Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y(1) receptor antagonist, in vivo.
The object of the present paper was to investigate the in vivo pharmacological profile of the dihydropyridine neuropeptide Y Y(1) receptor antagonist 1,4-Dihydro-4-[3-[[[[3-[spiro(indene-4,1'-piperidin-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridine dicarboxylic acid, dimethylester (H 394/84). The renal vasoconstrictor response to neuropeptide Y in anaesthetized rats was dose-dependently antagonized by H 394/84 (ID(50) value=41+/-4 nmol/kg/min), whereas the renal vascular responses to noradrenaline and angiotensin II were only slightly affected by H 394/84 (500 nmol/kg/min). In pigs pretreated with reserpine and transection of sympathetic nerves (depleted of noradrenaline), H 394/84 dose-dependently antagonized renal and femoral vasoconstrictor responses evoked by sympathetic nerve activation (neuronally released neuropeptide Y) and exogenous neuropeptide Y. Significant inhibition was seen already at 1.0 nmol/kg/min, when plasma levels of the antagonist reached 29+/-4 nM. Around 70% of the antagonism remained 90 min after H 394/84 was given. The disposition of H 394/84 fits a biexponential model with initial and terminal half-lives of 2.6 and 48 min, respectively. H 394/84 (100 nmol/kg/min) did not inhibit vascular responses to neuropeptide Y Y(2) receptor-, alpha-adrenoceptor- or purinoceptor-activation in the pig in vivo. It is concluded that H 394/84 is a potent neuropeptide Y Y(1) receptor antagonist with rather long duration of action in vivo. The selectivity and specificity in vivo is more than 100-fold, and H 394/84 antagonizes vascular responses to exogenous and endogenous, neuronally released, neuropeptide Y with similar potency.
Malmström
R E
RE
Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institute, S-17177, Stockholm, Sweden. rickard.malmstrom@fyfa.ki.se
Balmér
K C
KC
Weilitz
J
J
Nordlander
M
M
Sjölander
M
M
D000758:Anesthesia; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009525:Niacin / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010599:Pharmacokinetics; D010671:Phenylurea Compounds / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D012110:Reserpine / Q000494:pharmacology; D013379:Substrate Specificity; D013552:Swine; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
C435203:H 394-84; D009478:Neuropeptide Y; D010671:Phenylurea Compounds; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D000804:Angiotensin II; D009525:Niacin; D012110:Reserpine; D009638:Norepinephrine