Biomedical subjects

B Wilffert

Publications and source records attributed to B Wilffert.

At least 73 records · Page 4Linked to original sources

PubMed1985

Calcium utilization in the vasoconstriction to enantiomers of SK&F 89748-A.

The effects of calcium entry blockade on the vasoconstriction to the selective alpha-1 adrenoceptor agonists d- and I-SK&F 89748-A (1,2,3,4-tetrahydro-8-methoxy-[5-methylthiol] -2-naphthalenamine HCl) in pithed rats and in rat and guinea-pig isolated aortas were studied. The log-dose response curves for the increase in diastolic pressure in pithed rats to i.v. injections of both enantiomers of SK&F 89748-A were maximally shifted only 5-fold to the right after pretreatment of the animals with nifedipine (1 or 3 mg/kg i.a.) or l-verapamil (0.3 or 1 mg/kg i.a.), showing the relative insensitivity of the vasopressor responses to SK&F 89748-A to these calcium entry blockers. In the rat isolated aorta, the contractile responses to the l-enantiomer of SK&F 89748-A were significantly more susceptible to calcium entry blockade with l-verapamil, nifedipine and D600 than the d-isomer. The contractions of the guinea-pig isolated aorta to both isomers proved highly insensitive to calcium slow channel blockade by D600. These results indicate that the contractions of vascular smooth muscle in pithed rats in vivo and of guinea-pig isolated aortas in vitro initiated by the d-and l-isomers of SK&F 89748-A are largely dependent upon processes not requiring an influx of extracellular calcium. The differential sensitivity to calcium entry blockade of the contractile responses of rat isolated aortas to the d- and l-isomers of SK&F 89748-A may reflect different ways of interaction of both enantiomers with the alpha-l adrenoceptor on rat aorta.

Adrenergic alpha-Agonists↗

PubMed1985

Interference of enantiomers of lofexidine with alpha-adrenoceptors.

Some alpha-adrenoceptor-mediated cardiovascular activities and alpha-adrenoceptor binding affinities for (+)- and (-)-lofexidine (Dexlofexidine and Levlofexidine) have been studied in comparison with racemic lofexidine. In pithed normotensive rats, i.v. (-)-lofexidine elicited pressor effects at doses (0.1-30 micrograms/kg), which were approximately 20 times lower than those of the (+)-isomer. Both yohimbine and prazosin in selective amounts of 1.0 and 0.1 mg/kg (i.v., -15 min), respectively, attenuated the increase in diastolic pressure induced by (+/-)-, (+)- and (-)-lofexidine, showing the involvement of alpha 1- as well as alpha 2-adrenoceptors in the vasopressor responses. No differences were observed in the sensitivity of the pressor effects of the (+)- and (-)-enantiomers to blockade by either yohimbine or prazosin. Following i.v. administration to pentobarbitone-anaesthetized normotensive rats, (-)-lofexidine (0.5-5.0 micrograms/kg) was found about 20 times more effective than the dextrorotatory isomer in decreasing mean arterial pressure and heart rate. The increase in heart rate evoked by electrical stimulation in pithed rats was dose-dependently reduced by (+/-)-, (-)- and (+)-lofexidine, the (-)-isomer being about 30 times more potent than the (+)-isomer. Similarly, the electrical stimulation-induced increase in diastolic pressure was also most effectively impaired by the laevorotatory enantiomer of lofexidine. (-)-Lofexidine showed an approximately 9-fold higher affinity than (+)-lofexidine for the alpha 2-adrenoceptor-like binding sites in rat brain membranes identified by [3H]-clonidine and was 4 times more potent at displacing [3H]-prazosin from alpha 1-adrenoceptors. It is concluded that the alpha-adrenoceptor activity of lofexidine resides predominantly in the (-)-isomer. The isomeric activity ratio of the enantiomers of lofexidine (about 20-fold) is higher than normally found for other imidazolines.

Animals↗

PubMed1985

Cardiovascular effects and interaction with adrenoceptors of urapidil.

Urapidil is a novel antihypertensive agent, chemically related to uracil. Its cardiovascular profile was evaluated in a variety of pharmacological models. Urapidil caused a significant decrease of blood pressure in intact rats, both hypertensive (SHR) and normotensive (WKY), as well as in alpha-glucochloralose-anaesthetized cats. Reflex tachycardia was not observed. An analysis in pithed rats showed that urapidil is an alpha-adrenoceptor blocking drug with an obvious selectivity for postsynaptic alpha 1- over alpha 2-adrenoceptors. The alpha 1-adrenoceptor blocking potency proved quantitatively less than that of prazosin. Experiments on isolated aorta preparations and radioligand binding studies confirmed the selectivity of urapidil for alpha 1- over alpha 2-adrenoceptors. The involvement of urapidil with presynaptic alpha 2-adrenoceptors proved negligible. Urapidil proved to possess modest but significant beta 1-adrenoceptor blocking activity, accompanied by a certain degree of intrinsic sympathomimetic activity (TSA) at the level of the cardiac beta 1-adrenoceptors. No significant interaction with vascular beta 2-adrenoceptors was observed. High doses of urapidil caused pressor effects of a probably unspecific nature; neither alpha-adrenoceptors nor 5HT-receptors were involved. When injected into the vertebral artery of the cat, urapidil caused a significant central hypotensive effect which was different from that of clonidine and related drugs, since it could not be blocked by yohimbine (alpha 2-receptor antagonist). Similarly, the modest sedation produced by urapidil in mice remained uninfluenced by yohimbine. The urapidil molecule does not contain any stereoisomers. Accordingly, one and the same molecule possesses the following pharmacodynamic properties: postsynaptic alpha 1-adrenoceptor blockade; weak postsynaptic alpha 2-adrenoceptor blockade; modest but selective beta 1-adrenoceptor blockade with ISA; central hypotensive activity not mediated by central alpha 2-adrenoceptors.

Animals↗

PubMed1984

Heterogeneity of the interaction between alpha 1- and alpha 2-adrenoceptor agonists with their respective receptors in the vascular system of the pithed rat.

The subdivision of alpha 1- and alpha 2-adrenoceptor-mediated pressor responses to different agonists based upon the influence of beta 2-adrenoceptor-mediated vasodilatation was further investigated in the pithed normotensive rat. The effect of salbutamol (4.18 X 10(-6) mol/kg) on the alpha 1-adrenoceptor-mediated increase in diastolic pressure due to dopamine and amidephrine as well as on the alpha 2-adrenoceptor-mediated pressor response to azepexole, DP-6,7-ADTN, M-7, TL-99 and dopamine was assessed. The alpha 1-pressor responses to amidephrine and dopamine were only slightly attenuated by salbutamol. The alpha 2-adrenoceptor-mediated increase in diastolic pressure due to B-HT 933 was strongly antagonized by salbutamol in contrast to the effect of dopamine, DP-6,7-ADTN and M-7. TL-99 occupied in intermediate position. The data do not support the existence of distinctly different subtypes of alpha 1- and alpha 2-adrenoceptors but favor the hypothesis that both alpha 1- and alpha 2-adrenoceptors are activated in a unique way by each of their respective agonists.

Adrenergic alpha-Agonists↗

PubMed1984

The contractions induced in rat and guinea-pig aortic strips by the alpha 2-adrenoceptor selective agonists B-HT 920 and UK 14,304 are mediated by alpha 1-adrenoceptors.

The alpha-adrenergic action of the selective alpha 2-adrenoceptor agonists B-HT 920 and UK 14,304 was investigated on helically cut preparations of rat and guinea-pig isolated aorta. The alpha 1-adrenoceptor selective stimulant (-)-phenylephrine was included for comparison. All agonists induced concentration-dependent contractions in both preparations. Calcium entry blockade by D 600 almost abolished the contractions evoked by B-HT 920 and UK 14,304 in rat aorta while those evoked in guinea-pig aorta were less strongly affected. Contractions elicited by (-)-phenylephrine were moderately impaired by D 600 in rat aorta whereas there was only a limited effect in guinea-pig aorta. Analysis of the prazosin and yohimbine antagonism of B-HT 920- and UK 14,304-evoked contractions showed the involvement of alpha 1-like adrenoceptors in rat and guinea-pig aorta, prazosin being approximately 1000 times more potent that yohimbine. The results show that B-HT 920 and UK 14,304 contract rat and guinea-pig aorta via alpha 1-like adrenoceptors which are not identical. It is submitted that rat and guinea-pig alpha 1-adrenoceptors activate different contractile processes.

Adrenergic alpha-Agonists↗

PubMed1984

Alpha 1-adrenoceptor-mediated vasoconstriction in vivo to enantiomers of SK & F 89748-A.

The pressor activity of the 1-enantiomer of SK & F 89748-A, 1,2,3,4-tetrahydro-8-methoxy-5-(methylthio)-2-naphthalenamine, in pithed normotensive rats was found comparable with that of 1-phenylephrine. The d-enantiomer was half as potent. The log dose-pressor effect curves for d- and 1-SK & F 89748-A were not influenced by reserpine treatment (2 X 5 mg/kg i.p., -48 and -24 h), were virtually unaffected 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) and phentolamine (1 mg/kg i.v., -15 min). Similar observations were made for the 1-enantiomer in pithed cats. It is concluded that d- and 1-SK & F 89748-A are potent, directly acting highly selective agonists of (vascular) postjunctional alpha 1-adrenoceptors. Potency and selectivity were equally pronounced for both enantiomers. The currently available selective agonists of alpha 1-adrenoceptors, including the optical isomers of SK & F 89748-A, cannot distinguish between alpha 1- and alpha 2-adrenoceptors. This conclusion is based on binding affinity since these affinities are linearly correlated as shown by radioligand displacement experiments.

Adrenergic alpha-Agonists↗

PubMed1984

Differential prejunctional effect of captopril and saralasin on neurogenic vasoconstriction in pithed normotensive rats.

The present study describes a differential inhibitory effect of captopril and [Sar1 Ala8]angiotensin II (saralasin) on the neurogenic vasoconstriction in pithed normotensive rats. In pithed normotensive rats with intact kidneys captopril more profoundly inhibited the vasopressor response to spinal stimulation than observed for saralasin. Bilateral nephrectomy also diminished the hypertensive response to spinal stimulation. After bilateral nephrectomy, 1 h previously, captopril but not saralasin diminished the hypertensive response to spinal stimulation. After bilateral nephrectomy, 18-24 h previously, captopril did not produce an additional reduction of the vasopressor response to spinal stimulation. In contrast, saralasin significantly potentiated the neurogenic vasoconstriction. The results suggest that both captopril and saralasin diminish the hypertensive response to spinal stimulation by producing dilatation of vascular smooth muscle in pithed normotensive rats. Apart from this common mechanism, a differential effect of captopril and saralasin on the neurogenic vasoconstriction can be observed. In contrast to saralasin, captopril may depress the neurogenic vasoconstriction in pithed normotensive rats by blocking the sympathofacilitatory action induced by subpressor levels of angiotensin II (AII). In pithed normotensive rats, saralasin may mimic the sympathofacilitatory action of subpressor AII.

Animals↗

PubMed1984

Alpha 1/alpha 2-adrenoceptor agonist selectivity of mono- and dihydroxy-2-N,N-DI-n-propylaminotetralins.

The pressor activities and the identity of the postjunctional alpha-adrenoceptors involved were determined for a series of congeneric mono- and dihydroxy-substituted 2-N,N-di-n-propylaminotetralins and N,N-di-n-propyldopamine (DPDA) following i.v. administration to pithed normotensive rats. The affinity for alpha 1- and alpha 2-adrenoceptor-like binding sites was obtained from radioligand displacement studies. The 5- and 7-OH substituted tetralins as well as DPDA were reasonably potent and about equieffective pressor agents. The 6-OH congener had almost no vasoconstrictor effects whereas the 8-OH positional isomer occupied an intermediate position. The 5,6- and 6,7-di-OH analogs very effectively raised the diastolic pressure of pithed rats. On account of the inhibition exerted by prazosin (0.1 mg/kg) and yohimbine (1 mg/kg) the 5- and 7-OH isomers as well as DPDA can be classified as mixed alpha 1/alpha 2-adrenoceptor agonists, the alpha 1-adrenoceptor-stimulating potency being more pronounced especially for the 5-OH congener. In addition, a significant contribution of serotonin receptors to the pressor responses to the 8-OH compound was detected. Similarly, alpha 2-adrenoceptors were mainly responsible for the vasoconstriction caused by the 6,7-di-OH isomer, whereas the 5,6-di-OH congener very selectively stimulated this alpha 2-type receptor in the lower dose range and alpha 1-adrenoceptor stimulation predominated at higher doses of this agonist. The 6,7-di-OH compound failed to activate vascular postjunctional beta 2-adrenoceptors. The results indicate that the alpha 1/alpha 2-adrenoceptor agonist selectivity depends on the position(s) and the number of hydroxy groups present as well as on the alkyl substitution at the amino function. 2-N,N-Di-n-propylamino-6,7-dihydroxytetralin may be a more suitable alpha 2-adrenoceptor selective agonist than M-7.

Animals↗

PubMed1984

Effect of pithing on the postjunctional sympatho-inhibitory action of captopril in cats.

Pithing of anaesthetized normotensive cats significantly lowered the arterial blood pressure and augmented plasma renin activity (PRA). Captopril dose-dependently diminished mean arterial blood pressure in both pithed and intact anaesthetized normotensive cats. The hypotensive effectiveness of captopril was most pronounced in pithed cats. Captopril inhibited the hypertensive response to intravenously administered noradrenaline in pithed cats, but did not attenuate the hypertensive response to noradrenaline in intact cats. The results do not exclude that the hypotensive activity of captopril in intact cats may be causally independent of the attenuating effect of converting enzyme inhibition on the postjunctional alpha-adrenoceptor mediated vasoconstriction as observed in pithed animals.

Animals↗

PubMed1984

Interactions between the putative calcium entry promotor Bay k 8644 and pressor responses produced by alpha 1- and alpha 2-adrenoceptor agonists in the pithed normotensive rat.

Interactions between the putative calcium entry promotor Bay k 8644 and both alpha 1- and alpha 2-adrenoceptor mediated increases in diastolic pressure were studied in the pithed normotensive rat. The alpha 2-adrenoceptor mediated pressor responses elicited by B-HT920, TL-99, DP-6,7-ADTN and B-HT958 were potentiated by Bay k 8644, reflected by a leftward shift and an increase in the maximum of the log dose-pressor response curves. The alpha 1-adrenoceptor-mediated effects elicited by cirazoline, methoxamine, (-)-amidephrine, St 587, (-)-phenylephrine and Sgd 101/75 were less enhanced by Bay k 8644. Only a leftward shift of the dose-response curves was observed, which was most pronounced for (-)-phenylephrine and Sgd 101/75. The alpha 1- and alpha 2-adrenoceptor-mediated pressor components of (-)-noradrenaline were similarly distinguished by Bay k 8644 as observed for the selective alpha 1- or alpha 2-adrenoceptor agonists. Effects of Bay k 8644 on the increase in diastolic pressure mediated by B-HT 920, St 587 and cirazoline were also studied after pretreatment with the calcium entry blocker nifedipine. After additional pretreatment with nifedipine the potentiation by Bay k 8644 observed for B-HT 920 and St 587 was more pronounced. The presence of nifedipine had no effect on the interaction between Bay k 8644 and cirazoline. It is concluded that Bay k 8644 behaves as a mirror image of nifedipine.+

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1984

Lack of relationship between intrinsic activity and susceptibility of pressor responses to blockade by nifedipine among the alpha 2-adrenoceptor agonists B-HT 920 and B-HT 958.

Following i.v. bolus injections into pithed normotensive rats, the maximal diastolic pressor responses to B-HT 920 and B-HT 958 amounted to 115 and 35 mm Hg, respectively. Prazosin (0.1 mg/kg, i.v., -15 min) was without effect on the log dose-pressor effect curve of B-HT 958, whereas yohimbine (1 mg/kg, i.v., -15 min) shifted this curve about 30-fold to the right, showing the exclusive participation of alpha 2-adrenoceptors in the vasoconstrictor response to B-HT 958. In doses of 10 and 30 mg/kg, B-HT 958 displaced the log dose-vasoconstrictor effect curve of B-HT 920 approximately 6- and 30-fold, respectively, to the right, illustrating the partial agonism of B-HT 958 at postjunctional vascular alpha 2-adrenoceptors. Despite the marked difference in intrinsic activity of B-HT 920 and B-HT 958, the calcium entry blocker nifedipine exhibited a comparable inhibitory action on the vasopressor responses to both agonists. This finding indicates that partial and full agonism at vascular alpha 2-adrenoceptors are not related to the susceptibility of the initiated pressor response to inhibition by calcium entry blockade.

Adrenergic alpha-Agonists↗

PubMed1984

Inhibitory dopamine receptors on sympathetic neurons innervating the cardiovascular system of the pithed rat. Characterization and role in relation to presynaptic alpha 2-adrenoceptors.

Additional experimental evidence was obtained for an inhibitory function of prejunctional alpha 2-adrenoceptors and/or dopamine receptors located on noradrenergic neurons innervating the heart and resistance vessels of the pithed normotensive rat. Mixed alpha 2-adrenoceptor/dopamine receptor agonists, differing in selectivity towards either receptor type, i.e. N,N-di-n-propyldopamine (DPDA), 2-N, N-di-n-propylamino-6, 7-dihydroxy-1,2,3,4-tetrahydro-naphthalene (DP-6,7-ADTN), B-HT 920 and B-HT 933 (azepexole) were used. In pithed normotensive rats, DPDA (30 and 100 micrograms/kg/min) dose-dependently inhibited the electrical stimulation-induced increase in diastolic pressure, but did not significantly affect the stimulation-evoked increase in heart rate. The inhibition exerted by DPDA was blocked by haloperidol and sulpiride (0.3 mg/kg of each), but not by yohimbine (1 mg/kg), indicating the involvement of dopamine receptors. In this respect, sulpiride and haloperidol were found approximately equipotent. DP-6,7-ADTN (10 and 30 micrograms/kg/min) impaired both tachycardic and vasoconstrictor responses in a dose-dependent manner. Sulpiride (0.3 mg/kg) only partially restored the DP-6,7-ADTN-depressed stimulation-evoked increase in diastolic pressure, whereas yohimbine (1 mg/kg) alone was without effect. The combination of both antagonists completely prevented the inhibition caused by DP-6,7-ADTN. On the other hand, yohimbine (1 mg/kg), but not sulpiride (0.3 mg/kg), selectively antagonized the DP-6,7-ADTN-induced inhibition of stimulation-evoked tachycardia. B-HT 920 (1, 3 and 10 micrograms/kg/min) very effectively reduced the increase in diastolic pressure and heart rate caused by electrical stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗

PubMed1984

Effect of chronic elevation of plasma calcium concentration by PTH or vitamin D3 on blood pressure and hypotensive activity of nifedipine in rats.

The influence of a chronically elevated total plasma calcium concentration on blood pressure and heart rate was investigated in conscious normotensive rats. The plasma calcium concentration was elevated by continuous subcutaneous infusion with parathormone (PTH) after parathyreoidectomy, and by oral treatment with vitamin D3. In both groups an elevated blood pressure was observed at the 1st day of treatment only. Blood pressure was returned to pretreatment values from the second day of treatments onwards. No significant changes in heart rate, due to hypercalcaemia, were observed. In hypercalcaemic rats, the calcium entry inhibitor nifedipine proved more potent in reducing blood pressure than in normocalcaemic control animals. Hydralazine was equipotent in reducing blood pressure in both groups. It is suggested, that the vasoconstrictor effects of a chronically elevated total plasma calcium concentration in conscious rats does not obviously result in a chronically elevated blood pressure, but rather in an enhanced sensitivity of the blood pressure towards calcium entry blockade.

Animals↗

PubMed1984

Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.

Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1984

Interaction between the calcium entry blocker nifedipine with the alpha 1-adrenoreceptor-mediated increase in diastolic pressure elicited by catecholamines.

In the pithed normotensive rat the effect of the calcium entry blocker nifedipine was studied on alpha 1-adrenoreceptor-mediated pressor responses of intravenously administered (-)-noradrenaline, dopamine and (-)-adrenaline as well as of (-)-noradrenaline released from sympathetic neurones by DMPP, tyramine, McN-A-343 and electrical stimulation of the spinal cord at the level Th5-L4. The alpha 1-adrenoreceptor-mediated pressor responses to both intravenously administered and neuronally released catecholamines were moderately antagonized by nifedipine. The alpha 1-adrenoreceptor-mediated increase in diastolic pressure elicited by DMPP was unique in its extreme insensitivity to blockade by nifedipine. The results support the hypothesis that phenylethylamine-like alpha 1-adrenoreceptor agonists induce an increase in diastolic pressure relatively independent of extracellular calcium in contrast to imidazolidine-like agonists. The data may be interpreted as indicating that each alpha 1-adrenoreceptor agonist activates the alpha 1-adrenoreceptor in a unique way.

Adrenergic alpha-Agonists↗

PubMed1984

Effect of salbutamol and the PDE-inhibitor RA 642 on the clonidine withdrawal syndrome in rats.

The effect of continuous subcutaneous infusion of clonidine and the influence of concomitant treatment with salbutamol as well as the acute effects of the PDE-inhibitor RA 642 on heart rate and blood pressure of conscious normotensive rats were studied. The severity of the cardiovascular clonidine withdrawal symptoms was positively related to the amount of clonidine infused during treatment. Concomitant infusion of salbutamol (12 mg/kg/day) and clonidine (300 microgram/kg/day) attenuated the clonidine withdrawal tachycardia in conscious normotensive rats. No difference existed in the isoprenaline induced tachycardia in pithed normotensive rats, 8-14 h after cessation of infusion with clonidine (300 microgram/kg/day) and saline, clonidine and salbutamol (12 mg/kg/day), or saline alone. The PDE-inhibitor RA 642 (12 mg/kg, i.p.) aggravated the clonidine withdrawal syndrome in conscious normotensive rats. These data may indicate that long-term treatment with clonidine induces a hyperactivation of the adenylate-cyclase/cAMP-system.

Albuterol↗

PubMed1984

Affinity of WY 26703 for central and peripheral alpha 1- and alpha 2-adrenoreceptors in the rat; comparison with yohimbine.

The antagonist activity of Wy 26703 at vascular postjunctional alpha-adrenoreceptors was quantified against the methoxamine and B-HT 920-induced increase in diastolic pressure in pithed rats. For Wy 26703 pA2-values (= -log dose antagonist evoking a 2-fold shift for the agonist dose-response curve) of 4.96 and 6.43 are found, respectively, whereas for yohimbine values of 5.72 and 6.83 have been reported. The blocking potencies of Wy 26703 and yohimbine have been compared at cardiac prejunctional alpha 2- adrenoreceptors in rats. pA2-values of 6.84 and 6.97, respectively, resulted for the antagonism against the B-HT 920-induced inhibition of stimulation-induced tachycardia. At central alpha-binding sites Wy 26703 and yohimbine were compared for their ability to displace [3H]-prazosin, [3H]-yohimbine and [3H]-clonidine from their specific binding sites in rat brain homogenates. For both compounds binding data indicated a preferential affinity for cental alpha 2- over central alpha 1-binding sites. Wy 26703 exhibited a greater selectivity for cental alpha 2- as compared with central alpha 2-sites than did yohimbine. It is concluded that Wy 26703 behaves as a potent alpha 2-adrenoreceptor blocking agent, that is more selective than yohimbine for postjunctional and central alpha 2-adrenoreceptors as compared with alpha 1-adrenoreceptors. At cardiac prejunctional alpha 2-adrenoreceptors both blocking drugs appeared to be equipotent.

Animals↗

PubMed1984

Invariable susceptibility to blockade by nifedipine of vasoconstriction to various alpha 2-adrenoceptor agonists in pithed rats.

The sensitivity of the increase in diastolic pressure brought about by the selective agonists of alpha 2-adrenoceptors, B-HT 920, B-HT 933, xylazine, UK-14,304, M-7, TL-99 and DP-6, 7-ADTN in pithed normotensive rats to blockade by the calcium entry inhibitor nifedipine has been investigated. To exclude any participation of vascular alpha 1- and beta 2-adrenoceptors, as well as cardiac beta 1-adrenoceptors, in the pressor responses, the study was made after treatment of the pithed rats with prazosin (0.1 mg kg-1) and (-)-propranol (1 mg kg-1). Without exception, the preferential agonists of alpha 2-adrenoceptors elicited vasoconstrictor responses which were susceptible to inhibition by nifedipine (0.03-1 mg kg-1) in a dose-dependent manner regardless of the differences in intrinsic activity of the compounds. The pressor activity was almost completely abolished after 1 mg kg-1 of nifedipine. The results show that vasoconstriction induced in pithed rats by various selective stimulating agents of postjunctional vascular alpha 2-adrenoceptors is invariably and equally sensitive to attenuation by nifedipine. This susceptibility of alpha 2-adrenoceptor-mediated vasoconstriction to impairment by blockade of calcium entry is not dependent on the nature, the potency or the efficacy of the agonist.

Adrenergic alpha-Agonists↗