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Biomedical subjects

J C van Meel

Publications and source records attributed to J C van Meel.

At least 19 recordsLinked to original sources
PubMed1996

Hypotensive effects of the angiotensin II antagonist telmisartan in conscious chronically-instrumented transgenic rats.

The effects after oral administration of the angiotensin II antagonist telmisartan (CAS 144701-48-4, BIBR 227) on arterial blood pressure and heart rate of conscious chronically-instrumented TGR (mREN2)27 transgenic rats were studied. Each dose of telmisartan (0.5, 1 and 2 mg/kg) was given for one week via the drinking water to transgenic rats and cardiovascular parameters were monitored via telemetry. Losartan and captopril were given for comparison. Telmisartan dose-dependently decrease mean arterial blood pressure by -33 mmHg at 0.5 mg/kg/d, -57 mmHg at 1 mg/kg/d, and -72 mmHg at 2 mg/kg/d. Heart rate was lowered by -33 bpm at the lowest dose and -39 bpm at the highest dose of telmisartan. The reference compounds losartan and captopril given via the drinking water also lowered blood pressure in these transgenic rats. The decreases in mean arterial blood pressure amounted to -13 mmHg at 1 mg/kg/d, -22 mmHg at 2 mg/kg/d and -33 mmHg at 4 mg/kg/d losartan and -54 mmHg at 10 mg/kg/d captopril. In general, heart rates slightly decreased after oral administration of both compounds. These data show that telmisartan was an effective antihypertensive agent in these transgenic rats at oral doses of > or = 0.5 mg/kg/d. The compound was more potent than losartan in reducing mean arterial blood pressure in the TGR (mREN)27 transgenic rats.

Administration, Oral↗
PubMed1995

Low concentrations of UD-CG 212 enhance myocyte contractility by an increase in calcium responsiveness in the presence of inorganic phosphate.

Recent data show that UD-CG 212 in nanomolar concentrations increases myofibrillar Ca++ responsiveness of chemically skinned cardiac preparations in the presence of elevated inorganic phosphate. We studied the effects of UD-CG 212 on cell shortening of intact myocytes and in addition measured the intracellular calcium transients with the aid of INDO-1 fluorescence in the presence of 5 mM inorganic phosphate. The validity of our experimental system was first tested with the calcium channel opener Bay k 8644. Bay k 8644 at 10(-8) M did not significantly influence myocyte shortening (+ 13.9 +/- 4.6%, n = 9) but at 10(-7) M and 10(-6) M significantly increased contraction by 40.1 +/- 13.6% and 52.5 +/- 17.0% respectively. Bay k 8644 at 10(-8) M increased the INDO-1 fluorescence ratio by 17.3 +/- 4.7% (P < 0.01; n = 9), and at 10(-7) M by 21.5 +/- 4.3% (P < 0.01; n = 9), whereas 10(-6) M Bay k 8644 had no significant effect on peak INDO-1 ratio. However, 10(-7) and 10(-6) M Bay k 8644 accelerated and broadened the calcium transients.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Effects of pimobendan and its metabolite on myofibrillar calcium responsiveness and ATPase activity in the presence of inorganic phosphate.

The effects of the cardiotonic agent pimobendan (CAS 118428-36-7, UD-CG 115 BS) and its main metabolite UD-CG 212 on dog cardiac myofibrillar calcium responsiveness and ATPase activity were studied at nominal free inorganic phosphate (Pi) and at 5 mmol/l Pi. A rightward shift of the pCa-tension relationship with a marked depression of maximal tension was observed in the presence of 5 mmol/l Pi. Pimobendan increased myofibrillar calcium responsiveness at concentrations > or = 10(-5) mol/l. These effects of pimobendan were significantly greater at 5 mmol/l Pi than at nominally free Pi. UD-CG 212 had no influence on myofibrillar calcium responsiveness at nominally free Pi, however, significant effects were observed at 10(-9) mol/l UD-CG 212 in the presence of 5 mmol/l Pi. UD-CG 212 (10(-8) mol/l) did not influence myofibrillar ATPase activity at pCa's 6.23, 5.99, and 4.36 with or without 5 mmol/l Pi, whereas pimobendan (10(-4) mol/l) had an effect only at pCa = 5.99 (without Pi) and pCa = 4.36 (+ 5 mmol/l Pi). The data suggest that the increase in myofibrillar calcium responsiveness at submaximal calcium concentrations by pimobendan and UD-CG 212 in the presence of 5 mmol/l Pi is brought about by a change in cross-bridge kinetics or by enhancement of thin filament activation by adjacent strong cross-bridges. At maximal calcium activation, pimobendan may additionally increase the population of strong cross-bridges.

Adenosine Triphosphatases↗
PubMed1994

Inhibitory effect of dithiothreitol on angiotensin II-induced contractions mediated by AT1-receptors in rat portal vein and rabbit aorta.

The disulfide-reducing agent dithiothreitol (DTT) has been shown to reduce angiotensin II (Ang II) subtype 1 receptor (AT1) binding sites in various tissues. Its effect on Ang II-induced contractions was studied in the rat portal vein and rabbit aorta. In the isolated rat portal vein, DTT shifted the concentration-response curve for Ang II to the right (DTT 0.5-3 mmol/l) and depressed the maximal response (DTT 1-3 mmol/l). DTT 5 mmol/l almost abolished the effect of Ang II. In the isolated rabbit aorta, the inhibitory effect of DTT was more pronounced and its pattern of effect was different, since DTT 0.3 and 0.5 mmol/l caused a progressive flattening of the concentration-response curve of Ang II. DTT (1 mmol/l) fully suppressed the effect of Ang II. A biphasic curve consisting of a high sensitivity component and a component of low sensitivity for Ang II was observed after pretreatment with DTT 1 mmol/l in the rat portal vein but not in the rabbit aorta. In the presence of DTT 1 mmol/l, the AT1-receptor antagonist losartan antagonized the high sensitivity response to Ang II in a competitive manner with a pA2 value very similar to that obtained in the absence of DTT, suggesting that this response to Ang II is mediated by those AT1-receptors which were not inactivated by DTT. The biphasic curve may be explained by the occurrence of a single AT1-receptor subtype existing in two different states. Another possibility might be the involvement of two AT1-receptor subpopulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships.

Starting from the recently reported nonpeptidic angiotensin II (AII) receptor antagonists DuP753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systemic variation of several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups results in highly active AII antagonists. Compounds with 6-membered lactam or sultam substituents in position 6 of benzimidazole showed receptor activities in the low nanomolar range but were only weakly active when given orally to rats. In contrast, analogous substitution of the benzimidazole moiety with basic heterocycles resulted in potent AII antagonists which were also well absorbed after oral application. The most active compound of this series, 33 (BIBR 277), was selected as a candidate for clinical development. On the basis of molecular modeling studies a binding model of this new class of AII antagonists to the AT1 receptor is proposed.

Angiotensin II↗
PubMed1993

Angiotensin II receptor antagonists.

The development of novel non-peptide compounds with high affinity for-angiotensin II (Ang II) receptors has greatly facilitated the subclassification of Ang II receptors into AT1- and AT2-receptor subtypes. Whereas PD 123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenyl-acetyl-4,5,6,7-tetrahydro- 1H-imidazol [4,5-c]pyridine-6-carboxylic acid) is the prototypical antagonist for AT2-receptors, DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl) methyl) imidazole, losartan) is the prototypical antagonist for AT1-receptors. So far, non-selective non-peptide Ang II receptor antagonists have not been identified although AT1/AT2 selectivity ratios of 17 and 37 have already been reported for BIBS 39 (4'-[(2-n-butyl-6- cyclohexylaminocarbonylamino-benzimidazole-1-yl)-methyl] biphenyl-2-carboxylic acid) and BIBS 222 (2-n-butyl-1-[4-(6-carboxy-2, 5-dichlorobenzoylamino)-benzyl]-6-N-(methylaminocarbonyl)- n-pentylaminobenzimidazole). Functional studies with AT1-antagonists indicate that Ang II antagonism at the receptor level can be rather complex. Experimental data suggests that not only are receptor binding kinetics involved, but also that additional binding sites, and possibly even AT1 subtypes, are involved. The antihypertensive activity of the AT1-antagonist DuP 753 is demonstrated in a high renin (2K 1C) and a low renin (TGRmREN2) hypertensive rat model. The kidney especially is very sensitive to Ang II and this organ seems to be a target for Ang II receptor antagonists. This can be demonstrated with experiments on the isolated rat kidney.

Amino Acid Sequence↗
PubMed1989

Pimobendan increases calcium sensitivity of skinned human papillary muscle fibers.

The calcium sensitizing effects of the cardiotonic agent pimobendan on force production were investigated on chemically skinned human papillary muscle fibres. The papillary muscles were obtained from patients undergoing mitral valve replacement operations. Tension was produced by different free calcium concentrations and 100 mumol/l of pimobendan shifted the pCa-tension relationship significantly to the left. The effects of pimobendan were concentration dependent (10-300 mumol/l) but additionally also correlated with the state of left ventricular performance of the patients. Skinned papillary muscle fibres obtained from patients with reduced ventricular performance were more sensitive to calcium as well as pimobendan compared with fibres from patients with normal left ventricular performance. No differences in response to pimobendan were observed between fibres from NYHA II and NYHA III heart failure patients.

Calcium↗
PubMed1989

Pimobendan increases survival of cardiomyopathic hamsters.

We investigated the effect of the new cardiotonic drug pimobendan on survival of hereditary cardiomyopathic hamsters. Untreated cardiomyopathic hamsters served as controls. A 50% mortality was observed after 280 days for the control group and after 318 days for the pimobendan-treated animals. After 340 days, survival was 0% for the untreated cardiomyopathic hamsters and 27% in the pimobendan-treated group. We conclude that pimobendan slows the progression of heart failure in cardiomyopathic hamsters.

Animals↗
PubMed1989

Hemodynamic profile of the cardiotonic agent pimobendan.

Pimobendan (UD-CG 115 BS) is a potent positive inotropic agent with vasodilatory properties. This hemodynamic profile was demonstrated in conscious rabbits chronically instrumented with Doppler flow probes. Pimobendan (10, 30, 100, and 300 micrograms/kg i.v.) increased cardiac output, stroke volume, heart rate, and mesenteric, renal, and hindquarter blood flow velocities, and decreased diastolic blood pressure. The positive inotropic effects of pimobendan and its effects on pre- and afterload were also shown in dogs with propranolol-induced depressed myocardial function. Pimobendan exhibited strong effects on stroke volume (up to 59%) and pulmonary capillary wedge pressure (up to -84%). The substance increased left ventricular (LV) dp/dtmax up to 150% and also had favorable effects on renal blood flow. Left ventricular function curves showed the usefulness of pimobendan in this acute heart failure model. Pimobendan is well absorbed and its duration of action is long. Positive inotropic effects of pimobendan were observed for 8-12 h after oral administration of 0.1-1 mg/kg to conscious dogs. It is concluded that pimobendan produces cardiovascular effects that may be useful in the treatment of congestive heart failure.

Administration, Oral↗
PubMed1988

Increase in calcium sensitivity of cardiac myofibrils contributes to the cardiotonic action of sulmazole.

The aim of this study was to investigate whether increasing calcium sensitivity of myofibrils plays a role in the positive inotropic activity of the cardiotonic agent sulmazole. We studied the effects of the stereoisomers of sulmazole on cardiac contractility in vivo and in vitro, arterial blood pressure, cardiac (Na-K)ATPase activity, cAMP/cGMP-phosphodiesterase activity of cardiac and smooth muscle tissue and calcium sensitivity of skinned myocardial fibres. Both stereoisomers of sulmazole were equipotent vasodilators in vivo and this can be explained by their equipotent cAMP- and cGMP-phosphodiesterase inhibitory activities in smooth muscle tissue. However, (+)sulmazole was a much stronger positive inotropic agent than (-)sulmazole in vivo and in vitro. This difference in inotropic activity cannot be explained by cAMP- or cGMP-phosphodiesterase inhibition or (Na-K)ATPase inhibition in cardiac tissue. Only (+)sulmazole produced a dose-dependent increase in calcium sensitivity of skinned myocardial fibres. Therefore, the calcium sensitizing effect on myofibrils evoked by (+)sulmazole might be responsible for the difference in inotropic activity observed between the stereoisomers of sulmazole.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Effects of some cardiotonic agents on contractility of skinned fibers from mammalian heart.

Nine cardiotonics of different chemical structure were investigated on their ability to influence calcium-induced isometric contractions of chemically skinned porcine myocardial fibers. It was found that at a concentration of 10(-4) mol/l amrinone, enoximone, imazodan, milrinone, piperanometozine and piroximone were without effect on calcium-induced tension development of skinned fibers. 3-Amino-6-methyl-5-phenyl-2(1H)-pyridinone (APP), pimobendan and sulmazole enhanced the isometric contractions induced by 0.66 mumol/l Ca++ concentration-dependently. The intrinsic activity of pimobendan was much higher than for sulmazole or APP. Comparing equieffective concentrations inducing 35% additional tension development, the rank order of potency was: pimobendan greater than APP greater than sulmazole.

Animals↗
PubMed1985

Comparison of some new positive inotropic agents in guinea pigs.

The pithed guinea pig is introduced as a model for evaluating positive inotropic and vasodilator effects of substances. The model was characterized by means of ouabain, isoprenaline and hydralazine. In this model, the effects of some new noncatecholamine, nonglycoside positive inotropic agents were compared with respect to an increase in LV-dp/dtmax, effects on heart rate and vasodilator effects. Comparing equieffective doses (inducing an increase in LV-dp/dtmax by 1,000 mm Hg/s), the rank order of potency was AR-L 100 greater than AR-L 57 greater than MDL-17043 greater than AR-L 115 greater than amrinone. The investigated substances also exhibited vasodilating effects. Comparing the doses which decreased diastolic blood pressure by 25 mm Hg, the order of potency was AR-L 57 greater than AR-L 115 greater than MDL-17043 greater than amrinone greater than AR-L 100.

Aminopyridines↗
PubMed1983

Differential effect of calcium entry blockers on alpha 1-adrenoceptor-mediated vasoconstriction in vivo.

The effects of the calcium entry blockers nifedipine, (-)-verapamil and the dihydropyridine derivative PY 108-068 were evaluated on the increase in diastolic pressure of pithed normotensive rats caused by the selective alpha 1-adrenoceptor agonists cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine, (-)-amidephrine and St 587 [(2-chloro-5-trifluoromethylphenylimino)-2-imidazolidine] as well as by the mixed alpha 1/alpha 2-adrenoceptor agonists clonidine and DPI [(3,4-dihydroxyphenylimino)-2-imidazolidine]. The calcium entry inhibitors (up to 3 mg/kg) caused 3- to 5-fold, parallel rightward shifts of the log dose-pressor effect curves to cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine and (-)-amidephrine accompanied by only a slight depression of the maximal pressor response. In contrast, the calcium entry inhibitors produced a dose-dependent profound depression of both maximum and slope of the log dose-pressor response curves to St 587 and clonidine. For DPI about 10- and 100-fold parallel displacements to the right without reduction of the maximum were found following treatment with 1 and 3 mg/kg of nifedipine, respectively. Infusion of vasopressin to counteract the vasodilatory action produced by the calcium entry inhibitors did not significantly change the pattern of interference observed under the conditions of decreased baseline diastolic pressure. The results indicate that alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat, which is characterized by its sensitivity to blockade by prazosin and its relative insensitivity to antagonism by yohimbine or rauwolscine, can be subdivided into two distinct processes which are differentially influenced by blockade of calcium entry.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1983

Correlation between the inhibitory activities of calcium entry blockers on vascular smooth muscle constriction in vitro after K+-depolarisation and in vivo after alpha 2-adrenoceptor stimulation.

Calcium entry blockers are known to depress the maximal increase in diastolic pressure induced in pithed rats by selective alpha 2-adrenoceptor stimulation. In order to substantiate the relevance of calcium fluxes in this interaction, a correlation between the potency of calcium entry blockers in pithed rats and their calcium antagonistic potency in vitro was investigated. Accordingly, the inhibition of calcium entry blockers with respect to alpha 2-adrenoceptor-mediated vasoconstriction was quantified in terms of -log ID50 values. As a measure of calcium antagonistic potency, the inhibitory activity of a number of calcium entry blockers on K+-induced contractions of rabbit thoracic aorta strips was determined and the negative logarithms of the 50% inhibitory concentrations, -log IC50, were calculated. A highly significant linear relationship was found between the in vitro, -log IC50, and the in vivo parameter, -log ID50, of the calcium entry blockers. This result suggests a similar type of interaction for the calcium entry blockers in vivo and in vitro, i.e. inhibition of a transmembrane influx of extracellular calcium.

Animals↗
PubMed1983

Hypotensive activity of tetrandrine in rats. Investigation into its mode of action.

The influence of tetrandrine on arterial pressure and heart rate of pentobarbitone-anaesthetized and conscious normotensive and hypertensive rats (SH rats, renal hypertensive rats, DOCA-salt hypertensive rats) was investigated. Tetrandrine administered intravenously (i.v.) to these animals caused an acute, long-lasting and dose-dependent decrease in mean arterial pressure. Heart rate was not significantly altered. In pithed rats, tetrandrine injected intraarterially 15 min previously impaired the increase in diastolic pressure induced by i.v. B-HT 920, a highly selective alpha 2-adrenoceptor-stimulating agent, in a dose-dependent manner. In a low dose, a parallel displacement to the right was observed, whereas for higher doses the shift was non-parallel. A high dose of tetrandrine shifted the pressor response curve of the alpha 1-adrenoceptor agonist, methoxamine, only slightly to the right and did not depress the maximal response. Tetrandrine also caused a moderate rightward shift of the vasopressor effect curve of vasopressin applied i.v. Tetrandrine displayed only minor affinities for specific binding sites in rat brain membranes for [3H]-prazosin (alpha 1-adrenoceptors) and for [3H]-clonidine (alpha 2-adrenoceptors). The results obtained suggest that the hypotensive effect of tetrandrine may be related to an impairment of vasoconstrictor tone mediated by vascular postsynaptic alpha 2-adrenoceptors.

Alkaloids↗
PubMed1983

Postsynaptic alpha 1- and alpha 2-adrenoceptor blocking properties of (dihydro)quinidine and (dihydro)quinine.

The antagonistic properties of the cinchona alkaloids quinidine, dihydroquinidine, quinine and dihydroquinine were evaluated with respect to alpha 1- and alpha 2-adrenoceptor-induced vasoconstriction in pithed normotensive rats. Radioligand displacement studies were performed to determine the in vitro affinities of the alkaloids for alpha 1- and alpha 2-adrenoceptors. Quinidine and dihydroquinidine were more effective alpha 1-adrenoceptor antagonists than quinine and dihydroquinine. Their weak to moderate alpha 1-sympatholytic activities were compatible with their in vitro affinity for alpha 1-adrenoceptors. The potencies of (dihydro)quinidine and (dihydro)quinine in inhibiting vascular postsynaptic alpha 2-adrenoceptor-mediated pressor effects were also weak and comparable in the lower dose range (15-250 mumol kg-1). In a dose of 300 mumol kg-1, dihydroquinidine exceeded the other alkaloids in activity. The alpha 2-adrenoceptor antagonistic actions of the alkaloids did not correspond with their actual affinity for alpha 2-adrenoceptors observed in vitro. A calcium antagonistic action is proposed to contribute to the interference of these drugs with the vasoconstriction governed by alpha 2-adrenoceptors. The interaction of quinine, quinidine and their hydrogenated products with vascular alpha 1- and alpha 2-adrenoceptors may explain their hypotensive properties as well as their therapeutic effect in certain forms of vascular disorders.

Adrenergic alpha-Antagonists↗