[Acute coronary vasomotor effects of nifedipine and its therapeutic efficacy in syndrome X]. / Effetti vasomotori coronarici acuti della nifedipina ed efficacia terapeutica nella sindrome X.

In 18 patients (12 females) presenting with effort-induced chest pain and normal coronary angiograms (syndrome X), 10 mg sublingual nifedipine increased the lumen of major coronary arteries (quantitative angiography) by 13% +/- 10 (p less than 0.01), coronary blood flow (thermodilution) by 23% +/- 26 (p less than 0.05), norepinephrine plasma concentration by 60% +/- 42 (p less than 0.01), and reduced the global ST segment shift during the effort stress test from 8.8 +/- 4.1 to 7 +/- 6.8 mm (p less than 0.03) at comparable maximal workload and at unchanged double product. There was a correlation (positive) of changes in flow with changes in coronary lumen diameter (r = 0.65, p less than 0.01), with ST segment response to exercise (r = 0.83, p less than 0.001), and with (inverse) norepinephrine plasma concentration (r = -0.70, p less than 0.01); no correlation was found between ST segment response and changes in arterial lumen diameter. In a few cases nifedipine did not improve or even worsened the response to exercise; in them coronary flow was unchanged or reduced and norepinephrine plasma levels were modestly or greatly increased, respectively. After 4-week treatment with nifedipine (10-20 mg 4 times daily), the effort ST segment shift was further diminished to 4.4 +/- 3.5 mm (p less than 0.03) despite a slightly increased double product. Plasma norepinephrine values, as compared to those following acute nifedipine, were reduced by 40% in patients with further improvement and unchanged in patients whose exercise performance did not vary.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute coronary vasomotor effects of nifedipine and therapeutic correlates in syndrome X.

In 18 patients (12 women) presenting with effort-induced chest pain and normal coronary angiograms (syndrome X), 10 mg sublingual nifedipine increased the lumen of major coronary arteries (quantitative angiography) by 13 +/- 10% (p less than 0.01), coronary blood flow (thermodilution) by 23 +/- 26% (p less than 0.05), norepinephrine plasma concentration by 60 +/- 42% (p less than 0.01) and decreased the global ST-segment shift during the effort stress test from 8.8 +/- 4.1 to 7 +/- 6.8 mm (p less than 0.03) at comparable maximal workload and at unchanged double product. There was a correlation (positive) of changes in flow with changes in coronary lumen diameter (r = 0.65, p less than 0.01) with ST-segment response to exercise (r = 0.83, p less than 0.001) and with (inverse) norepinephrine plasma concentration (r = -0.70, p less than 0.01); no correlation was found between ST-segment response and changes in arterial lumen diameter. In a few cases, nifedipine did not improve or even worsened the response to exercise; coronary flow was unchanged or decreased and norepinephrine plasma levels were modestly or greatly increased, respectively. After 4 weeks of treatment with nifedipine (10 to 20 mg 4 times daily), the effort ST-segment shift was further decreased to 4.4 +/- 3.5 mm (p less than 0.03) despite a slightly increased double product. Plasma norepinephrine values, as compared to those after acute nifedipine, were decreased by 40% in patients with further improvement and were unchanged in patients whose exercise performance did not vary.(ABSTRACT TRUNCATED AT 250 WORDS)

[Angiographic course of coronary atherosclerosis in angina pectoris. Its relation to 2 years' treatment with propranolol, nifedipine and nitrates]. / Evoluzione angiografica dell'aterosclerosi coronarica nell'angina pectoris. Relazione con il trattamento per 2 anni con propranololo, nifedipina e nitrati.

Calcium antagonists and beta-blockers may retard or inhibit atherogenesis. We tested whether nifedipine or propranolol may retard or induce regression of coronary atherosclerosis in man. In selected population of 113 patients with effort angina and proven coronary artery disease, the coronary cineangiographic pattern after 2 year therapy with nifedipine (Group 1, 39 patients), propranolol (Group 2, 36 patients), or isosorbide dinitrate (control group, 38 patients) was compared to the pre-treatment pattern. After 2 years the disease evolved to a different extent in the 3 groups. The number of lesions with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) as compared with controls (24). Patients with evidence of progression of old lesions, and appearance of new lesions were significantly fewer in Group 1 than in Group 2 and in control patients. Thus, nifedipine seemed more protective than either of the other drugs against coronary atherosclerosis. The coronary risk factors were within normal limits in the nifedipine treated group and remained so with treatment supporting that they were likely dissociated from influences on atherosclerosis. The evolution, at least as judged by the number of lesions with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. This may prospect that nitrate contrasted the evolution of the disease, or that propranolol made it worse, possibly through unfavourable modifications of serum lipids (28% rise of total triglyceride and 25% decrease of HDL cholesterol were already detectable at 12 months in Group 2).

[Greater efficacy of propranolol versus nifedipine in angina with 2 components, that results in varying influence on coronary vasomotility]. / Miglior efficacia di propranololo verso nifedipina nell'angina a doppia componente, quale risultato di influenze diverse sulla vasomotilità coronarica.

In 24 patients with stable spontaneous and effort-related angina, ischemic episodes at rest were not preceded by changes in circulatory variables (heart rate, systemic and pulmonary arterial pressures) that may raise myocardial oxygen consumption. We interpreted these episodes as caused by critical and reversible coronary flow reduction at the site of a stenotic lesion, and evaluated the clinical efficacy of nifedipine and propranolol in the treatment of this condition. Propranolol fully abolished or reduced the number of spontaneous ischemic episodes in a significantly larger number of patients than did nifedipine; it was also effective in several cases in whom nifedipine had failed or had even caused a paradoxic effect. Quantitative angiographic evaluation of the influence of nifedipine (Group 1, 12 patients, 10 mg sublingually) and propranolol (Group 2, 12 patients, 0.1 mg/kg intravenously) on the residual lumen diameter of 1 significant coronary stenosis in each patient showed that after nifedipine, the lumen was unchanged in 1, augmented in 7, and reduced in 4 cases; variations ranged between +1.59 and -1.2 mm, and their direction correlated closely with the influence of oral nifedipine on the episodes of spontaneous ischemia; and in no case did treatment with propranolol vary the stenosis lumen by more than 0.3mm. In this form of angina, a number of lesions seem to offer a compliant substrate for vasomotion and, possibly, for critical changes in flow. The vasomotor influences of nifedipine on these lesions are variable as well as the efficacy of the drug on the manifestations of ischemia at rest.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris.

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.

Superior efficacy of propranolol versus nifedipine in double-component angina, as related to different influences on coronary vasomotility.

PURPOSE: In 24 patients with stable spontaneous and effort-related angina, ischemic episodes at rest were not preceded by changes in circulatory variables (heart rate, systemic and pulmonary arterial pressures) that may raise the myocardial oxygen consumption. We interpreted these episodes as caused by critical and reversible coronary flow reduction at the site of a stenotic lesion, and evaluated the clinical efficacy of nifedipine and propranolol in the treatment of this condition. PATIENTS AND METHODS: The study was randomized, placebo-controlled, and crossover in design. Nineteen of the 24 subjects were men (mean group age, 59 years; range, 47 to 65 years). The study consisted of four four-day periods. The first and the fourth periods, during which patients received placebo, were single-blind. The treatment consisted of 80 mg of propranolol or 20 mg of nifedipine administered four times daily. The second and the third periods, during which patients received propranolol or nifedipine crossing over to the alternative drug in the next period, were double-blind and separated by a 24-hour interval. RESULTS: Propranolol fully abolished or reduced the number of spontaneous ischemic episodes in a significantly larger proportion of patients than did nifedipine; it was also effective in several cases in which nifedipine had failed or had even caused a paradoxic effect. Quantitative angiographic evaluation of the influences of nifedipine (Group 1, 12 patients, 10 mg sublingually) and propranolol (Group 2, 12 patients, 0.1 mg/kg intravenously) on the residual lumen diameter of one significant coronary stenosis in each patient showed that (1) after nifedipine, the lumen was unchanged in one, augmented in seven, and reduced in four cases; (2) variations ranged between +1.59 and -1.2 mm, and their direction correlated closely with the influence of oral nifedipine on the episodes of spontaneous ischemia; and (3) in no case did treatment with propranolol vary the stenosis lumen by more than 0.3 mm. CONCLUSION: In this form of angina, a number of lesions seem to offer a compliant substrate for vasomotion and, possibly, for critical changes in flow. The vasomotor influences of nifedipine on these lesions are variable as well as the efficacy of the drug on the manifestations of ischemia at rest. Propranolol produces no important variations of the coronary stenotic lesions, causes a decrease of heart rate that facilitates coronary flow in diastole, and reduces the baseline metabolic demand of the heart so that the threshold of ischemia during critical reduction of coronary flow may become elevated.

Hypoxia-induced pulmonary hypertension: nifedipine only temporarily reduces pulmonary artery pressure and vascular tone.

Fifteen patients affected by hypoxia-induced pulmonary hypertension were studied before and during (1st and 8th week) nifedipine (180 mg/die) treatment. Nifedipine reduced pulmonary pressure (33 +/- 4 vs 26 +/- 3 mmHg, p less than 0.02) after 1 week of treatment; this pulmonary hypotensive effect was due to a reduction of pulmonary vascular tone as assessed by a reduction of Y-intercept on the pulmonary pressure/flow plot drawn from invasive recordings of pulmonary pressure/cardiac output obtained during exercise. Oxygen breathing effects on pulmonary pressure were also measured with and without nifedipine. Oxygen significantly reduced pulmonary pressure only in the absence of nifedipine regardless of the severity of pulmonary hypertension. Therefore nifedipine is not suitable for long-term treatment of hypoxia-induced pulmonary hypertension and inhibits O2 capability to reduce pulmonary pressure.

Different coronary vasomotor effects of nifedipine and therapeutic correlates in angina with spontaneous and effort components versus Prinzmetal angina.

Flow impedance, probably of vasomotor origin, superimposed on severe coronary stenosis has been considered a trigger for the spontaneous component of angina occurring both on effort and at rest. To investigate more thoroughly this pathophysiologic aspect we evaluated (by means of quantitative coronary angiography) the acute vasomotor reaction to nifedipine (10 mg sublingually) of significant (greater than 50%) stenotic lesions in 22 patients with double-component angina. We also correlated this reaction with the clinical response (daily number of ischemic episodes evaluated by means of 48-hour Holter ambulatory monitoring) to treatment with nifedipine (20 mg four times a day); calcium channel blockade, in fact, is considered a specific remedy in cases of altered coronary vasomotility. Patients with Prinzmetal angina, who were known to have homogeneous coronary vasodilating reactions and favorable clinical responses to nifedipine, were studied by means of the same methods and served as the control group (14 patients). In double-component angina the residual lumen diameter of significant lesions was unchanged in two patients, enhanced in 10, and reduced in 10 after sublingual nifedipine; lumen variations from baseline values ranged from +1.29 to -1.56 mm. Acute changes in stenosis correlated closely with results obtained with oral treatment. In the group with Prinzmetal angina, coronary stenoses invariably responded with dilatation (the residual coronary lumen increased by an average of 69% of baseline); 100% of the patients in this group responded favorably to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Different vasomotor action of nifedipine on dynamic coronary obstructions and therapeutic response in effort and prinzmetal angina.

Variations induced by nifedipine (10 mg sublingually) in the residual lumen diameter of significant (greater than 50%) coronary lesions were assessed angiographically in 58 patients with effort angina (group 1) and in 19 patients with Prinzmetal angina (group 2). A relationship was sought between these acute variations of the stenotic lumen and the clinical response to treatment with the same drug (20 mg four times daily). Treatment efficacy was evaluated with exercise testing in group 1 and Holter monitoring in group 2. In group 1 the residual segment of stenotic diameter showed an increase, decrease, or no change with the calcium antagonist. Nifedipine failed to improve 40% of the cases (21% unchanged and 19% worsened) in group 1. In the same group of patients, the responses to exercise tests were dissociated from the acute vasomotor pattern. Changes in the pressure-rate product also did not explain the clinical results. In group 2 the majority of lesions had compliant portions, which invariably reacted to nifedipine with dilatation. All patients with the Prinzmetal form had relief of the anginal episodes with treatment. These data suggest that the therapeutic efficacy of nifedipine in classic effort angina probably is the net result of influences on the myocardial oxygen consumption and supply, and the acute coronary vasomotor pattern does not allow to predict the clinical response. Stenotic lesions in the Prinzmetal form possess a distinct sensitivity to the relaxant action of calcium channel blockade, which reasonably explains the highly positive response to treatment.

Nifedipine reduces pulmonary pressure and vascular tone during short- but not long-term treatment of pulmonary hypertension in patients with chronic obstructive pulmonary disease.

We evaluated in patients suffering from COPD-related pulmonary hypertension whether nifedipine therapy lowers acutely and chronically pulmonary vascular pressure and resistance and whether pulmonary transmural pressure may be further lowered by the combined use of nifedipine and oxygen. Changes of the pulmonary vascular tone were determined on the pulmonary driving pressure/flow curve, which was generated by upright exercise. Fifteen patients with COPD and mean pulmonary pressure greater than or equal to 20 mm Hg were studied at control (Week 0) and after 1 wk of nifedipine treatment (180 mg daily, Week 1). It was possible to pursue the same nifedipine daily dosage for 2 months in 10 patients, who were re-evaluated after 8 wk of treatment and after nifedipine withdrawal the following week. At Week 1, mean pulmonary transmural pressure was reduced (32.8 +/- 4.1 versus 27.3 +/- 2.8 mm Hg, mean +/- SE, p less than 0.05) via active pulmonary vasodilation because the pulmonary driving pressure/flow curve was shifted right and downward. Both mean transmural pulmonary pressure lowering effect and active pulmonary vasodilatation regressed during long-term nifedipine treatment. Oxygen reduced pulmonary transmural pressure (32.8 +/- 4.1 versus 28.6 +/- 2.9 mm Hg, p less than 0.05, Week 0); however, this effect always disappeared during nifedipine treatment. We conclude that nifedipine should not be used as long-term treatment for COPD-related pulmonary hypertension and that nifedipine inhibits the oxygen capability to reduce pulmonary pressure.

Coronary vasomotor and therapeutic influences of propranolol and nifedipine on the spontaneous component of mixed angina.

In 24 patients with spontaneous and effort-related angina (mixed angina), propranolol (80 mg q.i.d.) was significantly more beneficial than nifedipine (20 mg q.i.d.) on the number, duration and severity of the spontaneous manifestations. In some cases nifedipine elicited a paradoxical response. These patterns are unlikely to have resulted from different influences on the myocardial oxygen demands, since heart rate was steady before the occurrence of ischaemia and systemic arterial pressure was equally reduced in all patients. Sublingual nifedipine (10 mg) was tested in 12 patients and the residual lumen diameter of significant (greater than 50%) coronary stenoses (quantitative angiography) was unchanged in one, enhanced in seven and reduced in four of them. Lumen variations ranged from +1.59 to -1.2 mm and correlated closely with the results of oral nifedipine treatment. Propranolol (0.1 mg kg-1 i.v.) was tested in the other 12 cases and in none did variations of stenosis lumen diameter exceed 0.3 mm. These observations indicate that: in a number of lesions a portion of pliable wall may offer a compliant substrate for vasomotor influences; this may be the major factor whereby coronary obstructions cause spontaneous, besides effort-related angina; nifedipine is effective on the former manifestation provided that it does not promote stenosis constriction; propranolol may result in benefit through bradycardia facilitating coronary flow in diastole and reducing the baseline metabolic demands, to elevate the threshold of ischaemia during transient impedance to flow.

Nifedipine and angina pectoris. Short-term changes in quantitative coronary angiography with nifedipine and clinical response to treatment in effort-induced, mixed, and spontaneous angina pectoris.

Changes induced by nifedipine (10 mg sublingually) in the residual luminal diameter of significant (greater than 50 percent) coronary lesions were assessed angiographically in 69 patients with effort-induced angina (group 1), in 22 patients with mixed angina (group 2), and in 14 patients with Prinzmetal's angina (group 3). These changes were related to the clinical response to treatment with the same drug, as evaluated through diary records and Holter monitoring in the mixed (spontaneous component) and Prinzmetal forms and through exercise testing in effort-induced and mixed (effort-associated component) angina. In groups 1 and 2, segments of stenotic vessels showed either an increase or decrease or no change in diameter with the calcium antagonist; in group 3, the majority of the lesions had compliant portions which invariably responded with dilatation. Nifedipine failed to improve cases with exertional (20 percent [14/69] unchanged; 19 percent [13/69] worsened) and mixed (41 percent [9/22] exacerbated) forms; 100 percent of the 14 patients with the Prinzmetal form had relief of the anginal episodes. In group 1, the response to exercise tests was dissociated from the short-term vasomotor pattern, and the pressure-rate product failed to explain the clinical results. Forty-five percent (ten) of the patients in group 2 showed significant short-term widening of critical stenoses, as well as obvious improvement; patients who did worse with treatment in this group had reacted to nifedipine with narrowing of critical stenoses. These data suggest that the response to nifedipine of classic effort-induced angina is probably the net result of an interaction of changes in myocardial oxygen consumption and supply; coronary vasomotion has a role in mixed angina, and influences of nifedipine may be either favorable or unfavorable; stenotic lesions in the Prinzmetal form are quite sensitive to the relaxant action of calcium blockade, and this probably represents a background to the highly positive clinical response to treatment.

Coronary vasomotor and clinical effects of nifedipine in effort, mixed and Prinzmental angina.

Changes induced by nifedipine (10 mg s.l.) in the residual lumen diameter of significant (greater than 50%) coronary lesions were assessed angiographically in 69 patients with effort angina (Group 1), in 22 patients with mixed angina (Group 2), and in 14 patients with Prinzmental angina (Group 3). These changes were related to the clinical response to treatment with the same drug (diary records, exercise testing, Holter monitoring). In Groups 1 and 2 segments of stenotic vessels showed either increase, decrease or no change in diameter with the calcium antagonist; in Group 3 the majority of the vessels showed compliant portions which invariably responded with dilatation. Nifedipine failed to improve cases with exertional (21% unchanged, 19% worsened) and mixed (41% exacerbated) forms; all patients with the Prinzmental form had relief of the anginal episodes. In Group 1, the response to exercise tests were dissociated from the acute vasomotor pattern and the pressure-rate product failed to explain the clinical results. Fifty-two percent of the patients in Group 2 showed significant acute widening of critical stenoses as well as obvious improvement; patients in this group who did worse with treatment had reacted to nifedipine with narrowing of their critical stenoses. These data suggest that: the response to nifedipine of classic effort angina is probably the net result of an interaction of changes in myocardial oxygen consumption and supply; coronary vasomotion has a role in mixed angina and influences of nifedipine may be either favorable or unfavorable; stenotic lesions in the Prinzmental form are quite sensitive to the relaxant action of calcium blockade and this probably represents a background to the highly positive clinical response to treatment.

Calcium channel blockade with nifedipine reduces the systemic and the pulmonary vascular reactivity to adrenergic activation in hypertension.

In hypertension the systemic and the pulmonary circulation show exaggerated vascular tone and responsiveness to adrenergic stimuli. In 22 hypertensive men we tested whether the regulation of the two vascular beds is improved by calcium entry blockade with nifedipine. Mental arithmetic raised epinephrine plasma concentration (by 80%), cardiac output (CO) and blood pressure in both circuits, and caused systemic vasodilatation and pulmonary vasoconstriction. After the drug the epinephrine reaction was diminished (+20%), variations in CO and systemic blood pressure were almost unchanged and pulmonary vasoconstriction was abolished. A cold pressor test increased norepinephrine plasma concentration (by 24%), systemic and pulmonary pressure and resistance and did not alter CO. The norepinephrine response to cold was enhanced (+35%) by nifedipine, while systemic and pulmonary resistance rises were importantly attenuated (from +24% to +7% and from +41% to +1%, respectively), and greatly diminished the pressure reactivity. A sympatho-adrenal modulation by calcium blockade, per se, might have restrained the vasomotion during arithmetic. The impressive attenuation of the constrictor responses to cold, which was possibly associated with a potentiated sympathetic drive, prospects that the two circuits share a vascular contractile disorder in which calcium ions are involved.

Nitrendipine vs. long-acting nifedipine in mild, moderate and severe hypertension.

Long-acting nifedipine and nitrendipine, a nifedipine analogue, have been proposed for single-drug therapy of hypertension. In this study we compared the two preparations in three groups (10 subjects in each group) of mild (group 1), moderate (group 2), and severe (group 3) hypertensives. Drugs were administered for seven days (20 mg every 8 hr), according to a randomized, double-blind, crossover design. Blood pressure and heart rate readings were taken hourly, from 8 A.M. to 7 P.M., for the duration of the trial. In group 1, pressure was lowered to normal levels by both compounds and did not recover in the interval between one dose and the other, so that it remained normal throughout the day. In group 2, from an average of 170/109, values were reduced by the two preparations to 140/90 mm Hg within two hours, and then they tended to recover. This tendency was interrupted by the next dose. Because of this pattern, compared with the placebo period, pressure was substantially reduced during the twelve hours of the day; however, for a certain span it remained higher than normal. In group 3, the immediate responses to the two drugs were similar (from an average of 208/130, pressure was lowered to an average of 170/95 mm Hg), and then it tended to rise again and recovery was faster with nifedipine. Although pressure was significantly reduced throughout the day by both preparations, normotension was never achieved in this group. Neither drug induced a tachycardia reaction, altered renal or cardiac function, or affected body weight or plasma renin activity. The tendency to produce dependent edema was less pronounced with nitrendipine. In conclusion, these calcium channel antagonists were equally effective in mild and moderate hypertension, while in the severe from the action of nitrendipine was more persistent. Within the limits of the drug regimens used in this study, it seems that both preparations as monotherapy may be satisfactory in mild, questionable in moderate, and inadequate for severe hypertension, although the action of nitrendipine is more lasting.

Afterload reduction: a comparison of captopril and nifedipine in dilated cardiomyopathy.

Nifedipine and captopril are potent vasodilators and may be expected to help left ventricular failure by reducing afterload. Nifedipine (20 mg three times a day) and captopril (50 mg three times a day) were added to an optimal regimen of digitalis and diuretics in a double blind crossover trial in 18 cases of dilated cardiomyopathy. New York Heart Association functional class rating symptoms and exercise tolerance times improved on captopril but not on nifedipine. The reduction in pulmonary capillary wedge pressure and the increase of cardiac output on captopril indicated that the augmented functional capacity may have resulted in part from an improved performance of the left ventricle. Although there were comparable decreases in systemic vascular resistance and presumably in impedence to ejection by the left ventricle on both drugs, the dimensions of the ventricular cavity were found to be reduced by captopril and augmented by nifedipine, and only captopril reduced the afterload (wall stress). In addition, the force-length relation (between left ventricular end systolic stress and end systolic diameter) was shifted to the left of baseline by captopril and to the right by nifedipine, suggesting that muscle contractility was reduced by nifedipine and not by captopril. These results suggest that nifedipine and captopril have different effects on afterload and contractility and these may account for the different effects of these drugs on the performance of the heart and clinical responses.