methylnaltrexone and Hypertension

Topics: Abdominal Pain; Adult; Analgesics, Opioid; Anorexia; Chronic Disease; Diabetes Mellitus, Type 1; Drug Administration Schedule; Endoscopy, Gastrointestinal; Gastroparesis; Humans; Hypertension; Kidney Failure, Chronic; Male; Naltrexone; Narcotic Antagonists; Nausea; Neuralgia; Quaternary Ammonium Compounds; Substance Withdrawal Syndrome; Treatment Outcome; Vomiting

Endogenous opioid peptides have been implicated in the regulation of cardiovascular and renal function. We tested this hypothesis by examining whether the opioid antagonist naloxone alters the cardiovascular or renal responses produced by environmental stress (air stress) in conscious spontaneously hypertensive rats (SHR). Before naloxone administration, air stress produced significant increases in heart rate, mean arterial pressure, and renal sympathetic nerve activity, and it caused a decrease in urinary sodium excretion. After intravenous and intracerebroventricular administration of naloxone, the air stress-induced pressor and antinatriuretic responses were inhibited. Subsequent studies with a different opioid antagonist, the quaternary compound naltrexone methylbromide, also showed inhibition of the air stress-induced pressor and antinatriuretic responses and demonstrated opioid receptor specificity of this inhibition. Furthermore, since only intracerebroventricular and not intravenous administration of naltrexone methylbromide inhibited the pressor and antinatriuretic responses to air stress, a central nervous system site of action was established. The opioid antagonists caused inhibition of the pressor and antinatriuretic responses to air stress without affecting the air stress-induced increase in renal sympathetic nerve activity. Our investigations indicate that central endogenous opioid peptides contribute to the pressor and antinatriuretic responses that occur in conscious SHR during acute environmental stress.

Topics: Animals; Blood Pressure; Consciousness; Endorphins; Hemodynamics; Hypertension; Kidney; Male; Naloxone; Naltrexone; Narcotic Antagonists; Natriuresis; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Stress, Physiological

Intravenous naloxone or naltrexone produced transient, dose-related reductions in the mean arterial pressure (MAP) and heart rate (HR) of urethane-anesthetized spontaneously hypertensive rats (SHRs). Yet these same doses of narcotic antagonists reduced HR but not MAP of normotensive Wistar-Kyoto rats (WKYs). Such effects were not observed upon administration to SHRs of increasing doses of methylnaltrexone, which possesses no central activity. (+)-Naloxone, which does not block opiate receptors, reduced HR but not MAP of both SHRs and WKYs. These findings indicate that SHRs and WKYs differ in their MAP and HR responses to narcotic antagonists. The high doses required for effect plus the brevity of the responses suggest that these drug effects are perhaps not mu-opiate receptor-mediated; however, the methylnaltrexone and (+)-naloxone findings clearly implicate a central specificity of action. We conclude that narcotic antagonist-induced changes in MAP and HR in SHRs are possibly specific and central in origin yet not mediated by mu-opiate receptors.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Male; Naloxone; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stereoisomerism

Topics: Adrenalectomy; Animals; Clonidine; Endorphins; Humans; Hypertension; Male; Naloxone; Naltrexone; Psychophysiologic Disorders; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Social Isolation