Cardiovascular effects of intrathecally administered endothelins and big endothelin-1 in conscious rats: receptor characterization and mechanism of action.

Abstract

In conscious rats, the intrathecal (i.t.) injection of endothelin-1 (ET-1; 65-650 pmol) and endothelin-3 (ET-3; 162-650 pmol) produced dose-dependent increases of mean arterial blood pressure (MAP) accompanied by either a tachycardia or a bradycardia. A number of animals died by a sudden respiratory arrest. ET-3 was less toxic and less potent than ET-1 on MAP and heart rate (HR) while BQ-3020, a selective ETB agonist, had no toxic effect and exhibited only a weak pressor effect on blood pressure. The prior i.t. injection of 65 nmol BQ-123, a selective ETA receptor antagonist, blocked both the cardiovascular and toxic effects of ET-1 but failed to modify the cardiovascular effect evoked by i.t. substance P (6.5 nmol) or to cause intrinsic cardiovascular and toxic effects. While the pressor response to ET-1 was significantly inhibited after i.v. injection of phentolamine, the bradycardia was blocked by pentolinium. The cardiovascular response to ET-1 was, however, unaffected in rats either sympathectomized with 6-hydroxydopamine or pretreated with capsaicin. Furthermore, big ET-1 (100 pmol) caused toxic effects and delayed cardiovascular changes which were prevented by the prior i.t. administration of either BQ-123 (65 nmol) or 100 nmol phosphoramidon, an endothelin-converting enzyme (ECE) inhibitor. These results suggest: (1) that the cardiovascular and toxic effects of i.t. endothelins are mediated by ETA receptors in the rat spinal cord; (2) that the pressor response and bradycardia are likely due to the activation of the sympatho-adrenal nervous system and to a vagal reflex mechanism, respectively; and (3) that a phosphoramidon-sensitive ECE converts big ET-1 to ET-1 in the rat spinal cord.

• Authors: P Poulat, P D'Orléans-Juste, J de Champlain, M Yano, R Couture
• Journal: Brain research (Brain Res) Vol. 648 Issue 2 Pg. 239-48 (Jun 20 1994) ISSN: 0006-8993 [Print] Netherlands
• PMID: 7522926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin Receptor Antagonists
• Endothelin-1
• Endothelins
• Peptide Fragments
• Peptides, Cyclic
• Protein Precursors
• Receptors, Endothelin
• BQ 3020
• Substance P
• cyclo(Trp-Asp-Pro-Val-Leu)

Topics

• Amino Acid Sequence
• Animals
• Blood Pressure (drug effects)
• Dose-Response Relationship, Drug
• Endothelin Receptor Antagonists
• Endothelin-1
• Endothelins (administration & dosage, pharmacology)
• Heart Rate (drug effects)
• Hemodynamics (drug effects)
• Injections, Spinal
• Male
• Molecular Sequence Data
• Peptide Fragments (pharmacology)
• Peptides, Cyclic (pharmacology)
• Protein Precursors (administration & dosage, pharmacology)
• Rats
• Rats, Wistar
• Receptors, Endothelin (drug effects)
• Substance P (administration & dosage, pharmacology)
• Sympathectomy, Chemical