Beta-adrenergic receptors and reflex tachycardia after single and repeated felodipine administration in essential hypertension.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.     

Systemic and pulmonary hemodynamic effects of indapamide in patients with mild arterial hypertension

We studied the hemodynamic mechanism responsible for the antihypertensive effect of indapamide in eight patients with mild essential hypertension. Systemic and pulmonary hemodynamics were measured using direct techniques (right heart catheterization and thermodilution method), before and 7-10 days after oral treatment with indapamide (2.5 mg/day). Indapamide reduced mean arterial blood pressure from 120 +/- 1.6 (mean +/- SE) to 101 +/- 1.4 mm Hg (p less than 0.01), and mean pulmonary artery pressure from 21 +/- 0.59 to 17 +/- 1.05 mm Hg (p less than 0.01). Total peripheral vascular resistance (TPR) and pulmonary vascular resistance were reduced from 36 +/- 0.85 to 29 +/- 0.72 U/m2 (p less than 0.01) and from 4.3 +/- 0.17 to 3.8 +/- 0.18 U/m2 (p less than 0.01), respectively. Indapamide did not change cardiac index (CI) (3,311 +/- 61.6 vs. 3,325 +/- 72.1 ml/min/m2), heart rate (HR) (75 +/- 1.7 vs. 75 +/- 9 beats/min), mean rate of left ventricular ejection index 140 +/- 2.04 vs. 139 +/- 1.99 ml/s/m2, and stroke index (44 +/- 5.6 vs. 43 +/- 5.8 ml/m2). Mean pulmonary wedge pressure decreased from 7 +/- 0.6 to 5 +/- 0.5 mm Hg (p less than 0.05). Body weight, 24-h urinary volume, and hematocrit were unchanged after treatment. We conclude that the hemodynamic mechanism responsible for the antihypertensive action of indapamide is a reduction in TPR without changes in CI and HR.     

ULFS-49 causes bradycardia without decreasing right ventricular systolic and diastolic performance.

The effects of ULFS-49, a new calcium channel blocker, on right ventricular (RV) systolic and diastolic performance were evaluated in nine anesthetized, closed-chest dogs by load-insensitive indexes. ULFS-49 (0.3 mg/kg) decreased heart rate (HR) from 76 +/- 25 to 47 +/- 11 beats/min (p less than 0.01) and cardiac output (CO) from 1.89 +/- 0.62 to 1.42 +/- 0.72 L/min (p less than 0.01), as RV free wall end-diastolic area increased from 486 +/- 126 to 581 +/- 45 mm2 (p less than 0.01) and RV end-diastolic volume increased from 66.6 +/- 26.4 to 85.3 +/- 28.5 ml (p less than 0.05). Pacing at 100 beats/min ablated these hemodynamic and dimensional changes. RV free wall contractility was assessed by the slope and midrange intercept values of the relation between RV end-systolic pressure (Pes) and end-systolic free wall area (Aes) and between RV free wall segmental work (SW) and end-diastolic area (Aed). RV free wall stiffness was measured by exponential fit of the RV end-diastolic pressure (Ped)-Aed points during caval occlusion. With pacing at 100 beats/min, the slope of the Pes-Aes relationship was unchanged by ULFS-49 (0.52 +/- 0.29 vs. 0.60 +/- 0.35 mm Hg/mm2) as was the midrange intercept (382.3 +/- 114.7 vs. 387.1 +/- 121.5 mm2). After administration of ULFS-49, the slope of the SW-Aed relation increased from 31.8 +/- 14.4 to 37.3 +/- 17.7 mm Hg.mm2 (p less than 0.05) without changing the midrange intercept (410.5 +/- 108.1 mm2 vs. 413.0 +/- 107.0 mm2). Similarly, neither the position nor curvature of the Ped-Aed relation was changed by ULFS-49. These data demonstrate that ULFS-49 causes significant bradycardia and increases the size of the right ventricle without directly depressing RV free wall systolic or diastolic performance.     

Altered baroreflex control of heart rate in bradykinin B2-receptor knockout mice

Recently, we have shown that a knockout mouse strain lacking the bradykinin B2-receptor gene exhibits an accelerated heart rate (HR) under basal conditions, this alteration being associated with mildly elevated blood pressure (BP) levels and ultimately with the development of cardiomyopathy. The goal of the present study was to determine whether genetic disruption of the B2-receptor alters autonomic cardiovascular reflexes to acute or chronic changes in BP. The direct mean BP and HR levels of unrestrained B2 knockout mice (B2-/-) were higher than those of wild type (B2+/+) controls (131 +/- 2 vs. 105 +/- 2 mm Hg and 480 +/- 5 vs. 414 +/- 8 beats/min, P < 0.01 for both comparisons). The difference in HR observed between groups under basal conditions was nullified by the acute administration of propranolol and atropine as well as by hexamethonium; it was attenuated by long-term blockade of angiotensin AT1 receptors. In B2-/- mice, the presence of an alteration in baroreceptor regulation of HR was supported by a reduced gain in the HR responses to acute nitroprusside-induced hypotension or phenylephrine-induced hypertension (slope of the regression line: 0.82 +/- 0.07 vs. 5.58 +/- 0.08 beats/min per mmHg in B2+/+, P < 0.01), as well as by an exaggerated tachycardic response to chronic hypertension induced by clipping of the left renal artery (60 +/- 3 vs. 15 +/- 3 beats/min in B2+/+, P < 0.01). Our findings indicate that disruption of the bradykinin B2-receptor gene is associated with an impaired baroreflex control of HR. The combination of chronically elevated resting HR and impaired baroreflex control could contribute to the development of cardiomyopathy in these animals.     

Effect of salt loading on aldosterone response to long-term infusion of angiotensin II in rats.

We examined changes in plasma aldosterone level and blood pressure (BP) after long-term (12 days) intravenous infusion of angiotensin II (Ang II; 15 and 60 ng/min) with two different sodium intakes (0.66% and 8% salt-containing diet) in Wistar rats. Without salt loading, 15 ng/min of Ang II did not increase mean BP (112 +/- 1 vs. 112 +/- 2 mm Hg), but 60 ng/min of Ang II increased mean BP (144 +/- 3 mm Hg, p less than 0.01). However, the 8% salt diet not only enhanced the pressor effect of 60 ng/min Ang II (168 +/- 9 mm Hg, p less than 0.05), but also elevated mean BP with 15 ng/min of Ang II (159 +/- 3 mm Hg, p less than 0.01). On a normal-salt diet (0.66%), plasma aldosterone was increased by Ang II infusion from 11.3 +/- 0.3 ng/dl to 12.7 +/- 0.5 ng/dl (NS) at a rate of 15 ng/min Ang II, and to 15.7 +/- 0.4 ng/dl (p less than 0.01) at 60 ng/min Ang II. However, salt loading reduced Ang II-induced elevation of aldosterone: 11.3 +/- 0.5 ng/dl (less than 0.01) at a rate of 60 ng/min Ang II. Thus, salt loading diminished aldosterone response to Ang II, which might compensate salt-induced enhancement of the pressor effect of Ang II.     

Protection of CGS 10078B against ouabain-induced arrhythmia in the cat

CGS 10078B (CGS; 1-[2,3-dihydro-1,4-(2S)-benzodioxin-2-yl]-5-[2,3-dihydro-1,4-(2R)- benzodioxin-2-yl]-3-(1R,5S)-aza-1,5-pentanediol methane sulfonate) is an agent with alpha- and beta-receptor and calcium channel blocking actions. To study its antiarrhythmic activity, cats were anesthetized with alpha-chloralose, ventilated, and given atropine and gallamine. CGS (10 or 20 mg/kg, i.v.) was infused 15 min prior to ouabain. Bolus injections of ouabain (25 micrograms/kg, i.v.) were given every 15 min until death (D). Some cats were pretreated with reserpine (R; 5 mg/kg, i.p.) 24 h prior to the experiment. In other cats 6-hydroxydopamine (6-OHDA; 20 mg/kg, i.v.) was administered 3 days prior to CGS 20 mg/kg and ouabain. Data were compared with those of Lathers [Eur. J. Pharmacol. 64: 95, 1980], i.e., with 12 cats who received only ouabain and with 11 pretreated with timolol (T; 5 mg/kg, i.v.) prior to ouabain. After CGS (10 or 20 mg/kg, i.v.), but just prior to the first dose of ouabain, the blood pressure (BP) was decreased (p less than 0.05) from control (165 +/- 6 vs. 96 +/- 7, and 136 +/- 5 vs. 90 +/- 10 mm Hg, respectively). Comparable heart rate (HR) values were also decreased (p less than 0.05) from 225 +/- 17 to 166 +/- 14 and from 193 +/- 8 to 152 +/- 6 beats/min. 11 min after T, BP and HR had decreased (p less than 0.05) from 133 +/- 6 to 103 +/- 7 mm Hg and from 134 +/- 4 to 104 +/- 6 beats/min, respectively. Ouabain did not influence these decreases in BP and HR. CGS (10 or 20 mg/kg, i.v.) increased (p less than 0.05) the time to ouabain-induced arrhythmia (AR) and D. The magnitude of the protection appeared to be similar to that afforded by T. R given prior to CGS (20 mg/kg, i.v.) also increased the time to ouabain-induced AR and D while 6-OHDA increased the time to AR. The CGS protection against ouabain-induced AR was still present in animals pretreated with R or 6-OHDA. This indicates that the antiarrhythmic affect is not dependent upon adrenergic neuronal blockade.     

Demographic factors and the antihypertensive effect of diltiazem.

The maximum blood pressure (BP) decrease obtained after dose titration with calcium antagonists is said to be greater in older patients. Because the dose necessary to achieve this maximum effect may also vary, it is not clear whether the sensitivity to treatment is actually increased in older patients. We evaluated the possible influence of pretreatment BP, age, and weight on the BP and heart rate (HR) response to 14-day treatment with a fixed dose of 120 mg diltiazem twice daily (b.i.d.) in 231 hypertensive patients aged 24-82 years (44 +/- 27). Diltiazem decreased BP from 171 +/- 1/103 +/- 7 to 156 +/- 1/91 +/- 1 mm Hg. Decreases in both systolic and diastolic BP (SBP, DBP) were related to their pretreatment values (p less than 0.0001 for both). Although pretreatment SBP was related to age (p less than 0.0001), its decrease with diltiazem was not. Neither pretreatment DBP nor its decrease with diltiazem was related to age; BP decrease was not superior in elderly patients (aged greater than 60 years) as compared with that in younger patients (SBP -16 +/- 2 vs. -15 +/- 1 mm Hg, NS; DBP -13 +/- 1 vs. -12 +/- 1 mm Hg, NS). In conclusion, the response to this average dose of diltiazem is related to pretreatment BP and is not affected by patient's age. Because this result is at variance with the concept that calcium antagonists are more effective in the elderly, this concept should not be used as a general therapeutic guideline.     

Antihypertensive effect of lisinopril assessed by 24-hour ambulatory monitoring: a double-blind, placebo-controlled, cross-over study.

The antihypertensive effect of the angiotensin-converting enzyme (ACE) inhibitor lisinopril administered in a single dose of 20 mg was evaluated by ambulatory blood pressure monitoring (ABPM) in a double-blind, placebo-controlled, cross-over study. Twenty-four patients (21 men and 3 women, mean age 52 +/- 6 years) with mild to moderate hypertension were included in the study and randomly assigned to two consecutive treatments with lisinopril 20 mg and placebo, each administered for 4 weeks. On the last day of each treatment, BP was assessed by noninvasive 24-h ABPM. BP was significantly lower after lisinopril than after placebo in a 24-h period (mean 24-h systolic BP (SBP) with lisinopril 120 +/- 7 mm Hg and with placebo 135 +/- 9 mm Hg; mean day SBP with lisinopril 125 +/- 3 mm Hg and with placebo 142 +/- 5 mm Hg; mean night SBP with lisinopril 112 +/- 4 mm Hg and with placebo 124 +/- 6 mm Hg; mean 24-h diastolic BP (DBP) with lisinopril 76 +/- 6 mm Hg, and with placebo 87 +/- 8 mm Hg; mean day DBP with lisinopril 80 +/- 3 mm Hg and with placebo 93 +/- 4 mm Hg; mean night DBP with lisinopril 69 +/- 2 mm Hg and with placebo 79 +/- 5 mm Hg, p less than 0.001). Mean 24-h, mean day, and mean night heart rate (HR) did not differ significantly between placebo and lisinopril treatments. Repeated-measures analysis of variance (ANOVA) showed a significant influence on SBP (p less than 0.001) and DBP (p less than 0.001) throughout the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive efficacy of manidipine and enalapril in hypertensive diabetic patients

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.     

Antihypertensive monotherapy and cardiovascular responses to an acoustic startle stimulus

To determine contribution of the autonomic nervous system to cardiovascular reactivity to noise, acoustic startle stimulus (110 dB, 1-20 kHz, 0.150 s) was administered to 35 subjects (19 women, 16 men) with mild essential hypertension. Among these patients, 10 were unmedicated and 25 were receiving long-term monotherapy (10 were taking 100 mg atenolol, 5 were taking 10 mg prazosin, and 10 were taking 50 mg losartan daily). Polygraphic recordings were obtained in supine position. Blood pressure (BP) and heart rate (HR) levels were stable until the noise was administered. In the unmedicated group BP and HR were elevated during the first 10 s. BP returned to resting levels after this period. The calculated hemodynamic indexes showed a biphasic change in total peripheral resistance (TPR), with an overall vasoconstriction associated with the BP rise phase, preceding a delayed vasodilation. The lowest HR changes were observed in the beta-blocker group with increases of 6 beats/min and 3 beats/min after the first and second noise stimulations, compared with 10 beats/min and 5 beats/min in the unmedicated group. Prazosin significantly reduced the BP rises to 7 mm Hg and 6 mm Hg for systolic BP and diastolic BP after the first stimulation compared with 22 mm Hg and 17 mm Hg in the untreated group (p < 0.01). The second stimulation after prazosin determined -5 mm Hg and 1 mm Hg changes for systolic BP and diastolic BP respectively, compared to rises of 13 mmHg for systolic BP and 10 mmHg for diastolic BP in the untreated group (p < 0.01). The hemodynamic percentage changes resulting from the first stimulation indicated prazosin markedly reduced the noise-induced rise in TPR (p < 0.05). No effect of beta-blocker was detectable using percentage changes. The rises in BP were amplified in the losartan-treated subjects compared with the other groups. Because of a low resting TPR in this group, the percentage changes in TPR resulting from noise were amplified in the subjects treated with the AT1 receptor antagonist. In conclusion the acoustic startle stimulus appeared as a simple and reliable procedure for inducing transient increases due to a rise in TPR. Cardiovascular responses differed according to the antihypertensive monotherapy, with a limited effect of noise in the prazosin-treated group.     

Vasopressor effect of epinephrine with and without dopamine during cardiopulmonary resuscitation

We prospectively studied nine prehospital cardiac arrest patients (six M, three F; aged 60 +/- 8 yr) to determine the vasopressor response following incremental (1, 3, and 5 mg) doses of intravenous epinephrine given 5 minutes apart with or without dopamine 15 micrograms/kg/min. All patients were in ventricular fibrillation on arrival of the paramedics and were not resuscitated with standard advanced cardiac life support therapy. Cardiopulmonary resuscitation (CPR) was performed with a computerized Thumper at 60 compressions/min with a 50:50 downstroke-to-upstroke ratio. All patients were intubated and received 12 ventilations/min at a fraction of inspired oxygen of 80 percent. Radial artery pressure was monitored through a #20 gauge radial artery catheter inserted by cutdown within ten minutes after arrival at the emergency room. Five patients received epinephrine alone (group A) and four received epinephrine plus dopamine (group B). The patient's age, paramedic response time, arterial blood gases, and initial diastolic blood pressure (BP) did not differ significantly between treatment groups. Baseline systolic BP was significantly higher (p less than 0.01) in group B (68 +/- 10 mm Hg) than in group A (35 +/- 5 mm Hg). Epinephrine produced a dose-dependent vasopressor response in group A, but not in group B. In group A, peak systolic BP following epinephrine 1, 3, and 5 mg was 57 +/- 20, 69 +/- 23, and 76 +/- 27 mm Hg, respectively (p less than 0.05 for 5 mg vs. baseline). No statistically significant difference was observed among the respective values in group B (81 +/- 13, 80 +/- 18, and 78 +/- 19 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic dose-response effects of i.v. penbutolol in angina pectoris.

The haemodynamic dose-response effects of intravenous penbutolol, a newer beta-adrenoceptor antagonist with intrinsic sympathomimetic activity but without cardioselectivity, were evaluated in 10 patients with angiographically documented coronary artery disease. Following four logarithmetically cumulative i.v. boluses (0.5-4 mg dosage range) there was a log linear increase in plasma penbutolol concentration; the levels achieved (51 +/- 8 to 219 +/- 19 ng/ml) were in the therapeutic range (12 to 250 ng/ml). Penbutolol resulted in a linear decrease in heart rate (maximum delta HR - 4 beats/min; P less than 0.01); there was a small increase in pulmonary artery occluded pressure which reached its maximum at the lower doses (maximum delta PAOP + 1 mm Hg; P less than 0.01). The resting cardiac output, blood pressure and calculated systemic vascular resistance were unchanged. During 4 min steady-state supine bicycle exercise there was attenuation of exercise cardiac output (delta C.I. - 0.6 1 min-1 m-2; P less than 0.01) and systolic pressor response (delta SBP - 13 mm Hg; P less than 0.01) compared with control observations without change in other measured or derived variables. The haemodynamic profile of penbutolol compared favourably with other beta-adrenoceptor antagonists previously evaluated under similar conditions in patients with ischaemic heart disease. Over the i.v. dose-range evaluated penbutolol attenuated exercise-induced angina with a relatively modest depression of cardiac performance; the small change induced in resting haemodynamic variables may, in part, have been contributed to by the intrinsic sympathomimetic activity of penbutolol.     

Short-term effects of celiprolol on blood pressure and left ventricular performance in hypertensive cardiomyopathy.

Celiprolol (C) is a new selective beta 1-blocker with partial beta 2-agonistic activity. The purpose of this study was to explore its antihypertensive efficacy and its short-term effect on systemic vascular resistances (SVR), cardiac output (CO), left ventricular ejection fraction (LVEF), and left ventricular diastolic performance (LVDP). The Doppler technique was used. In an open-label study, 20 hypertensive patients (15 males, 5 females, age range of 29-68 years) with left ventricular hypertrophy detected by echography were daily treated with 400 mg of C in a single dose, for a period of 4 weeks. C reduced significantly the systolic blood pressure (SBP) and the diastolic blood pressure (DBP) (158 +/- 12 vs. 142 +/- 11 mm Hg, p < 0.05 and 101 +/- 6 vs. 87 +/- 4 mm Hg, p < 0.001, respectively) with a decrease in heart rate (74 +/- 12 vs. 67 +/- 8 beats/min, p = NS). The SVR decreased significantly (2,050 +/- 22 vs. 1,495 +/- 23 dyn/s/cm5, p < 0.001) with a slight but not significant increase in the CO (4.5 +/- 0.69 vs. 5.11 +/- 0.82 L/min). The LVEF did not decrease significantly (58 +/- 5 vs. 56.9 +/- 6%, p = NS) while the LVDP was modified favorably, significantly reducing the early diastolic deceleration time (EDDT) (199 +/- 61 vs. 132 +/- 80 ms, p < 0.01) and reducing the isovolumetric relaxation time (IVRT) (167 +/- 16 vs. 117 +/- 23 ms, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-acting lacidipine versus short-acting nifedipine in the treatment of asymptomatic acute blood pressure increase

We compared antihypertensive efficacy and safety of a single administration of equipotent doses of lacidipine versus nifedipine in the hypertensive urgencies. Twenty-nine asymptomatic essential hypertensive patients (nine men, 20 women) with a mean age of 55.03+/-11.19 years and baseline diastolic blood pressure (DBP) of > or =120 mm Hg after resting 30 min, not taking antihypertensive drugs for the last 24 h, were randomized in a single-blind fashion to receive lacidipine, 4 mg (LCD, 15 patients) or short-acting nifedipine, 20 mg (NFD, 14 patients) in a single dose. Blood pressure (BP) and heart rate (HR) were taken every 30 min during the first 8 h and every 2 h until 24 h of follow-up. Baseline BP values were similar in the two groups (LCD, 222.5+/-32.8/124.6+/-8.4 mm Hg vs. NFD, 215.9+/-20.6/128+/-7.7 mm Hg; p = NS). Both drugs promoted a significant reduction of systolic blood pressure (SBP; 169.6+/-27.8 vs. 170.6+/-25.3 mm Hg) and diastolic blood pressure (DBP; 104.1+/-16 vs. 102.9+/-12.4 mm Hg) after 8 h. However, either SBP (165+/-27.3 vs. 190.6+/-18.2 mm Hg; p = 0.008) and DBP (99.9+/-12.3 vs. 117.2+/-11.4 mm Hg; p = 0.001) were significantly higher in the NFD group after 24-h dosing. Eleven patients in the LCD group had a decrease in BP >25% of the baseline value both 8 and 24 h after the dose. Although 10 patients showed the same response in the NFD group 8 h after the dose, only four patients maintained these values at 24 h. One patient treated with NFD had a transient cerebrovascular ischemic attack. No adverse effects were observed in the LCD group. We conclude that the long-acting calcium antagonist lacidipine was more effective than the short-acting nifedipine in both controlling BP and maintaining this BP reduction over 8 h in essential hypertensive patients with acute asymptomatic BP increase.     

Effect of a new calcium antagonist, tiapamil, in hypertension of the elderly.

The antihypertensive effect of a single oral dose of tiapamil (450 mg) and placebo were compared in a single blind randomized cross-over study in 10 71-86 year old hypertensive patients. Blood pressure (BP) and heart rate (HR) were recorded every 15 min for 12 h by an automatic device. Tiapamil led to a decrease in mean daytime systolic (SBP) and diastolic (DBP) BP from 171 +/- 12/98 +/- 10 mm Hg to 159 +/- 11/90 +/- 9 mm Hg (P less than 0.001) without significant variation in HR. Thereafter patients received tiapamil 450 twice daily; by the seventh day of treatment mean daytime SBP and DBP were 155 +/- 13/85 +/- 14 mm Hg (P less than 0.001 vs placebo). The hourly mean values of SBP recorded for 8/12 h (first tiapamil day) and 10/12 h (seventh tiapamil day) were significantly lower than the corresponding values after placebo. We conclude that tiapamil in the elderly exerts a sustained antihypertensive effect lasting 12 h or more, with only minor variations in HR. This effect predominates on systolic pressure and is significant from the first dose.     

Role of A2A receptor in the modulation of myocardial reperfusion damage.

Adenosine protects myocardium from ischemia and reperfusion damage; however, the mechanism of action is still under discussion. We investigated whether (a) adenosine protects isolated crystalloid-perfused rabbit heart from ischemia/ reperfusion injury; (b) this action is receptor mediated and what receptor subtypes are involved, and (c) this action is dependent on an enhanced nitric oxide production. Our results showed a cardioprotective effect of adenosine (10(-4) M), of nonselective adenosine-receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA; 5 x 10(-6) M), and of A2A agonists CGS 21680 (10(-8) and 10(-6) M), 2-hexynylNECA (10(-7) M). On the contrary, A1 agonist CCPA (10(-8) and 10(-6) M) does not provide any protection. The effect has been achieved in terms of significant reduction in contracture development during reperfusion [diastolic pressure was 46.8 +/- 7.1 mm Hg (p < 0.01); 46.1 +/- 7.8 mm Hg (p < 0.01); 46.9 +/- 5.5 mm Hg (p < 0.01); and 59.3 +/- 6.7 mm Hg (p < 0.05) with 10(-4) M adenosine, 5 x 10(-6) M NECA, 10(-6) M CGS 21680, and 10(-7) M 2-hexynylNECA, respectively, versus 77.6 +/- 5.0 mm Hg in control]; reduced creatine phosphokinase release (13.5 +/- 1.6, 22.2 +/- 7.9, 14.2 +/- 3.3, and 14.1 +/- 4.5 U/gww in treated hearts vs. 34.6 +/- 7.2 U/gww in controls; p < 0.05); improved energy metabolism [adenosine triphosphate (ATP) content is 9.9 +/- 0.5, 10.4 +/- 0.6, 9.8 +/- 0.5, and 10.5 +/- 0.5 micromol/gdw in treated hearts vs. 7.6 +/- 0.2 micromol/gdw; p < 0.05]. Moreover, our data indirectly show a functional presence of A2A receptors on cardiomyocytes as the protection is A2A mediated and exerted only during reperfusion, although in the absence of blood and coronary flow changes. These activities appear independent of nitric oxide pathways, as adenosine and 2-hexynylNECA effects are not affected by the presence of a nitric oxide-synthase inhibitor (10(-4) M L-NNA).     

A placebo-controlled dose-response study of felodipine extended release in hypertensive patients

This placebo-controlled study assessed antihypertensive effect and tolerability of two dose levels of an extended release (ER) formulation of felodipine (Plendil), given once daily to patients in primary health care. The patients had mild to moderate hypertension and were randomized to receive felodipine ER (FER) 20 mg (n = 50), FER 10 mg (n = 50), or placebo (n = 51) in a 4-week, double-blind, parallel-group multicenter study. After 4 weeks, the 24-h reduction in supine diastolic BP (DBP) was greater (p less than 0.01) in both FER groups (7 +/- 6 and 8 +/- 5 mm Hg) than in the placebo group (4 +/- 6 mm Hg). The 24-h reduction in supine systolic BP (SBP) was greater (p less than 0.01) in the FER 20-mg group (14 +/- 11 mm Hg), but not in the FER 10-mg group, than in the placebo group (8 +/- 11 mm Hg). No significant difference in blood pressure (BP) was found between FER 10 and 20 mg. Heart rate (HR) did not differ between any of the groups, nor did body weight or routine laboratory parameters. During felodipine treatment, 17 patients (12 receiving FER 20 mg) were withdrawn mostly because of vasodilatory side effects such as headache and ankle edema. We conclude that FER 10 mg and 20 mg once daily had an antihypertensive 24-h effect and that FER 10 mg may be more suitable as initial dose.     

Antihypertensive effect of canrenone in a model where endogenous ouabain-like factors are present

The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.     

Inotropic responsiveness in hypertensive left ventricular hypertrophy: impaired inotropic response to glucagon and vasoactive intestinal peptide in renal hypertensive rats

Previous studies have shown that left ventricular (LV) hypertrophy in renal hypertensive rats (RHR) is associated with reduced responsiveness to beta-adrenergic stimulation (isoproterenol) but not to calcium or cardiac glycosides. To determine whether this impairment is restricted to beta-receptor agonists or extended to include other stimulants of the adenylate cyclase system, inotropic responses to glucagon and to vasoactive intestinal peptide (VIP) were determined in isolated paced hearts (Langendorff preparation) from RHR and strictly matched sham-operated controls. The response (delta peak LV +dP/dt) to both agonists was significantly reduced in RHR, whether expressed in absolute value or in percent of baseline. It averaged 59.3 +/- 19.3 (SE) mm Hg X s-1 in RHR at the highest dose of VIP (15 micrograms) and a perfusion pressure (PP) of 50 mm Hg as compared with 255 +/- 68.4 in controls (p less than 0.01). The responses to glucagon were determined at two levels of perfusion pressure--50 and 80 mm Hg--to determine the influence, if any, of possible alterations in myocardial perfusion on differences between the normal and hypertrophied hearts. At both PP levels the LV +dP/dt response was significantly lower in RHR--+ 374 +/- 103 vs. + 1,026 +/- 166 mm Hg X s-1 (p less than 0.005) or + 120 +/- 5 vs. + 143 +/- 7% of baseline value (p less than 0.02) for PP of 50 mm Hg; and 392 +/- 154 vs. + 1,732 +/- 251 mm Hg X s-1 (p less than 0.01) or + 112 +/- 4 vs. + 160 +/- 2% (p less than 0.001) for PP of 80 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Impact of Baseline HR and BP on the Tolerability of Carvedilol in the Elderly

BACKGROUND: The COLA (Carvedilol Open Label Assessment) II Study prospectively evaluated the tolerability of carvedilol in 1030 patients >70 years of age with chronic heart failure (CHF). Tolerability, defined as patients receiving > or =3 months of carvedilol and achieving a maintenance dosage > or =12.5 mg/day, was 80%. In a multivariate analysis, advanced age, low DBP, left ventricular ejection fraction, obstructive airways disease, and a presence of diabetes mellitus were predictors of tolerability. The aim of this analysis was to evaluate further the relationship between baseline HR, SBP, DBP and tolerability in COLA II. METHODS: Baseline HR, SBP and DBP data were available in 1009 patients (98%). These data were analyzed as both continuous and categorical variables. For the latter analysis, the following categories were created: HR <70, 70 < or = HR <90, HR > or =90 bpm; SBP <120, 120 < or = SBP <160, SBP > or =160 mm Hg; DBP <70, 70 < or = DBP <90, DBP > or =90 mm Hg. RESULTS: Baseline HR did not differ between patients who tolerated carvedilol (T) and those who did not (non-T) [81 +/- 16 vs 79 +/- 16 bpm]. However, SBP and DBP were significantly lower in the non-T versus the T group (131 +/- 20 vs 139 +/- 22 mm Hg for SBP [p < 0.001] and 77 +/- 11 vs 81 +/- 12 mm Hg for DBP [p < 0.001]). Seventy-four percent of patients in the lowest category for baseline HR (<70 bpm tolerated carvedilol versus 82% and 79% of those in the higher categories (p = not significant). Seventy percent of patients in the lowest category of baseline SBP (<120 mm Hg) tolerated carvedilol versus 80% and 89% of those in the upper categories (p < 0.001). Similarly, 73% of patients in the lowest category for DBP (<70 mm Hg) tolerated carvedilol versus 78% and 87% of those in the upper categories (p < 0.005). CONCLUSIONS: Carvedilol is generally well tolerated by elderly patients with CHF, even in those with low baseline BP or HR. However, a low baseline SBP or DBP does identify patients who are less likely to tolerate the drug. Baseline HR does not appear to significantly affect tolerability in this population.