Effects of the New Calcium Antagonist PN 200–110 on the Myocardium and the Regional Peripheral Circulation in Anesthetized Cats and Dogs

Hof, Robert P.; Hof, Akiko; Scholtysik, G; Menninger, Klaus

doi:10.1097/00005344-198405000-00006

Cited by 81 publications

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“…Therefore, the negative inotropic effect of Ca 2+-antagonists seems to be independent of the severity of heart failure. This is in line with studies by Rasmussen et al [44] indicating that in the failing human heart the density of dihydropyridine binding sites remains unchanged [17,18,23,24,25,36].…”

Section: Discussionsupporting

confidence: 92%

“…Since CaZ+-antagonists may also exert shortterm hemodynamic benefits in patients with heart failure (e.g., nitrendipine and isradipidine [42]) their action on smooth muscle cells might outweigh their negative inotropic potency [11,13,[21][22][23][24]54]. To test whether the rank order of potency of the various Ca 2 +-antagonists examined in this study is relevant in vivo, we compared the IC25 values (concentrations required for 25% decrease of the basal force of contraction) with therapeutically active free plasma concentration [2,19,22,33,40,48].…”

Section: Discussionmentioning

confidence: 99%

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Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

1990

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To evaluate the negative inotropic effect of various Ca2(+)-antagonists in human myocardium without additional influences of preload, afterload, or frequency, we examined their effects on isometric force of contraction in isolated human papillary muscle strips and in auricular trabeculae. The 1,4-dihydropyridines isradipine, nitrendipine, and nifedipine, the phenylalkylamine verapamil, and the benzothiazepine diltiazem exerted concentration-dependent negative inotropic effects. The potency of the investigated Ca2(+)-antagonists was identical in papillary muscle strips of patients with only moderate clinical signs of heart failure undergoing mitral valve replacement-operation (NYHA II-III) and in terminally failing (heart transplantation, NYHA IV) human hearts. The IC50 values were lower in auricular trabeculae than in papillary muscle strips. The difference was significant for nifedipine, nitrendipine, and verapamil. The restorative effects of external Ca2+ after pretreatment with Ca2(+)-antagonists were significantly less strong after pretreatment with 1,4-dihydropyridine than with non-dihydropyridines in papillary muscle strips. It is concluded that 1,4-dihydropyridines and verapamil and diltiazem did differently influence Ca2(+)-mediated increase in force of contraction. Moreover, a relation between the therapeutically active free plasma concentration in vivo and the negative inotropic potency in vitro can be found. This relation follows a rank order of potency for negative inotropism (isradipine less than or equal to nitrendipine less than diltiazem less than nifedipine less than verapamil) and might have clinical relevance in the treatment of patients with compromised cardiac function.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

1990

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“…It should be noted that before the ischaemia neither the endo/epi ratio nor the total coronary flow were significantly affected by PN treatment (Figures 5 and 6). These observations are at variance with previous in vivo studies in cats, where PN markedly increased coronary blood flow (Hof et al, 1984a). The discrepancy is probably attributable to the high baseline flow values (around 600 ml min-' per 100 g of tissue) in the present experiments with Tyrode-perfused isolated hearts, allowing little additional coronary reserve on which to see vasodilator effects.…”

Section: Discussioncontrasting

confidence: 72%

Cardioprotection by the calcium antagonist PN 200‐110 in the absence and presence of cardiodepression

Cook

Hof

1985

British J Pharmacology

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The globally‐ischaemic Langendorff rabbit heart model has been used to study the cardioprotective effects of the dihydropyridine PN 200‐110 (PN) at two doses, one having no negative inotropic effect and a higher dose causing a 62 ± 5% reduction in contractility. Following 45 min no‐flow global ischaemia, recovery was monitored for a period of 90 min reperfusion. Hearts were paced at a constant rate throughout experiments. Contractile force and coronary flow were recorded continuously. Tracer microspheres were injected at regular intervals to assess regional flow distributions, drill biopsies were taken to determine tissue high energy phosphate content, and enzyme leakage in the coronary effluent measured during the first 15 min of reperfusion. Untreated hearts recovered 21 ±2% of their initial contractile force and flow to all heart regions was reduced. In particular, endocardial flow fell to 20% of its pre‐ischaemic level, with the ratio of flow to the endocardium (endo)/epicardium (epi) decreasing from ca. 1.0 to 0.4. Hearts treated with 2 × 10−8 M PN (included in the perfusate from 30 min before ischaemia until 30 min after ischaemia) recovered 49 ± 2% of their initial, pretreatment contractile force, and following the ischaemia the endo/epi ratio was not significantly changed from the pre‐ischaemic value. The lower PN dose (3 × 10−10 M) afforded a lesser degree of protection, contractility recovering to 29 ± 4% of the initial level, with an endo/epi ratio of 0.7 after 90 min reperfusion. The two PN doses afforded a similar degree of protection against enzyme leakage which was in both cases significantly less than in untreated hearts. Myocardial ATP and creatine phosphate content was markedly reduced by the ischaemic episode. Neither PN dose modified this depletion. These results suggest that whilst cardiodepression may well offer protection against ischaemic damage, this is not the sole mechanism wherby PN (and possibly other calcium antagonists) can protect the heart. Preservation of blood flow to the inner layers of the left ventricular wall is likely to be one of the major factors underlying the enhanced recovery shown by PN.

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“…dine-3,5-dicarboxylate) and (isopropyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxy carbonyl-2,6-dimethyl-3-pyridine carboxylate), two new dihydropyridine derivatives with potent and selective calcium antagonist properties (Hof et al, 1982;1984a,b). Since PY which, in vitro, exhibit negative chronotropic effects (Hof & Scholtysik, 1983;Hof et al, 1984b), have been shown to decrease heart rate (HR) in anaesthetized cats (Hof et al, 1982;1984a) but to increase it in conscious animals (Hof & Scholtysik, 1983;Nievelstein et al, 1985), our study was performed in freely moving rats. In addition, the method used allowed, as previously described (Cerutti et al, 1985), measurement of diastolic blood pressure (DBP), a parameter which is of special importance for the assessment of the effect of vasodilator drugs.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular effects of two new calcium antagonists, PY 108‐068 and PN 200‐110, in conscious spontaneously hypertensive rats

Barrès

Cerutti

Morin

et al. 1988

British J Pharmacology

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1 The acute cardiovascular effects of PY 108-068 and PN 200-110 were studied by means of a computerized analysis of the intra-aortic blood pressure (BP) recorded continuously for 26 h in conscious unrestrained spontaneously hypertensive rats. Both compounds were studied at three doses (50, 100 and 200 lgkg-') and each dose was administered intravenously 5 times (09hOOmin, 14 hOOmin, 19hOOmin, 24hOOmin and 09hOOmin). Baroreflex sensitivity was measured 1 h following the last injection. 2 The two compounds were found to induce rapid (3 min) and dose-dependent falls in BP. After the first administration, these decreases reached -20% and -35% for systolic BP (SBP) and diastolic BP (DBP) respectively with PY 108-068 (200pgkg-') and -25% and -45% for SBP and DBP respectively with PN 200-110 (200 pg kg-'). 3 The duration of the reduction in BP increased with the dose and was much longer for PN 200-110 (180 min for SBP) than for PY 108-068 (20 min for SBP). 4 A tachycardia was associated with the decrease in BP which did not differ at 200 pg kg-' between PY 108-068 (+ 108 beats min-') and PN 200-110 (+ 103 beats min' ). Baroreflex sensitivity was not significantly increased by either drug. 5 The 5 repeated injections of PY 108-068 and PN 200-110 evoked similar responses. 6 In conclusion, both compounds exhibited marked hypotensive properties. PN 200-110 appeared to be more suitable for further development since its effects were found to be greater and much longer lasting than those of PY 108-068.

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Effects of the New Calcium Antagonist PN 200–110 on the Myocardium and the Regional Peripheral Circulation in Anesthetized Cats and Dogs

Cited by 81 publications

References 0 publications

Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

Cardioprotection by the calcium antagonist PN 200‐110 in the absence and presence of cardiodepression

Cardiovascular effects of two new calcium antagonists, PY 108‐068 and PN 200‐110, in conscious spontaneously hypertensive rats

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