PubMed Health⌕ Search

Biomedical subjects

B Wilffert

Publications and source records attributed to B Wilffert.

At least 55 records · Page 3Linked to original sources
PubMed1989

Effects of calcium entry blocking agents on 5-hydroxytryptamine- and noradrenaline-induced contractions of rat isolated jugular vein and aorta.

We calculated the contribution of the intracellular releasable calcium pool to the contractile responses induced by 5-hydroxytryptamine (5-HT) and noradrenaline (NA) by constructing time-response curves to the agonists in Ca2+-deficient medium in the isolated rat jugular vein and aorta. Biexponential curves were obtained compatible with a two compartment model. In the aorta the intracellular calcium pools are likely to be different for both 5-HT and NA. Moreover, we investigated the effect of maximally effective concentrations of calcium entry blocking agents (CEB's) on K+, 5-HT- and NA-induced contractions in Ca2+-containing medium. Only a moderate inhibiting effect of nifedipine, diltiazem, flunarizine and gallopamil on 5-HT- and NA-induced Ca2+ influx could be observed; in contrast, K+-induced Ca2+ influx could be antagonized completely. The calculated contribution of intracellular Ca2+ to 5-HT- and NA-induced contractions, obtained from the experiments in Ca2+-"free" medium was much lower than that obtained after pretreatment with CEB's, leading to the conclusion that after CEB-pretreatment a Ca2+ influx component persists. This hypothesis was supported by the observation that contractions in Ca2+-"free" medium consist of a monophasic, fast response only, whereas after CEB-pretreatment a response similar to the control, including a slow, sustained component, was obtained. The Ca2+ influx component not affected by maximally effective concentrations of CEB's seems to represent an inflow of extracellular Ca2+ directly into the cytosol and not into an intracellular calcium store.

Animals↗
PubMed1989

Different sensitivities for four calcium entry blockers of serotonin-, but not K+-induced contractions of isolated jugular vein and aorta of the rat.

We investigated the inhibitory effect of the calcium entry blockers (CEBs) nifedipine, diltiazem, flunarizine and gallopamil on K+-and serotonin (5-HT)-induced contractions of the rat jugular vein and aorta in vitro. In both tissues all four CEBs inhibited K+-induced contractions concentration-dependently in a similar manner in the same concentration range. Only a smaller contraction due to hyperosmolarity of the medium as the result of addition of 100 mmol/l KCl persisted. 5-HT-induced contractions were antagonized more strongly by nifedipine than by diltiazem and flunarizine, suggesting different sites of action. Moreover, the arterial preparation proved to be more sensitive to CEB pretreatment than the jugular vein preparation. Gallopamil influenced 5-HT-induced contractions also by an antiserotonergic effect.

Animals↗
PubMed1989

R 56865 differentiates between contractile agents with respect to the nifedipine-sensitive component in the isolated rat aorta.

The interaction of the benzothiazolamine R 56865 with the nifedipine-sensitive component of the serotonin (5-HT)-, angiotensin II (AII)- and arginine-vasopressin (AVP)-induced contractions was studied in the isolated rat aorta. Nifedipine caused concentration-dependently (10(-9)-10(-6) mol/l) a slight rightward shift accompanied by a limited depression of the maximum of the concentration-response curves for 5-HT-, AII- and AVP-induced contractions. R 56865 (10(-5) mol/l) antagonized the contraction elicited by 5-HT and AII in a similar manner as nifedipine. The effect of R 56865 on 5-HT- and AII-induced contractions was no longer observed after pretreatment with nifedipine. The AVP-induced contraction was not affected by R 56865 (10(-5) mol/l). As shown previously, R 56865 is a weak inhibitor of potential-operated channels but inactive on Ca2+ channels activated by NA. In conclusion, R 56865 does not only differentiate between depolarization and receptor-stimulation, but also between the activation of Ca2+ channels by different types of receptors. We propose that R 56865 may interact with Ca2+ channels at a site which plays a role in their activation.

Angiotensin II↗
PubMed1989

Effect of calmodulin antagonists on contraction and 45Ca movements in rat aorta.

To study the selectivity of calmodulin antagonists it was assumed that they should inhibit noradrenaline (NA)- and K(+)-induced contractions similarly without an accompanying inhibition of 45Ca uptake. Therefore, in isolated rat aorta the effects of W-7, calmidazolium and trifluoperazine on contraction and 45Ca uptake elicited by K+ and NA were investigated. Calmidazolium (10(-5)-10(-4) mol/l) elicited an incomplete inhibiton of K(+)- and NA-induced contraction and 45Ca uptake. Trifluoperazine inhibited the NA-induced contractions at lower concentrations (10(-8)-10(-6) mol/l) than the K(+)-induced contraction (10(-6)-10(-4) mol/l). The K(+)- and NA-induced 45Ca uptake was blocked by trifluoperazine (10(-5) mol/l). W-7 (10(-5)-10(-4) mol/l) inhibited the K(+)- and NA-induced contraction, however, in the same concentration range W-7 diminished the K(+)- and NA-induced 45Ca uptake. In conclusion, the results indicate that calmidazolium and trifluoperazine are hardly useful as calmodulin antagonists because of their additional properties, whereas W-7 seems to be the least unspecific of the calmodulin antagonists studies.

Animals↗
PubMed1988

Different effects of R 56865 and calcium entry blockers on K+- and noradrenaline-induced contractions and 45Ca uptake in rat aorta.

The effects of R 56865, nifedipine, verapamil, diltiazem and flunarizine on K+- and NA-induced contractions and K+-induced 45Ca uptake were compared in the isolated rat aorta. The calcium entry blockers concentration dependently inhibited the K+-induced contraction and 45Ca uptake over the same dose-range. R 56865 inhibited the K+-induced 45Ca uptake, but only partly inhibited the K+-induced contraction. The calcium entry blockers caused a slight rightward shift and a depression of the maximum of the concentration-response curve for the NA-induced contraction. In contrast, R 56865 caused a strong, dose-dependent rightward shift and a depression of the maximum, 10(-6) and 10(-5) M being equieffective. The effects of R 56865 and nifedipine were independent of each other. Nevertheless, the NA-induced increase in 45 Ca uptake, a putative model for Ca influx, was attenuated by R 56865. In conclusion, R 56865 is a weak inhibitor of the K+-induced Ca influx but is without effect on the NA-induced Ca influx. The discrepancy between its effects on K+-induced contractions and 45Ca uptake may be explained by an inhibition of the uptake of 45Ca from the cytosol into the 45Ca pool. The interaction between R 56865 and the alpha 1-adrenoceptor-mediated contractions may be explained by an action at a site that is distinct from the NA-binding-site on the alpha 1-adrenoceptor.

Animals↗
PubMed1988

The anti-ischaemic activity of the novel compound, CERM 11956, compared with that of bepridil and nifedipine in isolated guinea-pig hearts.

A comparison between the protective activity of bepridil, its novel derivative, CERM 11956, and nifedipine in isolated electrically paced guinea-pig hearts after 60 min of global ischaemia followed by 30 min of reperfusion has been made. All three compounds exerted a significant anti-ischaemic effect, as indicated by an improved recovery of functional parameters (left ventricular pressure and coronary perfusion), a delayed onset of the ischaemic contracture, and an enhanced recovery of biochemical (CrP, ATP and adenylate energy charge) parameters. The most pronounced anti-ischaemic activity was shown by the compound CERM 11956 at concentrations that displayed only minor negative inotropic activity. From the results it may be concluded that the new bepridil derivative, CERM 11956, is a promising and potent anti-ischaemic compound, which has little influence on haemodynamic parameters.

Adenosine Triphosphate↗
PubMed1988

Investigation of the mechanism of negative inotropic activity of some calcium antagonists.

An attempt was made to discriminate between calcium entry blockade and other calcium antagonistic mechanisms involved in the negative inotropic activity of nifedipine, verapamil, diltiazem, flunarizine, lidoflazine, and bepridil in isolated guinea pig hearts. For this purpose, we used the calcium entry promoter Bay K 8644 as a tool to modulate the process of calcium entry at the sarcolemmal level. The calcium ionophore A 23187 was employed to increase intracellular calcium content without interfering with calcium channels. Bay K 8644 interacted with nifedipine, verapamil, and diltiazem; however, only a small inhibitory effect on the negative inotropic responses of flunarizine, lidoflazine, and bepridil was observed. The positive inotropic response of A 23187 was not influenced by nifedipine and was only slightly decreased by verapamil or diltiazem. After addition of flunarizine, lidoflazine, or bepridil, however, the positive inotropic effect of A 23187 was completely abolished. These results suggest that the negative inotropic effects of the calcium entry blockers are not only the result of calcium entry blockade. Apparently, an additional calcium antagonistic effect also plays a role for flunarizine, lidoflazine, and for bepridil and, to a lesser degree, for verapamil and diltiazem.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Comparison of mucus flow rate, radiolabelled glycoprotein output and smooth muscle contraction in the ferret trachea in vitro.

1. The concentration-response curves for rate of mucus output, labelled-glycoprotein output and smooth muscle contraction in response to methacholine, phenylephrine and salbutamol were determined in the ferret trachea in vitro. 2. The potencies of methacholine and phenylephrine are both in order: smooth muscle contraction, glycoprotein output, rate of mucus output. 3. At lower concentrations methacholine is more potent than is phenylephrine on smooth muscle contraction, glycoprotein output and rate of mucus output. 4. Concentration-response curves for salbutamol show very little change in rate of mucus output but a large increase in glycoprotein output. 5. It is concluded that the glycoprotein output induced by salbutamol may come from a source different from those induced by methacholine and phenylephrine.

Albuterol↗
PubMed1988

Measurement of slowly exchanging 45Ca in rat aorta without using EGTA or lanthanum and its application to quantify the effects of the calcium entry blockers nifedipine and verapamil.

In rat aortic strips a method was developed to measure a fraction of slowly exchanging 45Ca, which correlates with contraction and the cytosolic Ca pool that is enhanced by K+-induced depolarization. In this method no EGTA or lanthanum are used, but the strips are washed for 45 min with a Tyrode solution at 4 degrees C. The K+ depolarization induced increase in 45Ca and contraction was concentration-dependently inhibited by verapamil and nifedipine. Since lanthanum and EGTA affect cellular membranes, this method may allow a more physiological approach to the measurements of slowly exchanging 45Ca.

Animals↗
PubMed1988

Anti-ischaemic activity of various calmodulin antagonists.

The anti-ischaemic activity of the calmodulin antagonists trifluperazine, felodipine, W-7 and calmidazolium has been investigated in electrically paced guinea-pig hearts, perfused according to Langendorff, which were subjected to 60 min of global ischaemia followed by 30 min of reperfusion. At concentrations that induced a comparable reduction in cardiac contractile force, trifluperazine, felodipine and to a lesser extent W-7, were associated with improvement of post-ischaemic functional (LVP and coronary flow) and biochemical parameters (CrP and ATP). Furthermore, felodipine and trifluperazine delayed the onset and suppressed the maximum tension of the ischaemic contracture was observed. In contrast, calmidazolium had no anti-ischaemic effects. This lack of anti-ischaemic activity of the most potent calmodulin antagonist calmidazolium, as well as the significant calcium entry blocking activity of both trifluperazine and felodipine suggest that additional factors besides calmodulin antagonism may contribute to the anti-ischaemic activity of these compounds.

Adenosine Triphosphate↗
PubMed1987

A comparison of the cardiac and vasodilatory effects of some calcium entry blockers in perfused isolated guinea-pig hearts.

The chronotropic, inotropic and coronary vasodilator actions of several calcium entry blockers have been compared in isolated guinea-pig hearts. Following the subdivision of calcium entry blockers as proposed by Spedding (1985), we have studied nifedipine (dihydropyridine) (group I), verapamil (phenylalkylamine) and diltiazem (benzothiazepine) (group II), flunarizine and lidoflazine (both diphenylalkylamines) as well as bepridil (group III). Moreover, the effect of the calcium entry blockers upon the calcium induced inotropic response was assessed. All calcium entry blockers displayed a clear negative inotropic, negative chronotropic and coronary vasodilating effect. The order of potency for the negative inotropic, coronary dilator and negative chronotropic actions of the calcium entry blockers was, for inotropy: nifedipine greater than verapamil greater than flunarizine = bepridil greater than lidoflazine greater than diltiazem, for coronary flow: nifedipine greater than verapamil greater than lidoflazine = flunarizine greater than diltiazem greater than bepridil, for chronotropy: nifedipine greater than verapamil greater than lidoflazine greater than flunarizine greater than diltiazem greater than bepridil. With respect to the cardiac parameters, the diphenylalkylamines were more potent in their action than described previously by other authors. Equi-effective doses with respect to the negative inotropic effect of the calcium entry blockers studied also displayed the same effectiveness upon calcium-induced inotropic responses. This suggests that the negative inotropic effect of the calcium entry blockers investigated is the result of a calcium antagonistic effect without the contribution of other actions of these drugs. However, the different potency orders for the coronary dilator and negative chronotropic actions of the calcium entry blockers and the differences in maximum for coronary dilator effects suggest that other mechanisms (such as calmodulin antagonism, adenosine uptake inhibition and sodium channel blockade), may contribute to these effects.

Animals↗
PubMed1986

Inhibitory effect of calcium antagonist drugs on vasoconstriction induced by vascular alpha 2-adrenoceptor stimulation.

A survey is given of the mechanisms of the antihypertensive effect of calcium entry blockers. The main background of the antihypertensive/hypotensive action is dilatation of precapillary arterioles (resistance vessels that cause a reduction in total peripheral resistance and, hence, a decrease in blood pressure). The vascular relaxation is caused by an inhibition of the transmembranous calcium influx and, probably less so, by interference with calmoduline. Calcium entry blockers significantly reduce the vasoconstriction induced by the excitation of vascular postsynaptic alpha 2 adrenoceptors. The inhibitory effect of calcium entry blockers is reversed by the calcium entry promoter Bay k 8644. The vasoconstriction induced by alpha 1-adrenoceptor stimulation is less generally influenced by calcium entry blockers than the alpha 2 effects. The interference with alpha 2-adrenoceptor-induced vasoconstriction may contribute to the vasodilator action of the calcium entry blockers, especially in hypertensive patients who show a hyperreactivity to pressor responses toward catecholamines.

Adrenergic alpha-Agonists↗
PubMed1986

Inhibitory effect of alpha-1 adrenoceptor stimulation on cardiac sympathetic neurotransmission in pithed normotensive rats.

In the present study we investigated the inhibitory effect of the selective alpha-1 adrenoceptor agonists cirazoline, amidephrine and St 587 on the cardiac sympathetic neurotransmission in pithed normotensive rats. Increases in heart rate were elicited by electrical stimulation of the cardiac sympathetic nerves or by i.v. administration of norepinephrine, isoproterenol or tyramine. Intravenous pretreatment of the animals with cirazoline, amidephrine or St 587 diminished the heart rate response to sympathetic stimulation significantly. However, the tachycardia produced by norepinephrine, isoproterenol or tyramine was also inhibited significantly by the selective alpha-1 adrenoceptor agonists. The selective alpha-1 antagonist prazosin blocked the sympathoinhibitory effect to alpha-1 adrenoceptor stimulation significantly. However, the inhibitory effect of cirazoline and St 587 was not suppressed completely by a maximally effective dose of prazosin. In contrast, the sympathoinhibitory action of amidephrine was antagonized completely by prazosin. However, the selective alpha-2 antagonist rauwolscine also produced a significant, albeit modest, attenuation of the sympathoinhibitory effect to amidephrine. The results of the present study indicate that alpha-1 adrenoceptor agonists, at relatively high doses, inhibit the sympathetic neurotransmission in rat heart. This sympathoinhibitory effect is mediated largely by alpha-1 adrenoceptors which are localized postjunctionally rather than prejunctionally.

Adrenergic alpha-Agonists↗
PubMed1986

Central and peripheral effects of S 3341 [(N-dicyclopropylmethyl)-amino-2-oxazoline] in animal models.

The effects on blood pressure and heart rate of S 3341 [(N-dicyclopropylmethyl)-amino-2-oxazoline] were investigated in rats and cats. Upon i.v. injection in pithed rats, S 3341 produced pressor responses which were antagonized by prazosin as well as by yohimbine. In pentobarbitone-anesthetized rats S 3341 produced a short-lasting increase in mean arterial pressure, followed by a long-lasting reduction. During a 12-day, continuous subcutaneous infusion in conscious spontaneously hypertensive rats, S 3341 reduced blood pressure and heart rate. Upon cessation of treatment, an overshoot of heart rate and blood pressure lability occurred. The hypotensive effect was abolished by reserpinization of the rats. S 3341 was more potent in reducing mean arterial pressure upon infusion via the vertebral artery than after infusion via the femoral artery of chloralose-anesthetized cats. S 3341 did not prolong the hexobarbitone-induced loss of righting reflex in mice. S 3341 was more potent in displacing [3H]clonidine than [3H]prazosin from their specific binding sites in rat brain membranes. These data characterize S 3341 as a clonidine-like, centrally acting antihypertensive drug. The lack of sedative effect, as assessed by the prolongation of hexobarbitone-induced sleeping in mice, remains to be clarified.

Adrenergic alpha-Agonists↗
PubMed1985

Differential selectivities of RU 24969 and 8-OH-DPAT for the purported 5-HT1A and 5-HT1B binding sites. Correlation between 5-HT1A affinity and hypotensive activity.

RU 24969 and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) inhibited the specific binding of [3H]5-HT (2 nM) to rat brain membranes with shallow displacement curves. The displacement data were best fitted with a model of two independent, high and low affinity binding sites. Following addition of spiperone (1 microM) as a selective ligand for the putative 5-HT1A recognition site of [3H]5-HT, the displacement curve of RU 24969 underwent a leftward shift, whereas spiperone induced a shift to the right for the displacement curve of 8-OH-DPAT. In contrast to spiperone, pindolol (1 microM) shifted the displacement curve of RU 24969 to the right. These results suggest that RU 24969 possesses preference for the purported 5-HT1B subtype of central 5-HT1 recognition site. The reported significant linear correlation between hypotensive activity following intravenous (i.v.) administration to anesthetized rats and affinity for the central 5-HT1 binding site could only be maintained by incorporation of the affinity of RU 24969 for its low and 8-OH-DPAT for its high affinity binding site. Based on the proposal that the 5-HT1A site corresponds to the high affinity site of 8-OH-DPAT and the low affinity site of RU 24969, it is hypothesized that the late depressor phase of 5-HT agonists in rats is mediated by activation of peripheral (vascular) 5-HT receptors which have similarities with the 5-HT1A subtype of central 5-HT1 recognition site.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Effects of the irreversible alpha-adrenoceptor antagonists phenoxybenzamine and benextramine on the effectiveness of nifedipine in inhibiting alpha 1- and alpha 2-adrenoceptor mediated vasoconstriction in pithed rats.

In pithed normotensive rats, i.v. injection of the selective alpha 1-adrenoceptor agonist cirazoline produced vasoconstriction which was largely resistant to inhibition by nifedipine. On the other hand, the pressor effects of the selective alpha 1-adrenoceptor agonists St 587 and Sgd 101/75 were much more effectively blocked by nifedipine, although not as effectively as the pressor effects to the selective alpha 2-adrenoceptor agonist B-HT 920. The sensitivity to inhibition of vasoconstriction in pithed rats to the different agonists increased in the order cirazoline much less than St 587 less than Sgd 101/75 less than B-HT 920. Phenoxybenzamine (3-300 micrograms/kg, i.v., -60 min) irreversibly antagonized the vasoconstriction to cirazoline, St 587, Sgd 101/75 and B-HT 920. After treatment of the rats with phenoxybenzamine the potency and efficacy of nifedipine in antagonizing vasoconstriction to alpha 1-, but not to alpha 2-adrenoceptor activation was dose-dependently enhanced. The potency of nifedipine to inhibit alpha 1-adrenoceptor-mediated vasoconstriction by cirazoline, St 587 and Sgd 101/75 was increased maximally to the level of efficacy at which nifedipine antagonized B-HT 920-induced vasoconstriction. The dose of phenoxybenzamine required to maximally increase the potency and efficacy of nifedipine to antagonize vasoconstriction of the alpha 1-adrenoceptor agonists was inversely related to the level of sensitivity to blockade by nifedipine of the vasoconstriction they produced. In contrast, pretreatment of rats with the irreversible antagonist, benextramine (10 mg/kg, i.v., -100 to -60 min) did not increase the potency or efficacy of nifedipine to antagonize vasoconstriction to cirazoline, St 587, Sgd 101/75 or B-HT 920, despite irreversible blockade of alpha 1- and alpha 2-adrenoceptors. These data suggest that phenoxybenzamine, but not benextramine, selectively inhibits the alpha 1-adrenoceptor mediated vasoconstrictor mechanism that is independent of influx of extracellular calcium. Moreover, the results show that the existence of receptor reserve or the number of alpha 1-adrenoceptors activated does not determine the relative contribution of calcium influx-independent mechanisms in alpha 1-adrenoceptor-mediated vasoconstriction.

Animals↗
PubMed1985

Calcium dependency of vasoconstriction mediated by alpha 1- and alpha 2-adrenoceptors.

A survey is given of the calcium dependency of vasoconstriction mediated by alpha 1- and alpha 2-adrenoceptors. In all species studied and with all drugs investigated, it has been confirmed that alpha 2-adrenoceptor-mediated vasoconstriction is sensitive to calcium entry blockade with calcium antagonists, both in vivo and, under suitable experimental circumstances, also in vitro. The calcium entry promotor (calcium agonist) Bay k8644 appears to behave as a mirror image of the calcium-entry blockers. alpha 1-Adrenoceptor-agonist-induced vasoconstriction shows a differential picture with respect to the dependency of extracellular calcium. Accordingly, the vasoconstriction induced by the alpha 1-agonists cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine, and (-)-amidephrine is not primarily dependent upon an influx of calcium, whereas other compounds like St 587 and Sgd 101/75 cause vasoconstriction which is very sensitive to drug-induced calcium entry blockade. It may be possible that different recognition sites of the alpha1-adrenoceptors are involved. In this connection, the calcium-entry promotor Bay k8644 does not simply behave as the mirror image of calcium entry blockers.

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