dynorphins and Hypotension

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

The endogenous opioid peptide (EOP) dynorphin and opioid receptors have been found in the heart. This opioid system plays important roles in cardiovascular regulation and is involved in the pathophysiology of shock, heart failure and myocardial ischaemia. The aim of this study was to evaluate whether the EOP dynorphin modulates or potentiates ischaemia-induced arrhythmias and whether its effects are prevented by the opiate antagonist naloxone. Following coronary artery occlusion, all rats in the control group developed ischaemia-induced arrhythmias, bradycardia and hypotension, which were significantly potentiated by pre-treatment with dynorphin and attenuated by treatment with naloxone. The results clearly indicate that EOPs may be released when myocardial ischaemia occurs, thus causing arrhythmias, bradycardia and hypotension. Dynorphin and naloxone, by virtue of their opioid agonistic and antagonistic actions, respectively, potentiate and attenuate these fatal complications secondary to myocardial ischaemia. This suggests that EOPs play an important part in ischaemic heart disease.

Topics: Animals; Arrhythmias, Cardiac; Bradycardia; Dynorphins; Female; Heart Conduction System; Hypotension; Male; Myocardial Ischemia; Naloxone; Rats; Rats, Sprague-Dawley; Shock, Cardiogenic

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

Intravenous injection of dynorphin A-(1-10) amide (Dyn, 81-324 nmol/kg) induced a dose-dependent hypotensive effect in the rat. This effect was antagonized by pretreatment with immunoglobulin G, purified from a specific antiserum raised against alpha-human atrial natriuretic peptide (anti-hANP-IgG), as well as by high doses of naloxone (2 or 10 mg/kg). In addition, a 12-fold increase in plasma level of atrial natriuretic peptide-like immunoreactivity (ANP-IR) was found following Dyn administration, which was accompanied by a significant decrease of atrial ANP-IR. These results suggest that the stimulated release of ANP-IR from the atrium may constitute one of the mechanisms for the depressor effect of dynorphin peptides.

Topics: Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Dynorphins; Heart Atria; Hypotension; Immunoglobulin G; Male; Myocardium; Peptide Fragments; Rats; Rats, Inbred Strains; Time Factors