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.

In vivo characterization of the novel neuropeptide Y Y1 receptor antagonist H 409/22.

We studied the effects of the novel neuropeptide Y (NPY) Y1 receptor antagonist H 409/22, and its inactive enantiomer H 510/45, on vascular responses evoked by endogenous and exogenous NPY in the pig in vivo. H 409/22 and H 510/45 were given as 30-min infusions, and the antagonistic effects and circulating plasma concentrations were measured. The initial and terminal half-lives of H 409/22 in plasma were approximately 3 and 30 min, respectively. In pigs pretreated with reserpine and transection of sympathetic nerves (depletion of noradrenaline), sympathetic nerve stimulation evoked nonadrenergic vasoconstrictor responses in kidney and hindlimb, mediated by neuronally released NPY. Significant inhibition of these vasoconstrictor responses, as well as of vascular responses to injections of exogenous NPY, were seen during a low-dose infusion of H 409/22 (1.8 nmol/kg/min), when plasma levels of the antagonist reached 77 +/- 8 nM. Greatest inhibitory effects were seen at the highest dose of H 409/22 (180 nmol/kg/min, giving plasma levels of 7.4 +/- 0.6 microM) when all vascular responses evoked by NPY were strongly attenuated or largely abolished. H 510/45 did not affect any of the vascular responses studied. It is concluded that H 409/22 potently and dose-dependently antagonizes vascular responses to exogenous and endogenous NPY in the pig, and thus represents an interesting tool for studies on NPY Y1 receptor-mediated effects in vivo.

The neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226: equal effects on vascular responses to exogenous and endogenous NPY in the pig in vivo.

1. The antagonistic effects of the neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226 on equally prominent vascular responses evoked by sympathetic nerve stimulation and exogenous NPY were compared during different intravenous (i.v.) infusions of the antagonist (0.19-190 nmol kg-1 min-1 for 30 min). 2. High frequency sympathetic nerve stimulation in reserpine-treated pigs in vivo evoked non-adrenergic vasoconstrictor responses in kidney and hind limb, in the latter followed by a long-lasting phase of decreased blood flow. The vascular response in the kidney and the long-lasting phase in hind limb resembled the effects of exogenous NPY administered i.v. (kidney) and intraarterially (i.a.) (in the hind limb, which only responded to higher NPY doses). 3. Plasma levels of BIBP 3226 reached a plateau within 20 min and the inhibitory effects on vascular responses were studied during the last ten minutes of infusion. The elimination of BIBP 3226 from plasma was found to fit a two-compartment model with an alpha-phase of 2.0 +/- 0.2 min and a beta-phase of 20.1 +/- 0.9 min. 4. Significant inhibition of presumably Y1 receptor-mediated vascular responses evoked by both endogenous and exogenous NPY in kidney and hind limb was seen even during low-dose infusion of BIBP 3226 (1.9 nmol kg-1 min-1), when plasma levels of the antagonist reached 59 +/- 8 nM. The maximum inhibitory effects of BIBP 3226 were seen during the highest-dose infusion (190 nmol kg-1 min-1), when the long-lasting vasoconstrictor responses in hind limb to sympathetic nerve stimulation and exogenous NPY administration (i.a.) were abolished. Simultaneously, the vascular responses in kidney to exogenous NPY were inhibited by 89% and to sympathetic nerve stimulation by 60%. 5. It is concluded that BIBP 3226 has a short half-life in plasma and should preferably be given by i.v. infusions to maintain blockade and avoid non-specific effects. Furthermore, BIBP 3226 dose-dependently and with similar potency antagonizes vascular responses to exogenous and endogenous NPY both in the kidney and hind limb of the reserpine-treated pig in vivo. Thus, inhibition of vascular responses to exogenous NPY may be a good indicator of the dose of this antagonist needed to inhibit sympathetic Y1 receptor-transmission.