Pressor Responses In Pithed Rat Research Articles

Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists

The discovery, in vitro and in vivo studies of the highly potent AT1 antagonist 12a (BR-A-657, Fimasartan) antagonists are presented. A series of pyrimidin-4(3H)-one derivatives as losartan analogue were synthesized and evaluated for a novel class of AT1 receptor antagonists. Among them, 12a containing thioamido moiety displayed both high in vitro functional antagonism and binding affinity [IC50=0.42 and 0.13nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED50 of 0.018mg/kg. Moreover, in vivo evaluation in furosemide-treated rat and conscious renal hypertensive rat models and the pharmacokinetic study showed that 12a is a highly potent and orally active AT1 selective antagonist having stronger in vivo potency than losartan.

Superiority of YM598 over atrasentan as a selective endothelin ET A receptor antagonist

The binding affinities of (E)- N-[6-methoxy-5-(2-methoxyphenoxy)[2,2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598) for native human endothelin ET A and ET B receptors expressed in human coronary artery smooth muscle cells (CASMC) and a human melanoma cell line, SK-Mel-28, respectively, were examined, and the results compared with those for the endothelin receptor antagonists atrasentan and bosentan. The in vivo endothelin ET A receptor inhibitory activities of YM598 and atrasentan were also compared through the suppression of the big endothelin-1-induced pressor response in pithed rats. K i values of YM598, atrasentan, and bosentan for native human endothelin ET A receptors were 0.772, 0.0551, and 4.75 nM, while those for native human endothelin ET B receptors were 143, 4.80, and 40.9 nM, respectively. The calculated selectivity ratios of YM598, atrasentan, and bosentan for endothelin ET A versus ET B receptors were 185, 87 and 8.6, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner on both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but closely similar on oral administration. These results suggest that YM598 has high selectivity for native human ET A against ET B receptors, and that YM598 is superior to atrasentan as an ET A receptor antagonist with regard to pharmacological bioavailability in rats.

(+)-Nantenine isolated from Nandina domestica Thunb. inhibits adrenergic pressor responses in pithed rats

The effects of (+)-nantenine on various pressor responses, recently reported exerting competitive antagonistic activity at the α 1-adrenoceptor/5-hydroxytryptamine (5-HT) 2A receptor, were examined in vivo. (+)-Nantenine (0.03–3 mg/kg) caused a dose-dependent inhibition of the pressor response to phenylephrine (α 1-adrenoceptor agonist) or 5-HT (5-HT receptor agonist) in both anesthetized and pithed rats. The pressor response to UK 14304 (5-Bromo- N-[2-imidazolin-2-yl]-6-quinoxalinamine) (an α 2-adrenoceptor agonist) was inhibited by (+)-nantenine (0.003–3 mg/kg) in pithed rats in a dose-dependent manner without affecting the angiotensin II-induced pressor response in anesthetized rats. The pressor response to sympathetic nerve stimulation was also inhibited by (+)-nantenine (0.3–3 mg/kg) in a dose-dependent manner. (+)-Nantenine (3 mg/kg) facilitated the norepinephrine release induced by sympathetic nerve stimulation in pithed rats. In the guinea pig vas deferens, the initial component of contractions induced by electrical field stimulation was enhanced by (+)-nantenine (1–30 μM) in a concentration-dependent manner, while the later component was inhibited by it. These data suggest that (+)-nantenine has antagonistic activities on α 1-adrenoceptors, α 2-adrenoceptors and 5-HT 2A receptors in pithed rats.

Effects of P5, a novel oxazolo(3,2-a)pyridine derivative with a long-acting antihypertensive activity, on different agonist-mediated pressor responses in pithed rats.

1. An oxazolo(3,2-a)pyridine derivative P5, described chemically as (+/-)-ethyl-7-(3-nitrophenyl)-5,8a-dimethyl-6-methoxycarbonyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridin-8-carboxylate, is a novel compound that has been synthesized as a possible antihypertensive prodrug of the 1,4-dihydropyridine type. Its antihypertensive activity was described in a previous study by the authors (Morán, Martin, Velasco, Martin, San Roman, Caballero, Puebla, Medarde & San Feliciano, 1997). 2. The aim of this work was to establish in vivo, the possible mechanisms participating in this antihypertensive action. Accordingly, we examined the effect of P5 on the pressor responses induced in pithed rats by noradrenaline (an alpha1-, alpha2- and beta-adrenoceptor agonist), xylazine (an alpha2-adrenoceptor agonist), methoxamine (an alpha1-adrenoceptor agonist), angiotensin I, angiotensin II, L-NAME (a nitric oxide synthase inhibitor) and BayK 8644 (a calcium channel agonist) and compared them with those of nifedipine, used as the reference drug. 3 Intravenous (i.v.) administration of P5 (2.5-10 mg kg(-1)) inhibited the pressor responses to noradrenaline (1 microg kg(-1)), xylazine (80 microg kg(-1)), angiotensin I (0.5 microg kg(-1)), angiotensin II (0.5 microg kg(-1)), BayK 8644 (30 microg kg(-1)) and L-NAME (10 mg kg(-1)). Nifedipine (10 microg kg(-1), i.v.) reduced the pressor responses to all these agonists and also to methoxamine (2 microg kg(-1)). 4. However, P5 was more effective than nifedipine in inhibiting these responses and its inhibitory effect lasted longer. Intravenous infusion of calcium gluconate (1 ml kg(-1) min(-1)) reversed the reduction in the pressor responses as a result of nifedipine. The effects of P5 were only reversed at 2-3 h after administration. 5 These results suggest that P5 has a strong capacity to inhibit the pressor responses to several agonists after its i.v. administration and that such effects are related to its potent antihypertensive activity.

Ethenesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

α-Adrenoceptor-mediated pressor responses in pithed rats fed diets with different calcium contents

Results of many clinical and experimental studies indicate an inverse relationship between dietary calcium and the prevalence of hypertension. Our study was designed to evaluate the alterations in arterial blood pressure and the changes in α-adrenoceptor-mediated vascular reactivity in normotensive Sprague–Dawley and spontaneously hypertensive rats (SHR) fed from weaning (3 weeks of life) three diets: normal calcium (Ca 1%), low calcium (Ca 0.1%), and high calcium (Ca 2.5%). The systolic and the diastolic arterial blood pressures were measured weekly by the tail cuff method. The plasma calcium levels in the animals were also measured regularly by colourimetric methods, and the α-adrenoceptor-mediated vascular reactivity was evaluated by measuring the pressor responses to α-adrenoceptor agonists in pithed rats. These determinations were carried out at the end of the feeding periods (9 weeks of life in Sprague–Dawley rats and 20 weeks of life in SHR) and also at the moments when maximal differences in arterial blood pressure were observed between the conscious animals fed the normal calcium diet and those fed the other two diets. Dietary calcium deficiency increased arterial blood pressure in both strains but calcium supplements were effective to lower this only in hypertensive animals. The plasma calcium levels were altered in both strains when calcium administration was not normal. The low-calcium diet did not modify the pressor responses to either the α 1-adrenoceptor agonist, methoxamine, or the α 2-adrenoceptor agonist, B-HT 920 (5-allyl-2-amino-5,6,7,8-tetrahydro-4 H-thiazolo-(4,5- d)-acepin-dihydrochloride, talixepole), in the normotensive and the hypertensive rats. On the contrary, the high-calcium diet caused a definite decrease in α 1- and α 2-adrenoceptor-mediated vascular reactivity in both strains. The changes in the α-adrenoceptor-mediated vasoconstrictor responses were observed in pithed 9-week old Sprague–Dawley rats and in pithed 20-week old SHR, but none were observed in pithed 15-week old SHR, although at this age maximal differences in arterial blood pressure between the animals fed the high- and the normal calcium diet were observed. The results of this study suggest that the mechanisms implicated in the effects of dietary calcium supplements on arterial blood pressure are clearly different from the mechanisms, which bring about changes in arterial blood pressure when the diet is deficient in calcium. The results of this study also show that calcium administration causes variations in α-adrenoceptor-mediated vascular reactivity, but this is probably not the only mechanism implicated in the calcium effect on arterial blood pressure.

Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist.

The discovery, in vitro and in vivo studies of the highly potent ETA antagonist EMD 122946 are presented. This compound displayed high binding affinity and functional antagonism [IC50 = 3.2 x 10(-11) M, pA2 = 9.5 (ETA)] and inhibited the ET-1 induced pressor response in pithed rats with an ED50 of 0.3 mg/kg. In conscious spontaneously hypertensive rats and in DOCA-salt hypertensive rats the compound lowered mean blood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bioavailability in rats and monkeys.

3 N-Methylbiphenylsulfonylurea and -carbamate substituted imidazo[4,5- b]pyridines. Potent antagonists of the ANG II AT 1 receptors

The synthesis and the SAR study of imidazo[4,5- b]pyridine biphenyl sulfonylureas and -carbamates as highly potent AT 1-selective ANG II receptor antagonists are described. Several members of this new class of antagonists efficiently inhibited the ANG II-induced pressor response in pithed rats after iv and intraduodenal (id) administration.

P3-71 - Inhibitory effects of angiotensin II-antagonists on sympathetic nerve-mediated pressor response in pithed rats

P3-71 - Inhibitory effects of angiotensin II-antagonists on sympathetic nerve-mediated pressor response in pithed rats

Effects of MPC-1304, a novel Ca 2+ entry blocker, on α-adrenoceptor-mediated pressor responses in pithed rats

MPC-1304 is a novel Ca 2+ entry blocker of the 1,4-dihydropyridine type. In the present study, the effect of oral administration of MPC-1304 on α-adrenoceptor-mediated pressor responses was examined in pithed rats and compared with that of nifedipine. Drugs were administered orally to conscious animals before pithing. MPC-1304 (0.3–3 mg/kg) and nifedipine (1–10 mg/kg) inhibited pressor responses to norepinephrine, phenylephrine ( α 1-adrenoceptor agonist), UK-14304 ( α 2- adrenoceptor agonist), and sympathetic nerve (spinal cord segments) stimulation. MPC-1304 was roughly 3 times more potent than nifedipine in inhibiting these responses. The inhibitory effect of MPC-1304 (3 mg/kg) on the pressor response to UK-14304 lasted longer than that of nifedipine (3 mg/kg). At the same time, plasma concentrations of MPC-1304 were lower than those of nifedipine. These results suggest that MPC-1304 has a great ability to inhibit pressor responses to norepinephrine and peripheral sympathetic stimulation after its oral administration, and that this effect of MPC-1304 is closely correlated with its potent antihypertensive activity.

The pharmacology of RS‐15385‐197, a potent and selective α2‐adrenoceptor antagonist

1. RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulphonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at alpha 2-adrenoceptors. 2. RS-15385-197 had a pKi of 9.45 for alpha 2-adrenoceptors in the rat cortex (pA2 in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pKi of only 6.32 (pA2 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pKi of 9.18. 3. RS-15385-197 showed unprecedented alpha 2 vs. alpha 1 adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pKi of 9.45 in displacing [3H]-yohimbine and 5.29 in displacing [3H]-prazosin (alpha 2/alpha 1 selectivity ratio in binding experiments > 14000). The compound had a pA2 of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pKB of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA2 of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (alpha 2/alpha 1 selectivity ratio in functional experiments > 4000). 4. RS-15385-197 was highly selective for alpha 2-adrenoceptors over other receptors: the compound showed low affinity for 5-HT1A (pKi 6.50) and 5-HT1D (pKi 7.00) receptor subtypes, and even lower affinity (pKi < or = 5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, beta-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [3H]-idazoxan, which provides further evidence that these sites are not related to alpha 2-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 microM RS-15385-197. 5. RS-15385-197 was non-selective for the alpha 2A- and alpha 2B-adrenoceptor subtypes in that the pKi for the alpha 2A-adrenoceptor in human platelets was 9.90 and the pKi for the alpha 2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the alpha 2-adrenoceptor subtype in hamster adipocytes (pKi 8.38). 6. In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD50 5 and 7 microg kg-1, i.v., respectively; 96 microg kg-1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD50 7 microg kg-1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg-1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for alpha2 vs. alpha1-adrenoceptors was maintained in vivo.8 RS-15385-197 is therefore a very potent, selective, competitive alpha2-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of alpha2-adrenoceptors.

(Phenylmethoxy)phenyl derivatives of omega-oxo- and omega-tetrazolylalkanoic acids and related tetrazoles. Synthesis and evaluation as leukotriene D4 receptor antagonists.

Two series of (phenylmethoxy)phenyl compounds derived from the structure of LY163443 were synthesized and evaluated as leukotriene D4 receptor antagonists. In the omega-[(phenylmethoxy)phenyl]-omega-oxoalkanoic acid series, 5-[4-[(4-acetyl-2-ethyl-3-hydroxyphenyl)methoxy]phenyl]-3,3-dimethyl-5- oxopentanoic acid (8) was the most potent antagonist of LTD4-induced contractions of guinea pig ileum (pKB of 7.60) and LTD4 pressor response in pithed rats (ED50 of 1.4 mg/kg iv). Replacing the carboxylic acid function with 5-tetrazole gave slightly more potent compounds. In the omega-[5-[[(phenylmethoxy)phenyl]alkyl] tetrazolyl]alkanoic acid series, replacing the carboxylic acid with 5-tetrazole gave compounds that were equally effective in the guinea pig ileum but more potent in vivo against the LTD4 pressor response in rat. The pKB value in the guinea pig ileum for 1-[2-hydroxy-3-propyl-4- [[4-[[2-[3-(1H-tetrazol-5-yl)propyl]-2H-tetrazol-5-yl]methyl ] phenoxy]methyl]phenyl]ethanone (25) was 7.87 and the ED50 for antagonism of the LTD4 pressor response was 4.0 mg/kg iv. The sodium salts of 8 (9) and 25 (26) given by the iv route of administration antagonized LTD4-induced cardiovascular alterations in anesthetized rat and LTD4-induced bronchoconstriction in guinea pig in a dose-dependent manner. Oral activity was also demonstrated against the LTD4-induced bronchoconstriction in guinea pig.

FMRF-amide and L-Arg-L-Phe increase blood pressure and heart rate in the anaesthetised rat by central stimulation of the sympathetic nervous system

The neuropeptide FMRFamide (L-Phe-L-Met-L-Arg-L-Phe-NH2) increases mean arterial blood pressure (MABP) and heart rate (HR) in the anaesthetised rat at concentrations ranging from 10-1000 micrograms/kg. Here, we demonstrate that peptides containing L-arginyl-L-phenylalanine (L-Arg-L-Phe), the C-terminal sequence of FMRFamide, mimic its haemodynamic effects. L-Arg-L-Phe was approximately 4 fold more potent in increasing MABP and HR than FMRFamide. In 40 different peptides investigated, the following order of potency of the effective compounds was established: L-Arg-L-Phe-L-Ala = L-Arg-L-Phe greater than FMRFamide greater than L-Met-L-Arg-L-Phe = L-Arg-L-Trp greater than L-Arg-L-Tyr greater than D-Arg-L-Phe = L-Arg-L-Phe-OMe greater than L-Arg-L-Leu = L-Arg-L-Ile greater than L-Lys-L-Phe greater than L-Arg-L-Met. L-Arg-L-Phe or FMRFamide did not cause any pressor response in pithed rats, indicating a central mechanism of action. In anaesthetised rats, intravenous injections of FMRFamide or L-Arg-L-Phe (100 micrograms/kg) were associated with a 2-3 fold increase in plasma noradrenaline levels, whereas plasma adrenaline levels remained unchanged. Thus, L-Arg-L-Phe may represent the active principle of FMRFamide acting by a central mechanism involving the release of noradrenaline from sympathetic nerve terminals.

Equal potency of nifedipine to inhibit α1-(dobutamine and BDF 6143) and α2-adrenoceptor (B-HT 920) induced pressor responses in pithed rats; lack of effect of phenoxybenzamine

Intravenous (i.v.) dobutamine and BDF 6143 were partial agonists in increasing diastolic pressure in β-adrenoceptor-blocked pithed rats. The log dose-pressor effect curves were not influenced by yohimbine (1 mg/kg i.v., −15 min) but were markedly shifted to the right by prazosin (0.1 mg/kg i.v., −15 min) indicating the exclusive involvement of α 1-adrenoceptors. Nifedipine (0.1–1 mg/kg i.a., −15 min) non-competitively inhibited the pressor effects of dobutamine and BDF 6143 as well as of the α 2-adrenoceptor agent B-HT 920 with equal potency. The −log ED 50 values calculated for nifedipine amounted to 6.25 ± 0.12, 6.16 ± 0.14 and 6.20 ± 0.10, respectively. Phenoxybenzamine (3 or 10 μg/kg i.v., −60 min) did not affect the effectiveness of nifedipine (0.1 mg/kg) to inhibit the pressor effects of dobutamine and BDF 6143. Following treatment with Bay k 8644 (1 mg/kg i.a., −15 min), the log dose-pressor effect curves for dobutamine and BDF 6143 were shifted to the left and the maximum responses were elevated. Our findings suggest that the α 1-adrenoceptor-induced pressor effects of dobutamine and BDF 6143 rely heavily on the influx of Ca 2+, and are indistinguishable in this respect from the effects initiated by α 2-adrenoceptor stimulation. The data further support the view that the sensitivity of α-adrenoceptor-mediated pressor effects to inhibition by Ca 2+ entry blockers depends on the extent to which Ca 2+ influx contributes to the overall response and is not determined by the intrinsic activity or by the receptor reserve of the α-adrenoceptor agonist.

Inhibition of the α1-and α2-adrenoceptor-mediated pressor response in pithed rats by raubasine, tetrahydroalstonine and akuammigine

The relative potencies of raubasine, tetrahydroalstonine (THA) and akuammigine on α 1- and α 2-adrenoceptors were assessed by comparing their effects on the rise in blood pressure induced by stimulation of the sympathetic outflow from the spinal cord or by injection of noradrenaline in pithed rats. Akuammigine was inactive in both cases. Raubasine preferentially antagonized the effects of electrical stimulation while THA antagonized the effects of injected noradrenaline. The results suggest that raubasine preferentially blocks α 1-adrenoceptors while THA is more selective for α 2-adrenoceptors.

Phenoxybenzamine-induced inhibition of cirazoline pressor responses in pithed rats pretreated with organic or inorganic calcium entry blocking drugs

In groups of propranolol-treated pithed rats pretreatment with either verapamil (1 mg/kg i.a., 20 min) or the inorganic calcium entry blocker (CEB), cobalt (23.8 mg/kg i.a., 20 min) reduced maximum obtainable pressor responses to the relatively selective α 2-adrenoceptor agonist B-HT 920 (0.1–1000 μg/kg i.v.) equally, by approximately 50%. Verapamil and cobalt at these doses had little or no effect upon pressor responses induced by the relatively selective α 1-adrenoceptor agonist cirazoline (0.1–1000 μg/kg i.v.). Phenoxybenzamine (0.1 mg/kg i.v., 15 min) displaced to the right and reduced by 44% the maximum obtainable pressor responses to cirazoline. Treatment of animals with the combination of either verapamil or cobalt followed by phenoxybenzamine, at the dose levels and pretreatment times given above, produced significantly greater inhibitions of cirazoline pressor responses (83% and 88% reduction in the maximum obtainable pressor responses to cirazoline respectively) than were observed following administration of phenoxybenzamine alone. Since yohimbine (1 mg/kg i.v.) did not significantly affect the residual responses to cirazoline following treatment with phenoxybenzamine the mechanism responsible for this interaction between CEBs and phenoxybenzamine is not mediated via postjunctional α 2-adrenoceptors. Additional studies are required to assess the involvement of a possible subtype of α 1-adrenoceptors which appear to mediate vascular responses sensitive to CEBs.

Effects of chemical sympathectomy by 6-hydroxydopamine on alpha-adrenoceptor-mediated pressor responses in pithed rat.

The effects of 6-hydroxydopamine (6-OHDA) treatment of neonatal and adult rats on vasopressor responses to postsynaptic alpha-adrenoceptor activation were studied in adult pithed rats. The pressor response to electrical stimulation of the thoracosympathetic outflow (T7-T9) was markedly reduced after neonatal or adult 6-OHDA treatment, indicating a functional destruction of the sympathetic input to the vasculature. Pressor response curves to injected noradrenaline (a nonselective alpha-agonist) and phenylephrine (a selective alpha 1-agonist) were shifted to the left in all 6-OHDA-treated animals. However, the pressor response to the selective alpha 2-agonist M-7 (5,6-hydroxy-2-dimethylamino tetralin) was unaltered in all the 6-OHDA-treated animals. It is concluded that functional destruction of peripheral sympathetic nerve endings in vascular smooth muscle by treatment of neonatal or adult rats with 6-OHDA produces an increased pressor response to alpha 1-adrenoceptor agonists, but not to alpha 2-adrenoceptor agonists in the pithed rat.

Hypotensive activity of calcium entry blockers in rats. Relationship with depression of α2-adrenoceptor-mediated vasopressor responses

The hypotensive activity of a series of calcium entry blockers and various other vasodilators was quantified in pentobarbitone-anesthetized rats. Hypotensive activity was correlated linearly with the potency of these vasoactive agents to depress α 2-adrenoceptor-induced pressor responses in pithed rats. However, vasodilation as such also influenced α 2-adrenoceptor-mediated vasoconstrictor processes. For this reason, the depressive action of the vasodilating compounds on α 2-adrenoceptor-induced pressor effects was also determined during vasopressin infusion, which counteracted the vasodilation induced by the vasoactive compounds. It was found that the hypotensive activity exerted by the calcium entry blockers was directly related with their inhibitory activity to depress α 2-pressor responses. This relationship was not observed for the other vasodilators. The results provide further evidence for the hypothesis that vasodilatation induced by calcium entry blockers is caused by the selective impairment of that part of the vascular tone which is maintained by vascular postjunctional α 2-adrenoceptors.

Correlation between the affinity for [ 3H]mianserin-labelled receptors in brain and antagonism of the serotonin pressor response in pithed rats

Correlation between the affinity for [ 3H]mianserin-labelled receptors in brain and antagonism of the serotonin pressor response in pithed rats

Effects of 5HT uptake inhibitors on the pressor response to 5HT in the pithed rat. The significance of the 5HT blocking property

A study was made of the effects of several serotonin (5HT) uptake inhibitors on 5HT-induced pressor responses in pithed rats, 5HT uptake into rat brain synaptosomes and 5HT-induced contractions of rat ileum in vitro. All drugs except desimipramine were potent uptake inhibitors (IC 50 < 10 −7 M). Femoxetine, chlorimipramine, imipramine and desimipramine all inhibited 5HT-induced contractions of the rat ileum in vitro and the pressor response to 5HT in vivo. FG 7051, FG 7052 and dexchlorpheniramine were weak 5HT antagonists on the rat ileum but potentiated the pressor responses to 5HT; the most potent uptake inhibitor, FG 7051, was the strongest potentiator. These results suggest that uptake inhibition is important for this potentiation. It is concluded that 5HT uptake inhibitors with potent 5HT receptor blocking properties antagonize the pressor response to 5HT and mask the potentiation due to uptake inhibition.