Pressor responses induced by Bay K 8644 involve both release of adrenal catecholamines and calcium channel activation.
1. The dihydropyridine calcium channel activator, Bay K 8644, is believed to increase mean arterial blood pressure in several animal models, as a result of direct activation of vascular smooth muscle cells by increasing calcium influx through the voltage-dependent calcium channels. The purpose of the current study was to elucidate further the mechanism of action of Bay K 8644, by examining the possibility that the pressor response to Bay K 8644 may also be the result of indirect activation of the vascular smooth muscle cells by release of adrenal catecholamines. 2. Intravenous administration of Bay K 8644 increased mean arterial pressure in a dose-dependent manner in conscious, normotensive rats. This pressor response was blocked by calcium channel blockers (nifedipine, verapamil, and diltiazem) at doses lower than were necessary to decrease resting mean arterial pressure. 3. alpha-Adrenoceptor antagonists (phentolamine, yohimbine, and prazosin) completely blocked the Bay K 8644-induced pressor responses and converted them to depressor responses. Adrenalectomy did not alter the inhibitory effect of phentolamine on the pressor response to Bay K 8644. However, adrenalectomy or adrenal demedullectomy prevented the phentolamine-induced reversal of the Bay K 8644 pressor response to a depressor response. In addition, adrenalectomy did not affect the ability of phentolamine to reverse the pressor response to exogenous adrenaline administration to a depressor response. 4. These data suggest that the pressor response to Bay K 8644 may involve both direct activation of vascular smooth muscle cells and indirect activation of the muscle cells by release of adrenal catecholamines.
Moreland
S
S
Squibb Institute for Medical Research, Department of Pharmacology, Princeton, New Jersey.
Ushay
M P
MP
Kimball
S D
SD
Powell
J R
JR
Moreland
R S
RS
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; D002395:Catecholamines; D007473:Ion Channels; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester