Vascular hyporeactivity persists despite increased contractility after long-term administration of isosorbide dinitrate in portal hypertensive rats

Background/Aims: Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamics. Isosorbide dinitrate is an effective portal hypotensive drug. The present study aimed to investigate whether chronic administration of isosorbide dinitrate could affect vascular responsiveness in portal hypertensive rats.Methods: Portal hypertension was induced by partial portal vein ligation. Sham-operated (Sham) rats served as controls. There were four animal groups for this study: portal vein ligation-isosorbide dinitrate groups, portal vein ligation-vehicle (Veh) group, Sham-isosorbide dinitrate group and Sham-Veh group. Isosorbide dinitrate (5 mg · kg⁻¹ · 12 h⁻¹ was given by gavage for 8 days starting 1 day before ligation and continuing thereafter. Mesenteric arteries were removed for contractile study after hemodynamic measurement.Results: Contractile responses to KCl (15–90 mM) and phenylephrine (10⁻⁹−10⁻⁴ M) were recorded. Both vascular reactivity and sensitivity were significantly reduced in portal vein ligation rats as compared to Sham rats. Chronic isosorbide dinitrate treatment reduced portal venous pressure in portal vein ligation rats. Moreover, the maximal contractile responses to KCl and phenylephrine were significantly enhanced in both portal vein ligation and Sham rats after isosorbide dinitrate treatment, but relative hyporeactivity persisted in portal vein ligation rats. In contrast, a single dose of isosorbide dinitrate did not alter the contractile sensitivity or reactivity to KCl or phenylephrine in either portal vein ligation or Sham rats.Conclusion: Our results show that long-term administration of isosorbide dinitrate enhanced vascular contractility in both portal vein ligation and Sham rats, but relative hyporeactivity persisted in portal vein ligation rats.     

Regression of left ventricular hypertrophy by at1 receptor blockade in renal transplant recipients

AT₁ receptor antagonists control blood pressure (BP) effectively and reduce left ventricular hypertrophy in patients with essential hypertension. Because left ventricular hypertrophy is very common in renal transplant recipients, we examined the cardiovascular effects and the safety profile of the AT₁ receptor antagonist losartan in hypertensive renal transplant recipients. In 20 renal transplant recipients with stable renal graft function 50 mg of losartan was added to the preexisting antihypertensive treatment (no angiotensin-converting enzyme inhibitors) at least 6 months after renal transplantation. Twenty-four–hour ambulatory BP, two-dimensional-guided M-mode echocardiography, and duplex sonography, as well as renal function, red blood cell count, cyclosporine A and FK 506 levels, erythropoetin, and angiotensin II concentration were determined at baseline and after 6 months of therapy. With 24-h ambulatory BP measurement, systolic blood pressure (SBP) was reduced by 7.5 ± 2.4 mm Hg and diastolic blood pressure (DBP) by 4.5 ± 1.8 mm Hg (P < .01 and P < .05, respectively). Posterior, septal, and relative wall thickness decreased by 0.95 ± 0.2 mm, 0.91 ± 0.2 mm and 0.04 ± 0.01 mm, respectively (all P < .001). Left ventricular mass index decreased by 18.1 ± 4.7 g/m² (P < .01). Ejection fraction and midwall fractional fiber shortening as systolic parameters and the relation of passive-to-active diastolic filling of the left ventricle were unaltered. Serum creatinine and cyclosporine A concentration remained stable in all patients. Hemoglobin and hematocrit decreased by 1.0 ± 0.3 g/dL and 3.6% ± 0.9%, respectively (P < .002 and P < .001) without a change in serum erythropoetin level. In renal transplant recipients the AT₁ receptor antagonist losartan reduces left ventricular hypertrophy without altering systolic or diastolic function. It is safe with regard to renal function and immunosuppression, but slightly decreases hemoglobin level.     

Isosorbide dinitrate for the relief of severe heart failure after myocardial infarction.

Severe congestive heart failure secondary to myocardial infarction remains a difficult management problem. Although intravenous vasodilators and mechanical assist devices have been reported to improve the depressed hemodynamic function, these interventions are limited to the intensive care unit and cannot be used for long-term management. This study evaluates the hemodynamic and symptomatic response to sublingual administration to isosorbide dinitrate (5 to 10 mg) in seven consecutive patients with severe congestive heart failure after anterior wall myocardial infarction. Serial measurements of mean right atrial and pulmonary arterial end-diastolic pressure, mean blood pressure, heart rate and cardiac output were obtained during the control period and during the 4 hours after administration of isosorbide dinitrate. The peak response occurred approximately 30 minutes after drug administration with an 83 percent reduction in mean right atrial pressure (from 6 to 1 mm Hg, P less than 0.02), a 36 percent reduction in pulmonary arterial end-diastolic pressure (from 25 to 16 mm Hg, P less than 0.0001) and a 6 percent reduction in mean blood pressure (from 94 to 88 mm Hg (P less than 0.05). There were small but statistically not significant increases in cardiac index (from 2.3 to 2.6 liters/min per m2 and stroke work index (from 26 to 32 gm/beat per m2). The total systemic vascular resistance was reduced by 5 percent from 1,605 to 1,518 dynes sec cm-5 (P less than 0.10). The baseline heart rate of 105 beats/min was not significantly changed. The reduction in pulmonary arterial end-diastolic pressure became statistically significant (P less than 0.05) between 15 and 30 minutes after administration of isosorbide dinitrate and remained significant for 3 to 4 hours. This reduction of pulmonary arterial end-diastolic pressure to less than 22 mm Hg was associated with relief of the patients' pulmonary symptoms. The response to nitroglycerin (0.4 mg) was similar in magnitude but of much shorter duration (approximately 15 minutes for nitroglycerin versus 4 hours for isosorbide dinitrate in patients with and without congestive heart failure. The slope (calculated by dividing the change in cardiac index or stroke work index by the change in pulmonary arterial end-diastolic pressure) was significantly (P less than 0.05) depressed in the patients with congestive heart failure. These data demonstrate that the symptomatic pulmonary venous hypertension can be effectively relieved by isosorbide dinitrate without further compromising left ventricular function.     

Effects of acute intermittent hypercapnic hypoxia on insulin sensitivity in piglets using euglycemic clamp

Continuous hypoxia is associated with insulin resistance, altered glucose metabolism, and increased sympathetic nervous activity. This study examined the effect of 2 successive exposures to intermittent hypercapnic hypoxia (IHH) on glucose metabolism and insulin sensitivity in neonatal piglets. Piglets were assigned to 2 groups. One group was exposed to 2 × 90 minutes of hypercapnic hypoxia (8% O₂, 7% CO₂), intermittently in 6-minute cycles alternating with 6-minute air. The second group was given 2 × 90 minutes of air. Blood pressure, blood gases, glucose, insulin, and lactate were measured during exposures. Insulin sensitivity was assessed using the euglycemic clamp before and after the exposures. Piglets in the IHH group exhibited reduced PO₂ (from 111.4 ± 14.2 to 43.3 ± 21.7), increased PCO₂ (from 33.6 ± 1.9 to 49.4 ± 5.4), and lactic acidosis. Compared with air, IHH decreased blood glucose (control [CON] 4.44 ± 0.72 mmol/L vs IHH 2.67 ± 1.2 mmol/L, P = .007), insulin (CON 12.5 ± 7.4 μU/mL vs IHH 3.6 ± 3.1 μU/mL, P = .03), and mean arterial pressure (CON 143.0 ± 7.9 mm Hg vs IHH 112.5 ± 9.5 mm Hg, P < .001) over 90 minutes. Maximal insulin-stimulated glucose disposal was not different between the groups on either day, nor was endogenous glucose production. Overall, exposure to hypoxia in an intermittent pattern reduced sympathetic drive as indicated by blood pressure and did not alter insulin sensitivity, resulting in decreases in blood glucose and insulin. We speculate that an intermittent hypoxic stimulus results in failure of initiation of compensatory responses to increased energy requirements that would usually be observed during sustained exposure to hypoxia.     

Effects of long-term oral administration of isosorbide dinitrate on the antianginal response to nitroglycerin. Absence of nitrate cross-tolerance and self-tolerance shown by exercise testing.

Controversy exists regarding the ability of sustained-release orally administered nitrates to induce cross-tolerance to sublingual doses of nitroglycerin. Therefore this study compared the effects of isosorbide dinitrate and placebo on nitroglycerin-induced improvement in exercise testing in 28 patients with coronary artery disease. Maximal exercise tests were performed in all patients before and 10 minutes after sublingual administration of 0.6 mg of nitroglycerin both before and after 1 month of administration of either placebo or isosorbide. During the control period, nitroglycerin produced improvement in mean duration of exercise (placebo from 302 to 390 seconds and isosorbide from 302 to 391 seconds; both P < 0.001) and a derived index of maximal oxygen consumption (placebo from 21.1 to 24.5 and isosorbide from 21.1 to 24.8 cc/kg per min; both P < 0.001); maximal heart rate-blood pressure product remained unchanged (placebo from 23.3 to 23.7 × 10³ and isosorbide from 19.2 to 20.2 × 10³; both P < 0.05). During the posttreatment period nitroglycerin again resulted in increases in exercise duration (placebo from 306 to 368 seconds and isosorbide from 373 to 411 seconds; both P < 0.01) and a derived index of oxygen consumption (placebo from 21.3 to 23.7 and 23.9 to 25.4 cc/kg per min; both P < 0.01) whereas maximal heart rate-blood pressure product was without change with placebo (P < 0.05) but minimally higher after administration of isosorbide (20.7 to 22.8 × 10³; P < 0.01). An identical level of S-T segment improvement was achieved at maximal exertion after nitroglycerin in both groups. Thus the demonstration in this study of the ability to achieve equivalent improvements in exercise performance before and 1 month after isosorbide dinitrate therapy indicates that long-term oral administration of large doses of this long-acting nitrate does not result in cross-tolerance to the antianginal action of sublingually administered nitroglycerin. In addition, the long-acting nitrate achieved therapeutic efficiency without evidence of self-tolerance.     

Haemodynamic effects of oral salbutamol alone and in combination with sublingual isosorbide dinitrate in patients with severe congestive cardiac failure.

To examine possible augmentation of the effects of isosorbide dinitrate by salbutamol, haemodynamic measurements were made in 10 patients with severe chronic congestive cardiac failure who received isosorbide dinitrate 2.5 to 25 mg sublingually and salbutamol 4 to 12 mg orally, alone and in combination. Isosorbide dinitrate reduced mean left ventricular filling pressure from 29 to 18 mmHg and increased mean cardiac index from 1.7 to 2.0 1/min per m2, with no significant change in mean heart rate. Systemic arterial mean pressure fell from 85 to 72 mmHg. Salbutamol increased cardiac index from 1.8 to 2.2 1/min per m2. There was no significant change in left ventricular filling pressure, heart rate, or systemic arterial pressure. Compared with control, combined isosorbide dinitrate and salbutamol reduced left ventricular filling pressure from 27 to 19 mmHg and increased cardiac index from 1.8 to 2.7 1/min per m2, with no significant change in heart rate. Systemic arterial pressure fell from 82 to 75 mmHg. The reduction in left ventricular filling pressure by combined treatment was similar to that produced by isosorbide dinitrate alone, but the increase in cardiac index was significantly greater than that produced either by isosorbide dinitrate alone or salbutamol alone. Combined sublingual isosorbide dinitrate and oral salbutamol have an additive effect in improving left ventricular performance in patients with severe chronic congestive cardiac failure.     

Effects of isosorbide dinitrate on the response to atrial pacing in coronary heart disease.

To study the efficacy of isosorbide dinitrate in prevention of myocardial ischemia, 20 patients with angiographically proved coronary artery disease underwent atrial pacing (mean rate 138/min) before (P1), 10 minutes after (P2) and 65 minutes after (P3) sublingual administration of 5 mg of isosorbide dinitrate. The symptomatic, hemodynamic and metabolic responses were evaluated at rest and during each pacing period. Angina occurred in all subjects during P1. Angina did not recur or was less severe in 17 of 19 patients during P2 and in 19 of 20 patients during P3. Resting left ventricular end-diastolic pressure for the group was normal at 11 plus or minus 4 mm Hg (mean plus or minus standard deviation). On interruption of pacing at 4.5 minutes during P1, average end-diastolic pressure during sinus rhythm was abnormal (18 plus or minus 6 mm Hg). After administration of isosorbide dinitrate mean left ventricular end-diastolic pressure was significantly decreased at rest and remained normal when pacing was interrupted during P2 and P3. Brachial arterial pressure, cardiac index, tension-time index, left ventricular stroke work index and maximal rate of rise of left ventricular pressure were all diminished at rest before and during P2 and P3. S-T segment depression was less during P2 and P3 than during P1. Before isosorbide dinitrate was given, resting myocardial lactate extraction was 15 plus or minus 11 percent during P1 lactate extraction decreased to minus2 plus or minus 25 percent. Lactate extraction was significantly greater during P2 and P3 than during P1. This study demonstrates that sublingual administration of 5 mg of isosorbide dinitrate has a significant protective effect against pacing-induced myocardial ischemia at 10 and 65 minutes after administration.     

The use of isosorbide in the treatment of severe, uncontrolled hypertension

Isosorbide dinitrate was administered sublingually and compared with placebo in a double-blind, randomized fashion to determine its effectiveness and safety in the rapid control of severe arterial hypertension. In 11 patients who received 10 mg of isosorbide dinitrate, blood pressure (BP) dropped from 205 +/- 8/131 +/- 3 to 166 +/- 9/106 +/- 5 mm Hg at 120 minutes. In eight patients who received placebo, BP dropped from 203 +/- 8/130 +/- 3 to 193 +/- 11/122 +/- 5 mm Hg at 120 minutes. When 10 mg of isosorbide dinitrate was administered sublingually after 120 minutes to placebo-pretreated patients, their BP dropped to 161 +/- 7/105 +/- 6 mm Hg at 240 minutes. Our study group (19 patients) was compared with a "control" group (six patients) whose BP (203 +/- 12/132 +/- 8 mm Hg) was treated only with conventional antihypertensive medications and bed rest; five (83%) of the six controls achieved steady BP control at 24 hours vs nine (47%) of the 19 study patients pretreated with isosorbide. There were no side effects, including hypotension, orthostatic effect, and reflex tachycardia. Sublingual isosorbide safely and effectively lowers systolic and diastolic BP in patients with severe, uncontrolled arterial hypertension.     

Improved right ventricular systolic time intervals after digitalis in patients with cor pulmonale and chronic obstructive pulmonary disease

Although digitalis has been used to treat patients with cor pulmonale secondary to chronic obstructive pulmonary disease, its effect on right ventricular performance has not been conclusively determined. This study assessed the effects of acute digitalization on measurement of right ventricular systolic time intervals in patients with chronic obstructive pulmonary disease and cor pulmonale. The intervals were recorded before and 40 minutes after administration of ouabain, 1 mg intravenously, in nine men (mean age 58 ± 5 [standard deviation] years) with chronic obstructive pulmonary disease (mean maximal mid expiratory flow rate 0.29 ± 0.08 1 liters/sec) and electrocardiographic evidence of right ventricular hypertrophy.Ouabain produced significant reductions in right ventricular systolic time intervals, including the right ventricular preelection period (from 117 ± 23 to 102 ± 16 msec; P < 0.01), right ventricular ejection time index (from 397 ± 33 to 375 ± 24 msec; P < 0.01) and mean Q-P₂ index (from 509 ± 23 to 474 ± 8 msec; P < 0.001). In eight patients with simultaneously measured left ventricular systolic time intervals, similar changes were observed, including shortening of the left ventricular preejection period index (from 135 ± 9 to 117 ± 11 msec; P < 0.01), ejection time index (from 395 ± 18 to 379 ± 20 msec; P < 0.01), and the mean Q-A₂ interval (from 530 ± 16 to 495 ± 16 msec; P < 0.001). There were no significant changes in aortic or pulmonary arterial pressures. The results demonstrate that acute administration of digitalis produces significant improvement in right ventricular performance in patients with chronic obstructive pulmonary disease and cor pulmonale. The simultaneous shortening of right and left ventricular systolic time intervals is of comparable magnitude.     

Hemodynamic assessment of oral peripheral vasodilator therapy in chronic congestive heart failure: prolonged effectiveness of isosorbide dinitrate.

To evaluate the effectiveness of oral vasodilator therapy in chronic congestive heart failure, 20 mg of isosorbide dinitrate or placebo was administered orally in double-blind fashion to 25 patients with congestive heart failure. In 15 patients receiving isosorbide dinitrate, pulmonary arterial wedge pressure decreased 5 minutes to 5 hours after drug administration; the peak reduction was observed at 1 hour (from 23 to 14 mm Hg; P less than 0.001). Wedge pressure decreased to normal (12 mm Hg or less) in 8 of the 15 patients (Group I) but remained greater than 12 mm Hg in 7 (Group II). Reductions in mean systemic arterial pressure, systemic vascular resistance and pressure-time per minute also occurred. Indexes of pump output were unchanged in the 15 who received isosorbide dinitrate but tended to decrease slightly in Group I. Stroke index (from 23 to 26 cc/m2) and stroke work index (from 21.4 to 24.1 g-m/m2) increased slightly but significantly (P less than 0.05) in Group II. Thus the prinicpal hemodynamic action of isorbide dinitrate is marked and sustained reduction in left ventricular filling pressure without pronounced effect on cardiac output. This agent should be used in congestive heart failure primarily for relief of congestive symptoms.     

Use of End-Tidal Carbon Dioxide to Predict Outcome in Prehospital Cardiac Arrest

Study objective: End-tidal CO₂ (ETCOH₂) measurement can be used to predict death in prehospital cardiac arrest patients with pulseless electrical activity (PEA).Design: A prospective, observational study. Setting: An urban and rural emergency medical services system in northwestern Washington state. Participants: Ninety consecutive victims of prehospital cardiac arrest with PEA. Interventions: Patients were intubated in the field and treated using standard advanced cardiac life support protocols with on-line medical control. In addition, all patients were evaluated using mainstream ETCO₂ monitoring. In this study, a hypothetical decision was made to cease resuscitative efforts based on an ETCO₂ level of 10 mm Hg or less after 20 minutes of advanced cardiac life support. Results: The study included 90 patients (61 were men) with a mean age of 67.6±13.6 years (range, 27 to 95 years). The initial ETCO₂ averaged 11.7±6.6 mm Hg in nonsurvivors (range, 5 to 50 mm Hg) and 10.9±4.9 mm Hg in survivors (range, 5 to 24 mm Hg) (P >.672 [NS]). After 20 minutes of advanced cardiac life support, ETCO₂ averaged 3.9±2.8 mm Hg (range, 0 to 12 mm Hg) in patients in whom the theoretical decision was made to cease field resuscitation. In contrast, survivors' ETCO₂, just before restoration of circulation, averaged 31±5.3 mm Hg (range, 16 to 35 mm Hg) (P<.0001). Using an ETCO₂ of 10 mm Hg or less as a theoretical threshold to predict death in the field successfully discriminated between the 16 survivors to hospital admission (those that achieved return of spontaneous circulation) and 75 prehospital deaths. Of the 16 survivors to hospital admission, 9 died in the hospital, and 7 were discharged from the hospital alive. In 13 of the 16 survivors, the first evidence of return of spontaneous circulation, before a palpable pulse or blood pressure, was a rising ETCO₂. The logistic-regression parameters for the model are 4.4391+ETCO_2*-0.3624 (P<.0001). Sensitivity was 97.3%; specificity 100%; positive predictive value 100%; and negative predictive value 88.9%. Conclusion: This study suggests that a low ETCO₂ (10 mm Hg or less) can be used to predict irreversible death in patients with pulseless electrical activity undergoing prehospital advanced cardiac life support. If future studies validate this model, use of ETCO₂ may allow for triage decisions in the field. [Wayne MA, Levine RL, Miller CC: Use of end-tidal carbon dioxide to predict outcome in prehospital cardiac arrest. Ann Emerg Med June 1995;25:762-767.]     

Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs

Objectives. This study was undertaken to examine whether nitric oxide released in ischemic myocardium decreases the coronary vascular resistance and attenuates the severity of contractile and metabolic dysfunction.Background. Endothelium-derived relaxing factor, recently identified as nitric oxide, is a potent relaxant of coronary smooth muscle.Methods. The left anrterior descending coronary artery was perfused through an extracorporeal bypass tube placed in the carotid artery in 56 open chest dogs. After hemodynamic stabilization, we occluded this bypass tube to decrease coronary blood flow to one third of the control flow. Thereafter, we maintained a constant coronary perfusion pressure(40.9 ± 3.1mm Hg).Results. Under ischemic conditions, the coronary arteriovenous differences in nitrate and nitrite (end products of nitric oxide) increased (from 3.5 ± 0.4 [mean ± SEM] to 12.9 ± 2.1 μmol/liter, p < 0.01). ⁰-Monomethyl -arginine (3 μg/kg body weight per min, intracoronary) decreased the coronary arteriovenous differences in nitrate and nitrite (5.0 ± 0.9 μmol/liter, p < 0.05) and coronary blood flow (from 29.8 ± 0.5 to 18.1 ± 1.1 ml/100 g per min, p < 0.001). Fractional shortening (from 3.7 ± 1.0 to −1.3 ± 0.7%, p < 0.001) and lactate extraction ration (from −44.0 ± 4.1 to −59.2 ± 4.9%, p < 0.005) of the perfused area also decreased. These values were restored by the concomitant administration of -arginine. Blood flow to the endomyocardium was decreased relative to the epimyocardium. A reduction in coronary blood flow and worsening of myocardial contractile and metabolic functions due to the administration of ^G-monomethyl -arginine during ischemia were observed in denervated hearts. A reduction in coronary blood flow in ischemic myocardium was observed with the administration of ^W-nitro- -arginene methyl ester as well, although neither ^W-nitro- -arginine methyl ester nor ^G-monomethyl -arginine changed coronary blood flow and myocardial contractile and metabolic functions in the nonischemic myocardium. The cyclic guanosine monophosphate content of epicardial coronary artery increased due to myocardial ischemia; this increased was attenuated with ^G-monomethyl -arginine treatment.Conclusions. We conclude that endogenous nitric oxide predominantly decreases the coronary vascular resistance of ischemic endomyocardium, thereby improving myocardial contractility and metabolic function.     

Sex differences in substrate oxidation during aerobic exercise in obese men and postmenopausal obese women

The aim of this study was to compare substrate oxidation during aerobic exercise in obese men and postmenopausal obese women. Ten obese men (mean age, 55.4 ± 2.2 years; body mass index, 27.5 ± 0.4 kg/m²; peak oxygen uptake [Vo₂peak], 44.4 ± 1.9 mL/kg fat-free mass/min; mean ± SE] and 10 postmenopausal obese women (mean age, 57.2 ± 1.2 years; body mass index, 27.9 ± 0.5 kg/m²; VO₂peak, 39.9 ± 1.3 mL/kg fat-free mass/min) performed a 40-minute bout of cycling exercise at 50% VO₂peak. Blood samples were collected for assessment of metabolic variables and 17β-estradiol concentration at baseline and during aerobic exercise. Breath samples were collected to estimate carbohydrate and fat oxidation using a digital computer-based breath-by-breath exercise analysis system during aerobic exercise. Serum 17β-estradiol concentration was not significantly different between the men and women subjects at baseline (P > .05). Serum free fatty acid concentration tended to be higher in the men than in the women (P = .07) during the exercise, but the respiratory exchange ratio during exercise was lower in women than in men (P < .05). Fat oxidation adjusted for fat-free mass was higher (P < .05) in women than in men. These results suggest that fat utilization was higher during aerobic exercise in postmenopausal obese women than in obese men and did not depend on resting serum 17β-estradiol concentration.     

Comparative effects of captopril and isosorbide dinitrate on pulmonary arteriolar resistance and right ventricular function in patients with severe left ventricular failure: results of a randomized crossover study

We compared the short-term hemodynamic effects of isosorbide dinitrate (40 mg orally) and captopril (25 mg orally) in 18 patients with severe chronic heart failure in a randomized, crossover study conducted on consecutive days. Captopril and isosorbide dinitrate produced similar decreases in systemic vascular resistance, but whereas nitrate therapy decreased pulmonary arteriolar resistance significantly, captopril did not; the difference between the two drugs was highly significant (-25% vs -5%, p less than 0.001). Left ventricular filling pressures declined similarly with both captopril (-10.5 mm Hg) and with isosorbide dinitrate (-9.3 mm Hg), but because pulmonary arteriolar resistance fell significantly with nitrate therapy, mean right atrial pressure decreased more with isosorbide dinitrate than with captopril (-5.4 vs -2.8 mm Hg, respectively; p less than 0.001). Although systemic resistance declined similarly with both drugs, cardiac index increased more with nitrate therapy than during converting-enzyme inhibition (+0.47 vs +0.23 L/min/m2) (p less than 0.01), and therefore mean arterial pressure fell less with isosorbide dinitrate than with captopril (-10.5 mm Hg vs -16.7 mm Hg); p less than 0.05); two patients developed symptomatic hypotension with captopril, whereas none did so with the nitrate. The difference in the effects of the two drugs on cardiac index was not due to differences in their effects on heart rate, since heart rate fell similarly with both drugs, and thus both drugs produced similar increases in stroke volume index. These data indicate that, in patients with severe chronic heart failure, nitrates exert favorable dilating effects on the pulmonary circulation not shared by captopril.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of norepinephrine on insulin secretion and glucose effectiveness in non-insulin-dependent diabetes

It has previously been shown that in normal subjects, physiological elevation of norepinephrine (NE) impairs insulin sensitivity (Si) but does not influence insulin secretion. The aim of this study was to determine the effect of short-term physiological elevation of NE on insulin secretion, Si, and glucose-mediated glucose disposal, or the glucose effectiveness index (Sg), in non-insulin-dependent diabetes mellitus (NIDDM). Two intravenous glucose tolerance tests (IVGTTs) were performed in eight well-controlled NIDDM patients, using a supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. The IVGTTs were performed in random order after 30 minutes of either the saline (SAL) or NE (25 ng/kg/min) infusions, which were continued throughout the 3-hour IVGTT. Sg and Si were estimated by minimal model analysis of the IVGTT data as previously described. Plasma C-peptide was used to estimate insulin secretion rate using the ISEC program. NE infusion produced approximately a threefold increase in plasma NE, associated with (1) a significant reduction in glucose disposal ([K_G] SAL v NE, 0.73 ± 0.06 v 0.61 ± 0.06 × 10⁻² · min⁻², P < .05), (2) no reduction in Si (2.33 ± 0.8 v 2.62 ± 0.9 × 10⁻⁴ · min⁻¹/mU/L, NS), (3) a reduced mean second-phase insulin secretion rate (1.21 ± 0.19 v 1.01 ± 0.16 × 10⁻³ pmol/kg/min per mmol/L glucose, P < .05), (4) a significant increase in Sg (0.89 ± 0.08 v 1.63 ± 0.2 × 10⁻² · min⁻¹ P < .05), and (5) a corresponding increase in glucose effectiveness at zero insulin ([GEZI] 0.55 ± 0.13 v 1.30 ± 0.33 × 10⁻² · min⁻¹, P < .05). These results show that in contrast to normal subjects, physiological elevation of NE in NIDDM does not result in a reduction in Si, but causes a reduction in glucose disposal related to inhibition of insulin secretion that is only partially compensated for by increased Sg.     

Afterload reduction with nifedipine in aortic insufficiency

The acute hemodynamic effects of nifedipine were assessed In 12 patients with severe isolated aortic Insufficiency during control conditions and 30 minutes after administration of nifedipine (20 mg sublingually). Left ventricular end-diastollc pressure decreased from 19 ± 8 (mean ± standard deviation) to 9 ± 5 mm Hg (probability [p] < 0.0001), mean aortic pressure from 98 ± 12 to 80 ± 9 mm Hg (p < 0.0001), systemic vascular resistance from 1,135 ± 280 to 794 ± 176 dynes·s·cm^?5 (p < 0.0002) and rate-pressure product from 11,732 ± 1,727 to 10,022 ± 1,103 mm Hg⁺ beats/min (p < 0.01). Forward cardiac index increased by 24 percent, from 3.8 ± 1.1 to 4.4 ± 0.8 liters/min per m² (p < 0.04). Left ventricular end-diastolic volume, ejection fraction and total stroke work index did not change significantly. Regurgitant fraction, measured in five patients, changed parallel with systemic vascular resistance. Left ventricular function was maintained while both preload and afterload were decreased. Regurgitant flow was moderated and myocardial oxygen demand decreased. This hemodynamically favorable condition, due to nifedlpine, is clinically important and suggests the need for further therapeutic trials.     

Effect of selective and nonselective β-blockers on resting energy production rate and total body substrate utilization in chronic heart failure

Background: In chronic heart failure (CHF) β-blockers reduce myocardial oxygen consumption and improve myocardial efficiency by shifting myocardial substrate utilization from increased free fatty acid oxidation to increased glucose oxidation. The effect of selective and nonselective β-blockers on total body resting energy production rate (EPR) and substrate utilization is not known. Methods: Twenty-six noncachectic patients with moderately severe heart failure (New York Heart Association class II or III, left ventricular ejection fraction < 0.40) were treated with carvedilol (37.5 ± 13.5 mg/12 h) or bisoprolol (5.4 ± 3.0 mg/d) for 6 months. Indirect calorimetry was performed before and after 6 months of treatment. Results: Resting EPR was decreased in carvedilol (5.021 ± 0.803 to 4.552 ± 0.615 kJ/min, P < .001) and bisoprolol group (5.230 ± 0.828 to 4.978 ± 0.640 kJ/min, P < .05; nonsignificant difference between groups). Lipid oxidation rate decreased in carvedilol and remained unchanged in bisoprolol group (2.4 ± 1.4 to 1.5 ± 0.9 mg m²/kg min versus 2.7 ± 1.1 to 2.5 ± 1.1 mg m²/kg min, P < .05). Glucose oxidation rate was increased only in carvedilol (2.6 ± 1.4 to 4.4 ± 1.6 mg m²/kg min, P < .05), but did not change in bisoprolol group. Conclusions: Both selective and nonselective β-blockers reduce total body resting EPR in noncachectic CHF patients. Carvedilol compared to bisoprolol shifts total body substrate utilization from lipid to glucose oxidation.     

Differences in Ca-Handling and Sarcoplasmic Reticulum Ca-Content in Isolated Rat and Rabbit Myocardium

We made novel measurements of the influence of rest intervals and stimulation frequency on twitch contractions and on sarcoplasmic reticulum (SR) Ca²⁺-content (using rapid cooling contractures, RCCs) in isolated ventricular muscle strips from rat and rabbit hearts at a physiological temperature of 37 °C. In addition, the frequency-dependent relative contribution of SR Ca²⁺-uptake and Na⁺/Ca²⁺-exchange for cytosolic Ca²⁺-removal was assessed by paired RCCs. With increasing rest intervals (1–240 s) post-rest twitch force and RCC amplitude decreased monotonically in rabbit myocardium (after 240 s by 45±10% and 61±11%, respectively P<0.05, n=14). In contrast, rat myocardium (n=11) exhibited a parallel increase in post-rest twitch force (by 67±16% at 240 sP <0.05) and RCC amplitude (by 20±14%P<0.05). In rabbit myocardium (n=11), increasing stimulation frequency from 0.25 to 3 Hz increased twitch force by 295±50% (P<0.05) and RCC amplitude by 305±80% (P<0.05). In contrast, in rat myocardium (n=6), twitch force declined by 43±7% (P<0.05), while RCC amplitude decreased only insignificantly (by 16±7%). The SR Ca²⁺-uptake relative to Na⁺/Ca²⁺-exchange (based on paired RCCs) increased progressively with frequency in rabbit, but not in rat myocardium (66±2% at all frequencies). We conclude that increased SR Ca²⁺-load contributes to the positive force–frequency relationship in rabbits and post-rest potentiation of twitch force in rats. Decreased SR Ca²⁺-load contributes to post-rest decay of twitch force in rabbits, but may play only a minor role in the negative force–frequency relationship in rats. SR Ca²⁺-release channel refractoriness may contribute importantly to the negative force-frequency relationship in rat and recovery from refractoriness may contribute to post-rest potentiation.     

Age-related decrease in plasma growth hormone: Response to growth hormone-releasing hormone, arginine, and l-dopa in obesity

Aging is associated with a reduction in plasma growth hormone (GH) secretion in non-obese subjects. To determine whether or not age-related changes in plasma GH secretion exist in obese subjects, we measured (a) plasma GH response to growth hormone-releasing hormone (GRH; 1 μg/kg body wt), arginine (0.5 g/kg body wt), l-dopa (500mg), and (b) plasma glucose, insulin, and free fatty acids (FFAs) in 26 fasted obese subjects of various ages ranging from 16 to 71 years. Only subjects with a body mass index (BMI; kg/m²) between 30.0 and 39.0 were studied. Six subjects were adolescents, 9 were in their 20s, and 11 were 30 years or older. The mean peak levels of plasma GH in response to GRH, arginine, and l-dopa in obese subjects were 11.3 ± 2.1, 21.9 ± 4.4, and 5.2 ± 0.3 ng/mL in adolescents, 8.2 ± 1.6, 9.1 ± 1.5, and 3.1 ± 0.6 ng/mL in those in their 20s, and 4.5 ± 0.4, 7.3 ± 1.4, and 2.8 ± 0.3 ng/mL in those 30 years or older, respectively, showing a significant decrease in peak GH level with advancing age (P < .05 to P < .01). There was a negative correlation between the logarithmic increase in age and the peak GH response to GRH (r = −.635, P < .01), arginine (r = −.564, P < .01), and l -dopa (r = −.630, P < .01), and between the logarithmic increase in age and the integrated GH response to GRH (r = −.564, P < .01), arginine (r = −.612, P < .01), and l-dopa (r = −.551, P < .01) in all subjects. Plasma glucose, insulin, and FFAs did not change with age. There was no correlation between the peak GH level or the integrated GH response to these three stimuli and the plasma levels of glucose, insulin, and FFAs, respectively. Our findings suggest that in obese subjects advancing age reduces the secretory responsiveness of pituitary somatotropes to these three stimuli.     

Effect of isosorbide dinitrate on gastroesophageal reflux in healthy volunteers and patients with Chagas' disease

The effect of isosorbide dinitrate (ISD) on gastroesophageal reflux and gastric emptying during the 24-min period following a liquid meal was studied in healthy volunteers, Chagas' disease patients with normal esophageal motility (CD-1 group), and Chagas' disease patients with esophageal dysmotility (CD-2 group) with dynamic scintigraphy. At random, on two separate days, the subjects received 5 mg isosorbide dinitrate or an identical-appearing placebo tablet, by the sublingual route, and ingested a liquid test meal containing [^99mTc]phytate colloid before scintigraphic studies were performed. Gastroesophageal reflux episodes were more frequent (P=0.016) and gastroesophageal reflux indexes were greater (P<0.010) after isosorbide dinitrate than after placebo in CD-2 group (N=15) but not in healthy volunteers (N=14) or CD-1 group (N=9); six of seven CD-2 patients presenting with gastroesophageal reflux after isosorbide dinitrate had abnormal clearance of refluxate. Gastric emptying was similar in healthy volunteers (N=13), CD-1 patients (N=6), and CD-2 patients (N=13), and no effect of isosorbide dinitrate on it was detected in any of the groups. In separate studies, 5 mg isosorbide dinitrate reduced the lower esophageal pressure (P<0.01) in seven CD-2 patients. These results indicate that ISD increases the tendency towards GER in CD-2 patients, but not in healthy volunteers or CD-1 patients. This effect is probably related to an exceedingly intense relaxation of the LES caused by ISD in CD-2 patients. Considering the role of the destruction of the intramural neurons in the pathogenesis of the esophageal motor disorder in Chagas' disease, these findings are likely to be a consequence of the loss of the normal neural influences on the lower esophageal sphincter in Chagas' disease.