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Biomedical subjects

R E Weishaar

Publications and source records attributed to R E Weishaar.

At least 37 records · Page 2Linked to original sources
PubMed1989

Species differences in the positive inotropic response to DPI 201-106, a novel cardiotonic agent.

The positive inotropic activity of the novel cardiotonic DPI 201-106 was investigated in rat and guinea pig isolated hearts. For comparative purposes, the adenylate cyclase stimulant forskolin and the sodium channel agonist veratridine were also evaluated in both species. DPI 201-106 and veratridine produced greater inotropic effects in rat hearts than in guinea pig hearts, whereas forskolin produced comparable effects. In both species the inotropic response to DPI 201-106 and veratridine, but not forskolin, was reversed by the sodium channel antagonist tetrodotoxin. These results confirm that the positive inotropic effect of DPI 201-106 is due to stimulation of the sodium channel and demonstrate for the first time that species differences exist in the inotropic response to this novel cardiotonic drug.

Animals↗
PubMed1989

PD 122860: a novel dihydropyridine with sodium channel stimulating and calcium channel blocking properties.

The cardiac and vascular activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-[(4-pyridinyl-sulfonyl)methyl]-4-[2- (trifluoromethyl)phenyl]-3-pyridine carboxylase (PD 122860), a novel dihydropyridine, were investigated in vitro using rat heart and rabbit aorta, and compared with reference inotropic and vasodilator agents. In the rat heart, PD 122860 increased left ventricular contractility, decreased coronary resistance and altered the shape of the electrocardiogram T-wave. All three effects were observed at comparable concentrations of PD 122860. The inotropic response to PD 122860 was reversed by the Na+ channel blocker tetrodotoxin and blunted by the Na+-Ca++ exchange inhibitor dichlorobenzamil. The effects of tetrodotoxin and dichlorobenzamil on the inotropic response to the reference Na+ channel stimulant veratridine were comparable to PD 122860, whereas tetrodotoxin and dichlorobenzamil had no inhibitory effect on the inotropic responses to the adenylate cyclase stimulator forskolin or the Ca++ channel stimulant BAY K 8644. PD 122860 selectively relaxed potassium-contracted aortic rings and inhibited [3H]nitrendipine binding to rat brain membranes, suggesting that the vasodilator activity of PD 122860 is due to Ca++ channel blockade. In contrast to BAY K 8644, PD 122860 did not contract partially depolarized aortic rings, suggesting an absence of Ca++ channel stimulant activity. PD 122860 is a racemic mixture and both the vasorelaxant and [3H]nitrendipine binding inhibitory activities selectively reside in the (+)-enantiomer [(+)-PD 122860]. In contrast, the inotropic response resides with both enantiomers of PD 122860. It is therefore concluded that PD 122860 represents a unique dihydropyridine derivative which possesses both Na+ channel stimulating and Ca++ channel blocking activities.

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

Involvement of 1,25-dihydroxyvitamin D3 in regulating myocardial calcium metabolism: physiological and pathological actions.

The role of the prohormone vitamin D3 in regulating calcium and phosphate metabolism in the intestine, kidney, and bone has been known for several decades. Recent studies have provided evidence that vitamin D3, may also play an important role in regulating metabolism in other organs, including heart. This role has been suggested by the identification of a specific receptor for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, in these tissues, as well as the presence of a 1,25(OH)2D3-dependent calcium binding protein. Although administration of excessive quantities of vitamin D3 has been shown in many studies to produce myocardial calcinosis and heart failure, the importance of vitamin D3 in regulating myocardial metabolism under normal conditions has only recently been demonstrated. The purpose of the present review is to assess the current status of research regarding the pathological and physiological actions of vitamin D3 on the heart. The initial section of this report will focus on the pathological effects of excessive vitamin D3 on cardiovascular function, while the latter sections will describe recent studies related to the involvement of 1,25(OH)2D3 in regulating calcium homeostasis in ventricular cells and the relationship between vitamin D3 and myocardial contractility.

Animals↗
PubMed1988

Interaction between propranolol and calcium channel blockers in cardiac and vascular smooth muscle.

The ability of the beta-receptor antagonist propranolol to influence the response of isolated cardiac and vascular smooth muscle to several classes of calcium channel blockers was examined. For comparison, the interactions between propranolol and other classes of negative inotropic and vasorelaxant agents was also evaluated. The results of these studies demonstrate that propranolol pre-treatment significantly enhances the in vitro response to the dihydropyridine calcium channel blocker nifedipine, but not the thiazapine calcium channel blocker diltiazem. This enhancement was unrelated to the negative inotropic or vasorelaxant properties of these agents. In addition, propranolol pre-treatment of rat cortical membranes also enhanced the affinity of nifedipine for the 3H-nitrendipine binding site, but did not alter the effect of diltiazem on 3H-nitrendipine binding. These observations suggest that a direct interaction may exist between beta-receptor antagonists and dihydropyrine-type calcium channel blockers. This interaction may be an important factor in selecting drug therapy for conditions such as hypertension and angina.

Animals↗
PubMed1988

2-(2-Aryl-2-oxoethylidene)-1,2,3,4-tetrahydropyridines. Novel isomers of 1,4-dihydropyridine calcium channel blockers.

The title compounds are novel double bond isomers of 1,4-dihydropyridine-type calcium channel blockers (CCB). These derivatives were prepared by using the Hantzsch dihydropyridine synthesis. The assignment of structure was based on spectroscopic data and a regiochemically unambiguous synthesis. Several of the analogues inhibited [3H]nitrendipine binding with IC50 values as low as 25 nM. By comparison, nifedipine, a clinically useful 1,4-dihydropyridine CCB, inhibits [3H]nitrendipine binding with an IC50 of 1.6 nM. In the Langendorff rat heart preparation, treatment with the more potent derivatives produced marked dose-related increases in coronary flow with little or no effect on heart rate or contractility, except at the highest concentrations tested. The selectivity for vascular versus cardiac effects was similar to that of nifedipine, i.e., the concentration producing vasodilation was approximately 2 orders of magnitude lower than the concentration eliciting cardiodepression. These novel isomers extend the structure-activity relationships for calcium channel blockers into a series closely related to the 1,4-dihydropyridines.

Animals↗
PubMed1987

Subclasses of cyclic AMP phosphodiesterase in cardiac muscle.

Canine and guinea-pig left ventricular muscle contains multiple molecular forms of phosphodiesterase (PDE) which vary according to substrate specificity, stimulation by calmodulin and response to various selective and nonselective phosphodiesterase inhibitors. Both species possess a cyclic AMP-specific form of phosphodiesterase (PDE III). In the dog, both soluble and particulate forms of PDE III are present. The particulate form of PDE III is potently inhibited by cyclic GMP and the selective PDE III inhibitors imazodan (CI-914) and cilostamide, but is only weakly inhibited by the selective PDE III inhibitors Ro 20-1724 and rolipram. In contrast, the soluble form of PDE III in canine left ventricle is only weakly inhibited by cyclic GMP, imazodan and cilostamide, but is potently inhibited by Ro 20-1724 and rolipram. Guinea-pig left ventricle contains only one subclass of PDE III, which is potently inhibited by cyclic GMP, imazodan and cilostamide, but not by Ro 20-1724 or rolipram. However, whereas the imazodan-sensitive subclass of PDE III is a particulate enzyme in the canine left ventricle, in the guinea-pig this subclass of PDE III is a soluble enzyme. Both soluble and particulate PDE III's are (i) insensitive to calmodulin; (ii) possess comparable Km and Vmax values for hydrolysis of cyclic AMP; (iii) are equally inhibited by the nonselective PDE inhibitor theophylline, and (iv) are eluted from DEAE-cellulose anion-exchange resin by comparable concentrations of sodium acetate. The demonstration of distinct subclasses of the cyclic AMP-specific phosphodiesterase (PDE III) in canine left ventricular muscle associated with different domains of the cell suggests compartmentation of cyclic AMP. In addition, the observation that the imazodan-sensitive form of PDE III is a particulate enzyme in canine left ventricle and a soluble enzyme in guinea-pig left ventricle may explain the species differences which exist regarding the positive inotropic response to imazodan in these two species.

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

Cardiotonic agents. 5. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitriles and related compounds. Synthesis and inotropic activity.

Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Although the 4,6-dimethyl analogue 6a retained most of the activity of 5a, the 4-methyl analogue 8a was substantially less potent. The synthesis and structure-activity relationships are discussed.

Animals↗
PubMed1987

Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914).

A series of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones was synthesized and evaluated for positive inotropic activity. Only compounds with two small alkyl groups at C-4 showed significant activity. The structure-activity relationships for optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The phosphodiesterase inhibitory activity is also reported and correlated with the substitution pattern at C-4 in the pyrazolone ring.

Animals↗
PubMed1987

Cardiotonic agents. 7. Inhibition of separated forms of cyclic nucleotide phosphodiesterase from guinea pig cardiac muscle by 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and related compounds. Structure-activity relationships and correlation with in vivo positive inotropic activity.

The structure-activity relationships of a series of 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and related compounds were investigated for the in vivo inhibition of different forms of cyclic nucleotide phosphodiesterase (PDE) isolated from guinea pig ventricular muscle. With few exceptions, these 4,5-dihydropyridazinones were potent inhibitors of cardiac type III phosphodiesterase, which is a low Km, cyclic AMP specific form of the enzyme. The inhibitory effects on cardiac type I and type II phosphodiesterase, both of which hydrolyze cyclic AMP as well as cyclic GMP, were minimal. The most selective PDE III inhibitor was CI-930 (10), the 5-methyl analogue of imazodan (CI-914, 1), with an IC50 of 0.6 microM. The most potent inhibitor of PDE III was the 4,5,6,7-tetrahydrobenzimidazole analogue of 10 (31), with an IC50 of 0.15 microM. This paper describes the structural features that impart both selectivity for inhibiting type III phosphodiesterase and potency of inhibition. In addition, correlations between in vitro PDE inhibitory potency, in vivo positive inotropic potency, and physicochemical properties are discussed.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1987

Cardiotonic agents. 8. Selective inhibitors of adenosine 3',5'-cyclic phosphate phosphodiesterase III. Elaboration of a five-point model for positive inotropic activity.

Inhibitors of adenosine 3',5'-cyclic phosphate phosphodiesterase III (cAMP PDE III) were studied by using solid-state, solution, and theoretical methods in order to refine a five-point model for positive inotropic activity. Cyclic AMP PDE III inhibitors bear a striking resemblance to cAMP itself. This investigation supports the importance of an overall planar topography for selective and potent cAMP PDE III inhibition. (Possible reasons for the potency of certain nonplanar compounds are discussed.) Cardiotonics like imazodan (1; CI-914) and 2 (CI-930) can readily achieve essentially planar geometries, as shown with X-ray crystallographic, IR, UV, NMR, and theoretical data. Small alkyl substituents that occupy space corresponding to certain portions of the cAMP sugar region increase potency (see, e.g., 2, 4). Selective inhibition of cAMP PDE III can be achieved by mimicking the attractive electrostatic potential associated with the phosphate group (e.g., with an amide) and by providing an additional attractive potential spatially opposite to the previous one, in the vicinity of the adenine N1 and extending to N3 (e.g., with an imidazole), together with a partial dipole moment comparable to the adenine dipole moment. This extends and better defines our five-point model in terms of cAMP, a natural substrate for PDE.

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

Involvement of vitamin D3 with cardiovascular function. II. Direct and indirect effects.

To determine whether the changes in cardiovascular function that accompany vitamin D3 deficiency are the direct result of hypovitaminosis D3 or a response to the hypocalcemia that accompanies vitamin D3 deficiency, rats were maintained for 9 wk on a vitamin D3-deficient diet containing either low (0.4%) calcium or high (2.5%) calcium to prevent hypocalcemia. Rats were also maintained on the low-calcium, vitamin D3-deficient diet for 9 wk and then transferred to diets designed to reverse hypocalcemia or vitamin D3 deficiency. The results demonstrate that the changes in in vitro cardiac contractile function that accompany vitamin D3 deficiency 1) could not be prevented by preventing the hypocalcemia that normally accompanies vitamin D3 depletion or 2) could not be reversed by restoration of serum calcium to normal levels after the initial period of vitamin D3 depletion. In contrast, the change in in vitro vascular muscle contractile function observed in vitamin D3-deficient, hypocalcemic rats could be prevented by maintaining serum calcium at normal levels and also reversed by restoration of serum calcium to normal after an initial period of vitamin D3 deficiency. These observations indicate that hypocalcemia does not account for the changes in cardiac contractile function that result from vitamin D3 depletion and suggest a direct role for vitamin D3 or its metabolite 1,25-dihydroxyvitamin D3 in regulating cardiac contractility. Possible mechanisms underlying this direct effect were also explored.

Animals↗
PubMed1987

Subclasses of cyclic AMP-specific phosphodiesterase in left ventricular muscle and their involvement in regulating myocardial contractility.

Ventricular muscle contains a low Km, cyclic AMP-specific form of phosphodiesterase (PDE III), which is believed to represent the site of action for several of new cardiotonic agents including imazodan (CI-914), amrinone, cilostamide, and enoximone. However, species differences in the inotropic response to these agents have raised questions about the relationship between PDE III inhibition and cardiotonic activity. The present study demonstrates that these differences can be accounted for by the presence of two subclasses of PDE III in ventricular muscle and variations in the intracellular localization of these two enzymes. For these experiments, PDE III was initially isolated from canine, guinea pig, and rat left ventricular muscle. The results demonstrate that canine left ventricular muscle contains two functional subclasses of PDE III: an imazodan-sensitive form, which is membrane bound, and an imazodan-insensitive form, which is soluble. Although only weakly inhibited by imazodan, this latter enzyme is potently inhibited by the selective PDE III inhibitors, Ro 20-1724 and rolipram. Guinea pig ventricular muscle also contains the imazodan-sensitive subclass of PDE III. Unlike canine left ventricle, however, thi enzyme is soluble in the guinea pig. No membrane-bound subclass of PDE III was observed in the guinea pig. Rat left ventricle possesses only the soluble form of PDE III, which apparently represents a mixture of the imazodan-sensitive and imazodan-insensitive subclasses of PDE III. Measurement of in vivo contractility in these three species showed that imazodan exerts a potent positive inotropic effect only in the dog, in which the imazodan-sensitive subclass of PDE III is membrane bound.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Vitamin D3 and cardiovascular function in rats.

We have previously identified a receptor for 1,25-dihydroxyvitamin D3 in myocardial cells (Simpson, R.U. 1983. Circulation. 68:239.). To establish the relevance of this observation, we evaluated the role of the prohormone vitamin D3 in regulating cardiovascular function. In rats maintained on a vitamin D3-deficient diet for nine weeks, increases in systolic blood pressure (BP) and serum creatine phosphokinase (CPK) were observed. These increases coincided with a reduction of serum calcium from 10.3 to 5.6 mg/dl. However, while serum calcium remained depressed throughout the study, increases in BP and serum CPK were transient. After nine weeks of vitamin D3-depletion, but not after six weeks, ventricular and vascular muscle contractile function were also markedly enhanced. The increase in ventricular contractile function could not be prevented by maintaining serum calcium at 9.0 mg/dl during the period of D3-depletion. These observations suggest a primary role for the vitamin D3-endocrine system in regulating cardiovascular function.

Animals↗
PubMed1986

Multiple molecular forms of cyclic nucleotide phosphodiesterase in cardiac and smooth muscle and in platelets. Isolation, characterization, and effects of various reference phosphodiesterase inhibitors and cardiotonic agents.

Multiple molecular forms of cyclic nucleotide phosphodiesterase have been identified previously in several tissues and cell types using a variety of different isolation methods. In the present study, the different molecular forms of phosphodiesterase (PDE) were isolated from cardiac muscle (guinea pig left ventricle), vascular smooth muscle (bovine coronary arteries) and human platelets using the same isolation procedure in each instance. These enzymes were then characterized kinetically, and the effects of various reference PDE inhibitors and cardiotonic agents on each form were examined. A low Km, low Vmax form of phosphodiesterase (PDE I) was found in all three tissue/cell types. PDE I activity was stimulated by calmodulin in cardiac and smooth muscle, but not in platelets. In smooth muscle and platelets, PDE I preferentially hydrolyzed cyclic GMP, whereas cardiac muscle PDE I hydrolyzed cyclic AMP and cyclic GMP equally. A high Km, high Vmax form of phosphodiesterase (PDE II) was found in cardiac muscle and platelets, but not in smooth muscle. PDE II activity was not stimulated by calmodulin and there was no substrate specificity. A low Km, low Vmax cyclic AMP-specific form of phosphodiesterase (PDE III) was found in all three tissue/cell types. The activity of PDE III was not stimulated by calmodulin. The reference inhibitors theophylline and papaverine exerted non-specific inhibitory effects on all forms of phosphodiesterase. Other reference inhibitors (M & B 22,948 and dipyridamole) and several cardiotonic agents (AR-L 57, CI-914, CI-930, amrinone, and MDL 17,043) exerted selective inhibitory effects on only one molecular form of phosphodiesterase. The degree of selectivity was often dependent upon the tissue or cell from which the molecular form of phosphodiesterase was isolated. These studies demonstrate that there is heterogeneity regarding the number of phosphodiesterases present in various tissue/cell types, as well as their substrate specificity and their ability to be stimulated by calmodulin, and these different molecular forms of phosphodiesterase can be selectively inhibited by different pharmacological agents. The possibility exists that such selective inhibitors may produce discrete changes in cyclic AMP or cyclic GMP levels, and that these changes may be produced in specific tissues and/or cells.

Animals↗
PubMed1986

Isolation, stages of differentiation, and long term maintenance of adult rat myocytes.

Although a variety of techniques have been developed to isolate myocytes from adult hearts, the long term viability of such cells has only recently been investigated. In addition, relatively little is known about the stages of differentiation such cells proceed through following isolation. In the present study myocytes were isolated using two techniques, one involving retrograde perfusion via the aorta, and the other involving mechanical "shearing." In addition, several modifications were made to minimize the trauma normal associated with isolating myocytes from adult hearts. Both techniques yielded a high percentage of rod-shaped, quiescent myocytes, although myocytes isolated using the "shearing" method were less likely to remain viable for more than 24 hours. With both techniques those cells which remained viable for more than 24 hours proceeded through an identical pattern of differentiation leading to stable, attached cells which remained viable for up to four weeks. These results demonstrate that with the appropriate isolation techniques it is possible to maintain adult myocardial cells in culture for lengthy periods of time.

Animals↗
PubMed1986

Cardiotonic agents. 3. Synthesis and biological activity of novel 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones.

Several 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones were synthesized and evaluated for positive inotropic activity. The 1H-imidazol-4-yl regioisomers 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (25a) and 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (28a) were potent positive inotropic agents. By contrast, the corresponding 1H-imidazol-5-yl regioisomers 25b and 28b were only weak positive inotropic agents. Compounds 25a and 28a were also potent inhibitors of cardiac phosphodiesterase fraction III.

Animals↗
PubMed1985

Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent.

CI-914 is a novel positive inotropic agent whose cardiotonic activity is not due to inhibition of Na+, K+-ATPase or to stimulation of cardiac beta-receptors. CI-914 also has no direct effect on sarcoplasmic reticulum, mitochondria or adenylate cyclase activity. CI-914 does, however, exert a potent inhibitory effect on cardiac phosphodiesterase activity. In evaluating the effect of this agent on the different molecular forms of phosphodiesterase present in cardiac muscle, CI-914 was found to selectively inhibit PDE III, which is a low Km, cAMP-specific form of the enzyme (IC50 = 6.1 microM). This inhibitory effect was found to be competitive with respect to the substrate. Papaverine and theophylline on the other hand were found to inhibit all three forms of phosphodiesterase present in cardiac muscle. The role of phosphodiesterase inhibition in mediating the positive inotropic response to CI-914 is supported by the finding that this agent: (i) significantly elevates cyclic AMP levels in ventricular tissue; (ii) shifts the normal concentration-response to the beta-receptor stimulant isoproterenol to the left: and (iii) restores contractility to K+-depolarized papillary muscles.

Adenosine Triphosphate↗