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Biomedical subjects

J D Horowitz

Publications and source records attributed to J D Horowitz.

At least 91 records · Page 5Linked to original sources
PubMed1993

Captopril potentiates the effects of nitroglycerin in the coronary vascular bed.

OBJECTIVES: This study was designed to examine the effects of captopril on the coronary vascular responses to nitroglycerin. BACKGROUND: The vasodilator effects of nitroglycerin are mediated by sulfhydryl-dependent bioconversion and influenced by local and systemic neural and hormonal counter-regulatory factors. METHODS: In patients with angina pectoris, the effects of 10 days of treatment with the sulfhydryl-containing angiotensin-converting enzyme inhibitor captopril on the coronary vasodilator responses to intracoronary nitroglycerin (1- to 20-micrograms doses) were examined utilizing a double-blind, placebo-controlled, randomized design. The effects of captopril on the induction of nitroglycerin tolerance were also examined after a 20-h intravenous infusion of nitroglycerin. RESULTS: Captopril reduced mean arterial pressure at rest by 8 mm Hg compared with 3 mm Hg in the placebo group (p = NS) and did not affect baseline coronary blood flow (168 vs. 144 ml/min in the placebo group, standard error of the differences of means (SED) 26) or coronary vascular resistance (53 vs. 57 dynes.s.cm-5, SED 9). Intracoronary nitroglycerin increased coronary blood flow in a dose-dependent fashion in both the captopril and placebo groups (p < 0.001). However, captopril potentiated the effects of all doses of nitroglycerin and shifted the dose-response relationship to the left (p < 0.001). At the maximal dose of 20 micrograms, intracoronary nitroglycerin increased the coronary blood flow by a further 60% in the captopril group compared with placebo. After 20 h of intravenous nitroglycerin (24 +/- 3 micrograms/min), the coronary vasodilator responses to intracoronary nitroglycerin were attenuated (p < 0.02) in the placebo group. However, the responses to intracoronary nitroglycerin in the captopril group, remained similar to the responses observed before intravenous nitroglycerin exposure. CONCLUSIONS: Captopril potentiates the coronary vasodilator responses of nitroglycerin in both the absence and the presence of nitroglycerin tolerance. The mechanisms and therapeutic implications of this interaction require further exploration.

Aged↗
PubMed1993

Magnetic resonance angiography in the preoperative evaluation of abdominal aortic aneurysms.

Magnetic resonance angiography (MRA) and magnetic resonance imaging (MRI) are noninvasive techniques of visualizing blood vessels without the use of intravenous contrast or ionizing radiation. This prospective study assessed preoperative MRA and MRI in the evaluation of 28 patients with abdominal aortic aneurysm (AAA). MRI and MRA accurately predicted the extent of cephalad AAA, the patency of the superior mesenteric artery, and the course of the left renal vein, but were less accurate in defining the extent of caudal AAA, flow of the inferior mesenteric artery, and multiple renal arteries. This study suggests that MRI and MRA are alternatives to the combination of angiography and computed tomographic scan in the preoperative evaluation of patients with suspected AAA and no evidence of mesenteric or renal ischemia. When combined with preoperative segmental Doppler arterial studies, an accurate surgical plan may be formulated. Further refinements in image acquisition and postprocessing software analysis will advance the use of MRI and MRA for complete evaluation prior to elective AAA repair.

Aged↗
PubMed1993

Antiplatelet effects of nitroglycerin in healthy subjects and in patients with stable angina pectoris.

The effects of nitroglycerin (NTG) on platelet aggregation are controversial. Most in vitro investigations suggest that NTG suppresses platelet aggregation only at suprapharmacologic concentrations. We investigated various aspects of the antiaggregating effects of NTG in both normal individuals and in patients with stable angina pectoris not treated with nitrates. Platelets from patients exhibited hyperresponsiveness to ADP as an inductor of aggregation. Sublingual administration to patients of NTG (300 micrograms) decreased platelet aggregability; ADP concentrations inducing 50% aggregation were 3.3 +/- 0.3 microM after NTG versus 2.1 +/- 0.1 microM before NTG (p < 0.01). Consistent with previous findings, NTG was a weak inhibitor of platelet aggregation in vitro when added before induction of aggregation. When added after the beginning of aggregation, however, NTG induced both inhibition of developing aggregation and marked disaggregation at concentrations > or = 10(-8) M NTG; concentration associated with 50% reversal of aggregation was 1.4 +/- 0.3 x 10(-6) M. Therefore, antiplatelet effects of NTG in vitro are demonstrable in low, clinically achievable concentrations; previously reported effects of NTG have been underestimated owing to suboptimum experimental conditions. Platelets from patients with angina pectoris were 100-fold less responsive to the cyclic GMP-increasing and disaggregating effects of NTG in vitro, which, together with increased aggregability, could imply reduced platelet sensitivity to endogenous sources of nitric oxide (NO) in vivo. The observed antiplatelet effects of NTG raise the question of its potential utility to reduce the risk of thrombotic complications in patients with ischemic heart disease.

Adenosine Diphosphate↗
PubMed1992

Role of nitrates in unstable angina pectoris.

Unstable angina pectoris is a clinically heterogeneous process with patient symptoms varying between reduced threshold for exertional angina and the occurrence of multiple episodes of rest pain. The major factors in the pathogenesis of unstable angina appear to be intracoronary platelet aggregation and thrombus formation secondary to fissuring or rupture of atheromatous plaques, with associated coronary vasoconstriction due to release of constrictor materials from aggregating platelets and deficiency of endothelium-related vasodilator activity. The latter factor is of particular interest in view of the similar biochemical mechanisms of action of nitroglycerin (NTG) and endothelium-derived relaxing factor (EDRF). The efficacy of NTG in limiting platelet aggregation is also of particular interest in this condition. Medical therapy in patients with unstable angina usually requires use of multiple agents. In the short term, there is a strong case for the use of intravenous heparin both to relieve pain and to reduce the risk of acute myocardial infarction. Aspirin is perhaps less effective in the short term, but very useful in long-term treatment of such patients. Despite their widespread clinical use, beta-adrenoceptor antagonists are probably only marginally beneficial, whereas dihydropyridine calcium antagonists such as nifedipine are potentially harmful as monotherapy and of questionable use in combination with other drugs. Other agents that are effective in relieving ischemic symptoms are the nondihydropyridine calcium antagonists verapamil and diltiazem and the oxygen-sparing agent perhexiline maleate. Despite a paucity of controlled trial data, nitrates are used in the vast majority of patients with unstable angina.

Acetylcysteine↗
PubMed1992

Reversal of human platelet aggregation by low concentrations of nitroglycerin in vitro in normal subjects.

The potential reversal of platelet aggregation in vitro by nitroglycerin in low concentrations was explored using both optical aggregometry and electron microscopy. Venous blood was collected from a cohort of normal volunteers (20 men and 10 women) aged 21 to 65 years. Aggregation in platelet-rich plasma was induced by adenosine diphosphate in concentrations just sufficient to maintain a steady state of aggregation, without a spontaneous disaggregation phase (3.5 to 5 microM). Administration of nitroglycerin after the induction of aggregation caused both inhibition of the primary wave of developing aggregation and marked disaggregation. This combined effect was maximal when nitroglycerin was added at 0.5 minute after the beginning of aggregation. The observed reversal of platelet aggregation by nitroglycerin was concentration-dependent. Significant effects occurred with nitroglycerin concentrations greater than or equal to 10(-8) M. Concentration associated with 50% reversal of aggregation was 1.52 +/- 0.24 (SEM) x 10(-6) M. Electron microscopy revealed that 10(-6) M nitroglycerin induced a significant reduction in both platelet clumping and morphologic changes associated with aggregation. The results of the current study suggest a beneficial antiplatelet effect of nitroglycerin in restoring homeostasis in the face of incipient platelet aggregation. The clinical use of nitroglycerin in patients with acute ischemic syndromes may rest on this action.

Adenosine Diphosphate↗
PubMed1992

High-performance liquid chromatographic determination of sotalol in plasma. I. Application to the disposition of sotalol enantiomers in humans.

Two high-performance liquid chromatographic analytical methods have been developed for the measurement of dl-sotalol or d-sotalol and l-sotalol in plasma, using dl-atenolol as internal standard. Quantitation of dl-sotalol was carried out, following solid-phase extraction, on a 5-microns C18 reversed-phase column, with a mobile phase containing acetonitrile, ion-pairing reagent and distilled water, using ultraviolet detection at 235 nm. Quantitation of d-sotalol and l-sotalol was based on derivatisation with the chiral agent S-(-)-alpha-methylbenzyl isocyanate, followed by chromatographic separation on a 3-microns C18 reversed-phase column, with a mobile phase containing methanol, glacial acetic acid and distilled water, with fluorimetric detection at 220 nm excitation and 300 nm emission. A preliminary application of the latter method suggests that the disposition of sotalol in humans is not enantioselective.

Aged↗
PubMed1992

Sotalol-induced torsade de pointes: management with magnesium infusion.

A 69 year old woman was treated with sotalol (320 mg daily) for intermittent atrial fibrillation. Sotalol was initially well tolerated and reversion to sinus rhythm with sinus bradycardia occurred 4 weeks after initiation of therapy. Shortly thereafter, the patient developed recurrent syncope due to torsade de pointes. This was treated successfully with intravenous magnesium infusion and withdrawal of sotalol. Subsequently, the atrial fibrillation was adequately managed using amiodarone, with no recurrence of torsade de pointes. Development of bradycardia associated with reversion to sinus rhythm represents a potential cause of 'late' pro-arrhythmic effects of sotalol.

Aged↗
PubMed1991

Thiol-containing agents in the management of unstable angina pectoris and acute myocardial infarction.

The development of unstable angina pectoris and acute myocardial infarction is a process of platelet aggregation and thrombus formation associated with local coronary vasoconstriction. Regional deficiencies in endothelial vasodilator function, due to reduced formation of endothelium-derived relaxing factor (EDRF), may predispose to platelet aggregation and coronary vasoconstriction. Nitroglycerin (NTG), frequently utilized in the management of unstable angina pectoris and acute myocardial infarction, undergoes bioconversion, via a sulfhydryl-dependent process, to nitric oxide, which is identical or closely related to EDRF. Other products of the nitrate bioconversion "cascade" are various S-nitrosothiols, which, like nitric oxide, activate soluble guanylate cyclase, inducing increased formation of cyclic guanosine monophosphate. NTG potentially may act to correct a localized deficiency of EDRF effect, at both the vasculature and platelet levels. In patients with unstable angina, hemodynamic effects and therapeutic efficacy of intravenously infused NTG may be attenuated within hours. Combined therapy with NTG and intravenously infused N-acetylcysteine (NAC) results in potentiation of hemodynamic responses to NTG, markedly augments the effects of NTG on platelet aggregation, and reduces the incidence of acute myocardial infarction in patients with severe unstable angina pectoris. The combination of NTG with intermittent NAC infusion may increase the risk of hypotensive episodes in such patients, whereas continuous coinfusion of the drugs is better tolerated. The combination of NTG with thiol-containing agents, such as NAC, may be of therapeutic value in unstable angina pectoris and in evolving acute myocardial infarction. This is currently under investigation.

Acetylcysteine↗
PubMed1991

Acute heart failure: determinants of outcome.

We prospectively studied 69 consecutive patients hospitalized with a primary diagnosis of acute left ventricular failure so as to assess the impact of vasodilators on incidence and morbidity of acute symptomatic left ventricular failure. The determinants of duration of hospitalization, in-hospital mortality and symptomatic status 2 months after discharge were examined. There were 9 in-hospital deaths (13%), and survival at 60 days was 77%. Median duration of hospitalization was 9 days, and 33% of the surviving patients remained in New York Heart Association functional class III-IV 60 days subsequent to discharge. Of the patients, 49 (76%) had previously received treatment for left ventricular failure: 30 (61%) of these had received vasodilators, most commonly angiotensin converting enzyme inhibitors and nitrates. Ischaemic chest pain was present in 34 (49%) of the patients. Acute utilization of vasodilators (45% of patients) was largely limited to nitrate therapy associated with ischaemic chest pain (P less than 0.01). Multiple logistic regression revealed previous left ventricular failure, advanced age and hypokalaemia as significant correlates of prolonged hospitalization (greater than 9 days). Previous left ventricular failure was also predictive of persistent severe disability two months subsequent to discharge. No factor was a significant predictor of in-hospital death. Although preceding treatment with digoxin and incremental angiotensin converting enzyme inhibitor therapy tended to predict brief hospitalization, the parameter of acute ischaemia, other biochemical anomalies and modes of acute or chronic therapy were not significant correlates of any end point. We conclude that preceding disability, rather than mode of treatment, predicts an adverse outcome in acute left ventricular failure.

Acute Disease↗
PubMed1991

Increase in reactivity of human platelet guanylate cyclase during aggregation potentiates the disaggregating capacity of sodium nitroprusside.

1. Basal and stimulated guanylate cyclase activity during ADP-induced human platelet aggregation in comparison with the actions of sodium nitroprusside (SNP) on platelets was investigated. 2. Sodium nitroprusside exhibited both ex vivo and in vitro antiplatelet effects, as assessed by inhibition of subsequent ADP-induced aggregation in platelet-rich plasma. A strong correlation between decrease in aggregation and increase in platelet guanylate cyclase activity in the presence of SNP was obtained. 3. When SNP was administered after the induction of aggregation, it caused acceleration of disaggregation (in reversible aggregation) and produced disaggregation (under conditions of otherwise irreversible aggregation) which was time-dependent. 4. Platelet aggregation was accompanied by a transient increase in platelet cyclic GMP content and guanylate cyclase activation by the nitric oxide (NO) donor SNP. Changes in guanylate cyclase activity were haem-associated and probably reflected saturation of enzyme by haem. 5. Maximal SNP disaggregating effect coincided with peak guanylate cyclase responsiveness to SNP. 6. The present investigation provides evidence that increased responsiveness of platelet guanylate cyclase to NO during aggregation facilitates disaggregation in the presence of SNP. Thus, availability of NO (endogenous or exogenous) at sites of incipient platelet aggregation in vivo may play a pivotal role regarding limitation of this process.

Adenosine Diphosphate↗
PubMed1990

Acute myocardial uptake of digoxin in humans: correlation with hemodynamic and electrocardiographic effects.

Acute myocardial uptake of digoxin was measured at a constant paced heart rate (75 beats/min) for 30 min after an intravenous bolus injection of 500 micrograms of digoxin in 14 patients with ischemic heart disease. Myocardial digoxin content, determined by serial measurement of aortocoronary sinus digoxin concentration gradients and coronary sinus blood flow, was expressed relative to coronary sinus blood flow at rest and correlated with simultaneous hemodynamic and electrocardiographic changes. Myocardial digoxin uptake was extensive (4.1 +/- 0.7% of total injected dose at 30 min) and prolonged, with rapid initial uptake (75.3 +/- 6.6% of maximum at 3 min), followed by a variable phase of slower accumulation. Peak left ventricular positive first derivative of left ventricular pressure (dP/dt) increased progressively (p less than 0.01), with a similar time course to that of myocardial digoxin accumulation; maximal change was 18.5 +/- 4.7% at 27 min. The ratio of inotropic effect to myocardial digoxin content did not vary significantly over the period of the experiment. However, peak inotropic effects in individual patients were not significantly related to peak myocardial digoxin content. The spontaneous PR interval increased transiently, with a peak increase of 5.9 +/- 1.8% (p less than 0.05) 12 min after digoxin administration. It is concluded that after intravenous bolus administration, 1) peak effects of digoxin on atrioventricular (AV) conduction occur early, whereas positive inotropic effects increase progressively for greater than or equal to 27 min; and 2) digoxin accumulation in the human myocardium is prolonged and is a determinant of inotropic effects, but not of prolongation of AV node conduction.

Aged↗
PubMed1990

Nitrate tolerance induced by nicorandil or nitroglycerin is associated with minimal loss of nicorandil vasodilator activity.

In the current study, the vasodilator and tolerance-inducing actions of a recently developed organic nitrate vasodilator, nicorandil, were compared to nitroglycerin (NTG) in an isolated coronary artery preparation. The order of potency for relaxing U46619-constricted bovine-isolated coronary artery rings was NTG greater than isosorbide dinitrate (ISDN) greater than nicorandil. NTG was approximately 250-fold more potent than nicorandil (mean EC50 values for relaxation; 0.044 and 11.2 microM, respectively; n = 6-8). Coronary artery rings preexposed for 60 min to NTG (30 microM) were subsequently markedly less responsive to the relaxant effects of NTG (7.5-fold increase in mean EC50 value, 68.4% decrease in Emax; p less than 0.001) and ISDN (14.1-fold increase in mean EC50 value; p less than 0.001), although only marginally less responsive to nicorandil (1.75-fold increase in mean EC50 value; p less than 0.05). Thus, the coronary artery relaxant actions of nicorandil were significantly less affected by NTG-induced tolerance than were the relaxant actions of the related organic nitrate compounds, NTG and ISDN. To compare the tolerance-inducing actions of NTG and nicorandil, the relaxant actions of a series of nitric oxide (NO)-containing vasodilators were determined in control coronary artery rings and in rings preexposed for 60 min to either 30 microM NTG or 5,000 microM nicorandil. Quantitatively, similar changes in coronary artery ring responsiveness were produced by tolerance induced by NTG and nicorandil; marked attenuation of responsiveness to NTG and to the nonnitrate compound 3-morpholinosydnonimine (SIN-1), but only marginal attenuation of responsiveness to nicorandil and NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Determinants of acute hemodynamic and electrophysiologic effects of verapamil in humans: role of myocardial drug uptake.

To examine the relationship between myocardial verapamil content (MVC) and acute effects in humans, coronary sinus catheterization was used in 22 patients to determine myocardial uptake of verapamil after bolus intravenous (i.v.) verapamil (4 mg) injection. Verapamil-induced effects on hemodynamic and electrophysiologic parameters were measured simultaneously and correlated with MVC per unit baseline coronary sinus blood flow (MVC:F). Myocardial uptake of verapamil was rapid: peak MVC (1.2 +/- 0.2% of injected dose) occurred at 5.4 +/- 0.4 min; at 30 min, residual MVC was 71.1 +/- 3.4% of maximum. Peak MVC:F in individual patients was inversely related to the extent of coronary artery disease (p less than 0.005) but not to left ventricular (LV) systolic function. Verapamil produced significant (p less than 0.001) early reductions in arterial pressure and systemic vascular resistance (SVR); cardiac index (CI) increased, left ventricular (LV) positive dP/dt was unchanged. Verapamil prolonged (p less than 0.01) PR and AH intervals (maximum at 12-18 min) and atrioventricular (AV) nodal effective and functional refractory periods (ERP, FRP) (maximum at 30 min). In individual patients, the extent of changes in AH intervals (r = 0.69; p less than 0.05) and LV dP/dt (r = 0.62; p less than 0.05) correlated with peak MVC:F. We conclude that after i.v. injection, verapamil uptake by the human myocardium is rapid and more extensive in patients with minor coronary artery disease. Despite the hysteresis between MVC and drug effects, MCV is a determinant of inotropic and electrophysiologic effects of verapamil.

Adult↗
PubMed1990

Relationship between systemic and coronary vascular responses to digoxin and concurrent drug therapy with verapamil/beta-adrenoceptor antagonists in humans.

1. In 24 patients who were undergoing coronary arteriography for the assessment of ischaemic heart disease, the relationship between the systemic and coronary vascular responses to acute intravenous digoxin administration (500 micrograms) and concurrent drug therapy with the calcium antagonist verapamil (group I) or a beta-adrenoceptor antagonist (group II) or neither of these agents (group III) was examined. 2. Systemic vascular resistance (SVR) tended to rise rapidly after digoxin injection in patients in groups II and III, and tended to decline initially in patients in group I; however, these differences were not statistically significant (variance ratio [VR] = 0.77). 3. No significant differences were observed in coronary vascular responses to acute digoxin administration between the three groups of patients (VR = 0.34). 4. For the entire group of 24 patients, no statistically significant digoxin-induced effects on resistance could be demonstrated in either the systemic or coronary circulations, although in individual patients vasoconstrictor effects were observed. 5. We conclude that acute intravenous administration of digoxin does not consistently cause systemic or coronary vasoconstriction in patients with ischaemic heart disease. Variability in vasomotor responses to digoxin is not clearly related to concurrent drug therapy with verapamil or a beta-adrenoceptor antagonist. The observation that systemic vascular resistance tends to increase in the first few minutes after digoxin injection should be addressed in future studies.

Adrenergic beta-Antagonists↗
PubMed1989

Prediction of acute myocardial disposition of antiarrhythmic drugs.

Using peripheral blood concentration and myocardial content data (from coronary sinus catheterization and serial determination of transmyocardial drug concentration gradients) from a previous clinical study of the antiarrhythmic drugs lidocaine and mexiletine, we tested the hypothesis that two prospectively defined models of myocardial drug disposition could be used to predict myocardial drug content, in the first 30 min following bolus iv injection, from peripheral blood concentrations alone. Compartmental analysis of peripheral blood concentration data from prolonged blood sampling (three-compartment model) and from the first 30 min after drug injection (two-compartment model) was used to calculate drug content, during the first 30 min, in the second compartment of each of the models. The time course of calculated compartmental content was similar to that of the measured myocardial content in 16 of the 18 patients studied, although there were some differences in the time of peak content. This relatively noninvasive method may therefore be useful in predicting the time course of myocardial drug content after acute iv drug administration.

Anti-Arrhythmia Agents↗