- and alpha-endorphin, or closely related peptides might be the endogenous ligands for the receptors that are blocked by naloxone.

Topics: alpha-Endorphin; Animals; beta-Endorphin; Blood Pressure; Dynorphins; Endorphins; Enkephalin, Methionine; gamma-Endorphin; Hemorrhage; Hypotension; Immunization, Passive; Male; Naloxone; Oxymorphone; Peptide Fragments; Rats; Rats, Inbred Strains

Topics: Animals; Arginine Vasopressin; Blood Pressure; Dynorphins; Enkephalin, Leucine; Heart Rate; Hematocrit; Hemorrhage; Hypothalamo-Hypophyseal System; Pituitary Gland, Anterior; Rats; Shock, Hemorrhagic; Supraoptic Nucleus