Pharmacological characterization of the inhibitory effect of (R)-alpha-methylhistamine on sympathetic cardiopressor responses in the pithed guinea-pig.
1. The effect of (R)-alpha-methylhistamine (R-alpha-mHA), a selective histamine H3-receptor agonist, on increases in blood pressure and heart rate mediated by activation of the sympathetic nervous system induced by electrical stimulation of the spinal cord, was characterized in the vagotomized, pithed guinea-pig. 2. The frequency-dependent nature of (R)-alpha-mHA's effect on sympathetic cardiopressor responses was studied at frequencies between 1 and 20 Hz. (R)-alpha-mHA (10-100 micrograms kg-1, i.v.) produced a dose-dependent inhibition of the stimulated increase in both blood pressure (BP) and heart rate (HR). The inhibition was inversely related to frequency and maximum inhibition (BP, 61% at 1 Hz; HR, 50% at 1 Hz) was seen with 100 micrograms kg-1 of (R)-alpha-mHA. Treatment with the H3 receptor inactive stereoisomer, (S)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not inhibit the neurogenic sympathetic cardiopressor responses. 3. Pretreatment with thioperamide (1 mg kg-1, i.v.), a histamine H3 receptor antagonist, blocked (R)-alpha-mHA's inhibitory effect on stimulation-induced sympathetic cardiopressor responses. 4. Combined pretreatment with the H2-receptor antagonist cimetidine (3 mg kg-1, i.v.) and the H1-receptor antagonist chlorpheniramine (0.3 mg kg-1, i.v.) did not attenuate (R)-alpha-mHA's inhibitory effects. 5. (R)-alpha-mHA (100 micrograms kg-1) had no effect on the hypertensive or tachycardia effects induced by adrenaline (1 and 3 micrograms kg-1, i.v.). 6. Treatment with a combination of prazosin (1 mg kg-1, i.v.) and yohimbine (1.5 mg kg-1, i.v.) to block alpha 1- and alpha 2-adrenoceptors, abolished the sympathetic hypertension without affecting the inhibition of sympathetic tachycardia induced by (R)-alpha-mHA. Conversely, pretreatment with the beta-adrenoceptor antagonist propranolol (1 mg kg-1, i.v.), which blocked the sympathetic tachycardia, did not block (R)-alpha-mHA's inhibition of sympathetic hypertensive responses. 7. In adrenalectomized guinea-pigs, (R)-alpha-mHA (100 micrograms kg-1, i.v.) also produced a frequency-dependent inhibition of sympathetic hypertensive cardiopressor responses that was not significantly different from intact animals. 8. These results demonstrate that (R)-alpha-mHA produces a frequency-dependent inhibition of the cardiopressor responses due to activation of the sympathetic innervation to the resistance vessels and the heart.(ABSTRACT TRUNCATED AT 400 WORDS)
Hutchison
R W
RW
Schering-Plough Research Institute, Kenilworth, NJ 07033-9539.
Hey
J A
JA
D000315:Adrenalectomy; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002744:Chlorpheniramine / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D004837:Epinephrine / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000294:innervation; D006339:Heart Rate / Q000187:drug effects*; D017442:Histamine Agonists / Q000494:pharmacology*; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D013116:Spinal Cord / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014628:Vagotomy; D015016:Yohimbine / Q000494:pharmacology
D017442:Histamine Agonists; D008761:Methylhistamines; D010880:Piperidines; D015016:Yohimbine; D002744:Chlorpheniramine; C069357:alpha-methylhistamine; D002927:Cimetidine; C052075:thioperamide; D011224:Prazosin; D004837:Epinephrine