Flavodilol: a new antihypertensive agent.
Flavodilol, a new antihypertensive drug, was evaluated in a variety of test systems for better understanding of its biologic properties and the nature of its mechanism of action. Oral administration of the drug to spontaneously hypertensive rats (SHR) lowered arterial blood pressure (ABP) in a dose-related manner, and doses greater than 35 mg/kg increased duration but not magnitude of the response. In contrast, oral administration of flavodilol to normotensive rats did not significantly alter ABP at 35 mg/kg, although larger doses of 75 or 150 mg/kg significantly lowered ABP. In rats with DOCA/salt hypertension, flavodilol effectively lowered ABP to a degree similar to that observed in SHR. At antihypertensive doses, flavodilol did not alter blood pressure responses to a 90 degrees head-up tilt in SHR and did not influence cardiac output in conscious SHR. In addition, flavodilol did not appear to manifest its antihypertensive activity through an interaction with beta-adrenoceptors, dopamine (DA) receptors or prostaglandin synthetase. Daily oral administration of flavodilol to SHR for 4 days resulted in augmented vasopressor responses to exogenously administered epinephrine (EPI) or norepinephrine (NE) and attenuated responses to exogenously administered tyramine. In addition, flavodilol treatment attenuated in a dose-related manner ABP and heart rate (HR) responses of pithed SHR to electrical stimulation of sympathetic nerves. We conclude that flavodilol is an effective antihypertensive drug which decreases the release of NE from postganglionic sympathetic nerves, resulting in attenuation of peripheral noradrenergic function.
Kinsolving
C R
CR
Department of Pharmacology, Pharmaceutical Division of the Pennwalt Corporation, Rochester, New York 14623.
Watkins
B E
BE
Borrelli
A R
AR
Kaiser
F C
FC
Wu
E S
ES
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001341:Autonomic Nervous System / Q000187:drug effects; D001679:Biogenic Amines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013116:Spinal Cord / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001679:Biogenic Amines; D005419:Flavonoids; D013469:Sulpiride; C058114:flavodilol; D007213:Indomethacin