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Biomedical subjects

H R Kaplan

Publications and source records attributed to H R Kaplan.

At least 37 records · Page 2Linked to original sources
PubMed1983

Blood pressure and heart rate effects of alkyl ether phospholipids in conscious renal, spontaneously hypertensive, and normotensive rats.

The blood pressure and heart rate effects of a synthetic alkyl ether phospholipid and similar lipids derived from beef heart and egg yolk were studied in normotensive, renal, and spontaneously hypertensive rats. Each agent (1.25 to 10 micrograms/kg) produced a dose-related decrease in blood pressure and increase in heart rate in each model after rapid IV injection. The degree of blood pressure lowering was dependent upon the pretreatment blood pressure. Alkyl ether phospholipid was infused at 10 to 30 micrograms/kg/min to SHR and to platelet depleted SHR; comparable effects (blood pressure decreases and heart rate increases) were noted in both models. Reversal of the epinephrine pressor response was seen in all rats. When administered orally in ascending doses on three consecutive days, 50 and 150 micrograms/kg b.i.d. doses (Day 1 and 2) were inactive whereas 500 micrograms/kg b.i.d. (Day 3) decreased blood pressure by 25 +/- 8 and 21 +/- 8 mm Hg in renal and spontaneously hypertensive rats, respectively. Side effects (by all routes) included limp, cyanotic hind limbs and sedation and were similar in SHR and platelet depleted SHR. Significant, sustained blood pressure lowering was not achieved by any of the alkyl ether phospholipids in the conscious rat models at doses devoid of limiting side effects. The results of these studies show: 1) the BP, HR, and toxic profiles of all three alkyl ether phospholipids were qualitatively similar, 2) at doses causing significant BP lowering there was epinephrine reversal suggesting an alpha-adrenergic blocking component of action, 3) the BP, HR, and toxic effect profiles of alkyl ether phospholipid were comparable in normal and platelet depleted SHR and apparently not platelet-dependent, 4) sustained antihypertensive activity could be achieved by the oral route; however the effects were modest (12 +/- 4% decrease) and associated with limiting side effects.

Animals↗
PubMed1983

The methylenedioxyindenes, a novel class of "intracellular calcium antagonists": effects on contractility and on processes involved in regulating intracellular calcium homeostasis.

The 2-substituted methylenedioxyindenes are a novel class of "calcium antagonists" which have been characterized as acting intracellularly. In the present study, the effect of 2-propyl-methylenedioxyindene (p-MDI) on the contractility of isolated rabbit papillary muscles and aortic rings as well as on several metabolic processes believed to be important in regulating calcium movement within the cell was examined. p-MDI was found to exert a dose-dependent negative inotropic effect in the range of 1.0 X 10(-5) to 1.0 X 10(-3) M (1.0 X 10(-3) M p-MDI produced a total cessation of contractility). At a concentration of 1.0 X 10(-4) M p-MDI, this depressant effect could be partially reversed by increasing the level of calcium in the tissue bath. p-MDI also relaxed aortic rings previously contracted with 50 mM KCl or 10 microM norepinephrine, although the concentration of p-MDI required to relax norepinephrine-contracted rings was 3 times greater than that required to relax KCl-contracted rings. Such selectivity was also observed when the effects of verapamil on norepinephrine- and KCl-contracted rings were examined, but was not observed with papaverine. To determine whether the effects of p-MDI on cardiac and vascular smooth muscle were due to direct interference with any of the metabolic processes which regulate intracellular calcium homeostasis, the effects of p-MDI on isolated cardiac sarcoplasmic reticulum and mitochondria and on the intracellular calcium-binding protein calmodulin were examined. At concentrations which depressed cardiac contractility, p-MDI had no effect on 1) calcium transport, uptake or ethyleneglycol bis(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid-induced calcium release by sarcoplasmic reticulum, 2) calcium uptake by mitochondria or 3) calmodulin. p-MDI did, however, exert a biphasic effect of glutamate-supported mitochondrial respiration; stimulating oxygen consumption at concentrations of 1.0 X 10(-5) and 1.0 X 10(-4) M and inhibiting respiration at 1.0 X 10(-3) M. It is therefore concluded that p-MDI has no apparent direct effect on intracellular calcium movement per se and that the calcium antagonist effect of p-MDI may be due in part to calcium channel blockage. Inhibition of mitochondrial respiration may also contribute to the negative inotropic effect of high concentrations of p-MDI.

Animals↗
PubMed1983

Survey of new antihypertensive drugs: 1982.

Over 500 compounds reported to have antihypertensive activity have been cataloged from the world literature (1979-1982). The agents were classified according to mechanism: 1) drugs interacting at alpha-adrenoceptor sites; 2) beta-adrenoceptor antagonists; 3) drugs interacting with the autonomic nervous system by mechanisms other than 1 and 2; 4) inhibitors of the renin-angiotensin system; 5) diuretics; 6) vasodilator antihypertensives; and 7) drugs with miscellaneous mechanisms and/or sites of action. Within each class the drugs were subclassified and compounds that best fit the prototypes identified. The scheme is subjective, largely because of conflicting information cited in the literature. It is clear that many new drugs are at various stages of development. Whether or not these drugs will survive the scrutiny of rigorous and lengthy preclinical and clinical development, and in fact prove to be better antihypertensive agents than the currently marketed agents, remains to be established.

Antihypertensive Agents↗
PubMed1982

Angiotensin converting enzyme inhibitors: modifications of a tripeptide analogue.

Modified nonhydrolyzable tripeptide analogues of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1), designed to impart oral angiotensin converting enzyme (ACE) inhibitory activity, were made and evaluated in vivo and in vitro. The N-methyl and C5-methyl analogues of 1 were inactive. Insertion of heteroatoms (O, S, NH) into the C--C chain of 1 gave a series of compounds with high in vitro activity in the guinea pig serum ACE assay. The O-analogue was the most potent with an IC50 = 4.4 x 10(-9) M compared to 1 with an IC50 = 3.2 x 10(-9) M. The structure-activity relationships in this series of compounds lead one to speculate that the heteroatom provides an additional binding site to the surface of the enzyme; however, these compounds were inactive when tested for antihypertensive activity in the renal hypertensive rat at 30 mg/kg by the oral route (captopril is active at 1.0 mg/kg po).

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline: effect of changes at positions 2 and 5 of the hexanoic acid portion.

Several derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and tested for converting enzyme inhibition activity and blood pressure lowering effects in rats. One compound, 5(S)-benzamido-2(R)-methyl-4-oxo-6-phenylhexanoyl-L-proline (2a), had and I50 against angiotensin converting enzyme of 1.0 x 10(-9) M and is the most potent inhibitor prepared thus far in this class of compounds. Testing of 2a orally at 30 mg/kg for inhibition of the angiotensin I induced blood pressure increase in conscious normotensive rats gave 100% inhibition that required 143 min before the angiotensin I blood pressure response returned to 70% of the pretreatment control response. In the conscious renal hypertensive rat, 2a given orally at a dose of 3 mg/kg caused a lowering of blood pressure that reached its maximum of 40 mmHg 8 h following drug administration.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Pirmenol hydrochloride (CI-845) and reference antiarrhythmic agents: effects on early ventricular arrhythmias after acute coronary artery ligation in anesthetized rats.

The coronary artery-ligated rat was investigated as an experimental model for studying the effects of pirmenol hydrochloride and reference for studying the effects of pirmenol hydrochloride and reference agents on early ventricular arrhythmias. Coronary artery ligation caused 89% lethality (ventricular fibrillation) within 10 min in untreated control rats. Vagal stimulation applied during periods of high-rate ventricular tachycardia reduced sinus, atrioventricular nodal and ventricular ectopic beats, with no uncoupled ectopic beats seen during stimulation. Rats studied with composite epicardial electrodes showed continuous electrical activity throughout diastole. These factors indicate that a reentry mechanism is likely involved. Pretreatment with pirmenol afforded protection in a dose-related fashion. A dose of 1.25 mg/kg increased survival to 58%, and all rats dosed with 2.5 to 10 mg/kg survived. Suppression of ventricular fibrillation was dose related and was complete at 5 mg/kg. The pirmenol plasma levels of 1.2 +/- 0.1 microgram/ml seen after the 5 mg/kg dose are similar to plasma levels seen at clinically effective doses, as well as at doses effective in other experimental arrhythmias. The reference agent quinidine was also highly effective in this model, all rats pretreated with 5 mg/kg survived with reduced premature ventricular beats and without a single episode of ventricular fibrillation or death. Fibrillation and/or death were also reduced by the reference agents, bretylium, lidocaine, propranolol and verapamil. The high efficacy of pirmenol against early ventricular arrhythmias in this study further defines its spectrum of activity, and suggests that pirmenol may be effective in a clinical setting where a reentrant mechanism is operative.

Animals↗
PubMed1981

Synthesis and angiotensin-converting enzyme inhibitory activity of 3-(Mercaptomethyl)-2-oxo-1-pyrrolidineacetic acids and 3-(Mercaptomethyl)-2-oxo-1-piperidineacetic acids.

A number of gamma- and delta-lactam derivatives were synthesized and their in vitro angiotensin-converting enzyme (ACE) inhibitory activities were compared. The structures of these compounds were designed to include many of the important features of captopril. The synthesis involved the preparation of a variety of novel 3-methylene-2-pyrrolidinones (3-5 and 16) and 3-methylene-2-piperidinones (3a-5a, 10-12, and 17). The key intermediate 3-methylenelactams 3 and 3a were obtained from 3-(hydroxymethyl)lactams 2 and 2a by a direct dehydration with dicyclohexylcarbodiimide using cuprous iodide as a catalyst. Introduction of the sulfhydryl group was accomplished by a Michael addition of these alpha, beta-unsaturated lactams. The compound with the highest in vitro activity was 3-(mercaptomethyl)-2-oxo-1-piperidineacetic acid (7a). The activity of the 7a both in vitro and in vivo (dog) was shown to be less than that of captopril by a factor of about 100.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1981

Novel synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline and analogues: potent angiotensin converting enzyme inhibitors.

A new approach was developed for the synthesis of (S)-1-[5-(benzoylamino)-1,4-dioxo-6-phenylhexyl]-L-proline (1) and 23 analogues. The delta-(acylamino)-gamma-keto acid intermediates were obtained by a modified Dakin--West reaction using 3-carbomethoxypropionyl chloride. Acylation of L-proline and recrystallization of the mixture of diastereomers gave the optically pure title compound in three reaction steps. The in vitro angiotensin converting enzyme (ACE) inhibitory activity of 1 was confirmed. Some of the novel analogues (6, 11, 13, and 17) were also found to be potent inhibitors of ACE in vitro with an IC50 of 1.4-8.8 x 10(-9) M (IC50 for captopril = 0.9 x 10(-8) M). In vivo these compounds (6, 11, 17, and 18) were much less active than captopril, especially by the oral route. Against angiotensin I (AI) challenge in normotensive conscious rats, 1 and 6 produced less than 50% inhibition at 30 mg/kg po but 57 to 82% inhibition at 3 mg/kg iv. Inhibition by both routes lasted less than 1 h. In renal hypertensive rats, 1 and 15 of its analogues failed to produce significant blood pressure lowering effects, in contrast to the marked effects of captopril. Near maximum inhibition of AI was achieved by continuous intravenous infusions of 1 and 20, suggesting that limited oral activity may by due to degradation and/or clearance.

Angiotensin II↗
PubMed1979

Repeat abortions: blaming the victims.

A study of 1,505 women obtaining abortions in a freestanding abortion clinic in Western New York state revealed that women having repeat abortions were more likely to be using contraception at the time of conception than women having first abortions. However, nearly one-half the non-contracepting repeaters were not contracepting at the time of the repeat pregnancy. Repeaters who were not contracepting at the time of the repeat pregnancy listed medical contraindications or lack of supplies as the major reasons for not contracepting at the time of the present conception--indicating that they had tried one or more methods since their first abortion. Repeaters were sexually more active than first timers, thus increasing their statistical risk of unwanted pregnancy even as they contracepted more than first timers. The data indicate that both first timers and repeaters overwhelmingly reject the premise that abortion is a primary or even a back-up birth control method. The essential difficulty for repeaters appears to be that they are victims of technological, organizational, and logistical inadequacies as well as statistical probabilities rather than being motivationally deficient or indifferent to the dangers of unprotected sexual intercourse.

Abortion, Legal↗
PubMed1978

l-Bunolol and propranolol: oral and intravenous beta-adrenoceptor blocking activity in rats compared to dogs and humans.

To determine the pharmacological significance of reported differences between species in l-bunolol metabolism, oral and intravenous beta-adrenoceptor blocking activity against an isoproterenol-induced tachycardia was compared in dogs, rats, and humans. Propranolol was similarly studied in rats and dogs. Species differences in intravenous potency were minimal for both compounds in contrast to oral dose studies. Oral to intravenous ratios of doses causing a comparable degree of beta-adrenoceptor blockade after l-bunolol were: rat, 212; dog 4; and human, 5. For propranolol, the oral to intravenous dose ratios were 210 and 32 for the rat and dog, respectively. These pharmacological findings show major differences in the rat compared to dogs and humans and may be explained in part by differences in the urinary excretion patterns of l-bunolol in the various species.

Administration, Oral↗
PubMed1977

Levo-bunolol and propranolol: further evaluation of oral beta-blocking activity in conscious dogs.

The oral beta-adrenoceptor blocking activity of bunolol, propanolol, and their levo-isomers was compared against isoproterenol- and treadmill exercise-induced tachycardias in normal conscious dogs. Relative potencies against isoproterenol were (ascending order): propranolol=1, levo-propranolol=2, bunolol=40, and levo-bunolol=102. Large oral doses of levo-bunolol and propranolol suppressed exercise tachycardia by only 18% (range 10 to 22%). Compared to the isoproterenol response, the tachycardia associated with severe exercise in the healthy trained dog was largely resistant to beta-receptor blockade showing factors other than beta-receptor stimulation to be involved. Differences in duration of beta-blockade were observed at equiactive doses of levo-bunolol and propranolol. The isoproterenol response had returned to greater than 50% of control by 12 hr after propranolol but was less than 10% of control at 12 hr after levo-bunolol. The time to 50% recovery of the exercise tachycardia was 24 hr after levo-bunolol and 6 to 9 hr after propranolol. The results show oral levo-bunolol to be considerably more potent and to have a longer duration of action than propranolol in inhibiting both isoproterenol and exercise-induced tachycardias in conscious dogs.

Administration, Oral↗