Effects of the selective beta 1-adrenoceptor antagonist, nebivolol, on cardiovascular parameters in the pithed normotensive rat.
In the pithed rat we investigated the cardiovascular properties of d,l-nebivolol and its enantiomers. We used the increase in heart rate elicited by (-)-adrenaline and (-)-noradrenaline as a model for studying beta 1-adrenoceptors. A leftward shift of the logarithmic dose-pressor response curve of (-)-adrenaline reflects beta 2-adrenoceptor-blocking properties. The blood pressure responses of methoxamine, B-HT 920 and serotonin (5-HT) were studied in order to test whether d,l-nebivolol has alpha 1-, alpha 2- and 5-HT2-receptor-blocking properties. Furthermore, the interaction of d,l-nebivolol with the peripheral sympathetic neurotransmission was investigated in pithed rats by electrical stimulation of the spinal cord. d,l-Nebivolol and d-nebivolol (threshold concentration 10(-8) mol/kg) were demonstrated to be selective beta 1-adrenoceptor antagonists. l-Nebivolol was a factor of 1,000 less potent as beta 1-adrenoceptor blocker. Up to a dose of 10(-5) mol/kg, d,l-nebivolol appeared to have neither alpha 1-, alpha 2-, beta 2-, 5-HT2-, angiotensin II-receptor antagonistic, calcium entry blocking, converting enzyme inhibiting nor direct vasodilating properties and did not interact with the sympathetic neurotransmission in the vascular wall. An explanation for an antihypertensive effect independent of beta-adrenoceptor blockade as found in spontaneously hypertensive rats and man could not be found in this model, therefore we suggest that this blood-pressure-lowering effect does not originate from conventional peripheral mechanisms.
Schneider
J
J
Janssen Research Foundation, Neuss, FRG.
Fruh
C
C
Wilffert
B
B
Peters
T
T
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D008729:Methoxamine / Q000008:administration & dosage / Q000494:pharmacology; D000068577:Nebivolol; D009638:Norepinephrine / Q000494:pharmacology; D011292:Premedication; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D013116:Spinal Cord / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D001381:Azepines; D001578:Benzopyrans; D004983:Ethanolamines; D011985:Receptors, Serotonin; D000068577:Nebivolol; D012701:Serotonin; C024763:talipexole; D008729:Methoxamine; D009638:Norepinephrine; D004837:Epinephrine