Structurally novel antihypertensive compound, McN-5691, is a calcium channel blocker in vascular smooth muscle.
These studies were conducted to gain greater understanding of the mechanism of action of the chemically novel antihypertensive agent, McN-5691. McN-5691 (1 and 10 microM) prevented 60 mM KCl-induced contraction and calcium uptake and caused concentration-dependent relaxation (EC50 = 190 microM) of 30 mM KCl-contracted aortic rings. At or below 10 microM, McN-5691 had no effects on basal tone or calcium uptake (45Ca) in isolated rings of rabbit thoracic aorta. McN-5691 caused complete high affinity inhibition (Kd = 39.5 nM) of specific diltiazem binding to the benzothiazepine receptor on the voltage-sensitive calcium channel in skeletal muscle microsomal membranes. In contrast to diltiazem, McN-5691 inhibited specific dihydropyridine receptor binding, but the effect was biphasic with high (Kd = 4.7 nM) and low (Kd = 919.8 nM) affinity components. These findings suggest that McN-5691 is a voltage-sensitive calcium channel blocker. Unlike other calcium channel blockers, McN-5691 inhibited norepinephrine (NE)-induced contraction (10 microM) and calcium uptake (1 and 10 microM) and caused concentration-dependent relaxation (EC50 = 159 microM) of 1 microM NE-contracted rings of rabbit thoracic aorta. The vascular relaxant effects of McN-5691 were not related to increased calcium (45Ca) efflux from vascular smooth muscle cells. The effects of McN-5691 on NE-induced contraction were unrelated to intracellular mechanisms because McN-5691 did not affect NE-induced contraction in the absence of extracellular calcium. McN-5691 had weak activity in rat cerebral cortical membrane alpha-1 or alpha-2 adrenergic receptor binding assays. McN-5691-induced vasodilation of phenylephrine-contracted rat aortic strips was not reversible by high potassium, indicating that McN-5691 does not induce relaxation of blood vessels through potassium channel activation. In summary, these studies suggest that the primary vasodilator mechanism of McN-5691 is calcium channel blockade through competitive binding at the diltiazem site on the voltage sensitive calcium channel. McN-5691 may possess an additional vasodilator mechanism of action distinct from alpha adrenergic receptor blockade but involving a cell membrane-related event apparently leading to attenuation of receptor-operated calcium channel activity.
Flaim
S F
SF
Department of Biological, R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania.
Gleason
M M
MM
Hedberg
A
A
Shank
R P
RP
McCullough
J R
JR
Gill
A
A
Damiano
B P
BP
Brannan
M D
MD
Carson
J R
JR
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002021:Buffers; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009638:Norepinephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism
D002021:Buffers; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D015221:Potassium Channels; D011437:Propylamines; D011942:Receptors, Adrenergic, alpha; C055896:McN 5691; D002118:Calcium; D009638:Norepinephrine