The angiotensin II AT1-receptor antagonist candesartan improves functional recovery and reduces the no-reflow area in reperfused ischemic rat hearts.

It is not yet clear if cardiac angiotensin II is involved in the pathophysiology of myocardial ischemia/ reperfusion injury. The aim of this study was to investigate the effect of the angiotensin II AT1-receptor antagonist candesartan on myocardial functional recovery in isolated rat hearts subjected to ischemia and reperfusion. Three groups of hearts perfused in the Langendorff mode with Krebs-Henseleit buffer under constant pressure received either vehicle (n = 7), candesartan, 1 nM (n = 6), or 100 nM (n = 7) at the start of 30 min of global ischemia. The recovery of the double product was significantly higher in the candesartan, 100 nM, group (75+/-9.2%) than in the vehicle group (40+/-5.1%; p < 0.05). At the end of 30 min of reperfusion, left ventricular end diastolic pressure was lower in rats given candesartan, 100 nM, than in rats given vehicle (10+/-4.3 vs. 38+/-4.8 mm Hg; p < 0.05). After ischemia and reperfusion, there was a large no-reflow area in the vehicle group (28+/-3.1% of the left ventricle), which was reduced by candesartan, 100 nM (12+/-1.3%; p < 0.05). In rats given candesartan, 1 nM, there was a trend toward a higher recovery of the double product (73+/-13.4%), a lower left ventricular end-diastolic pressure (29+/-6.6 mm Hg), and a smaller no-reflow area (19+/-3.5% of the left ventricle) compared with the rats receiving vehicle. These trends did, however, not reach statistical significance. Our results demonstrate that candesartan reduces myocardial ischemia/reperfusion injury, thus indicating that endogenous cardiac angiotensin II is involved in the tissue injury after myocardial ischemia and reperfusion.     

The pharmacodynamics and pharmacokinetics of a new calcium antagonist nisoldipine in normotensive and hypertensive subjects

Summary The pharmacodynamic and pharmacokinetic profiles of nifedipine and nisoldipine were compared in a double blind, placebo-controlled study. Nisoldipine, 10 mg significantly reduced systolic blood pressure but nifedipine 20 mg retard did not, although both drugs had significant pharmacodynamic effects as evidenced by increased heart rates. The terminal elimination half-life in plasma was similar for both drugs with a mean of 2 h. The pharmacodynamics of nisoldipine were studied in 8 hypertensives following both acute and chronic administration. Antihypertensive efficacy was demonstrated after acute dosing and was maintained over 4 weeks of twice daily treatment as monotherapy.     

A novel diketopiperazine improves functional recovery given after the onset of 6-OHDA-induced motor deficit in rats

Background and purpose:

Cyclo-L-glycyl-L-2-allylproline (NNZ-2591), a modified diketopiperazine, is neuroprotective and improves long-term function after hypoxic-ischaemic brain injury in rats. The present studies were designed to examine both the neuroprotective and neurotrophic actions of NNZ-2591 on neurochemical and behavioural changes in a rat model of Parkinson''s disease.

Experimental approach:

To examine its protective effect, either NNZ-2591 (20 ng·day⁻¹) or saline was given intracerebroventricularly for 3 days starting 2 h after 6-hydroxydopamine (6-OHDA) induced unilateral striatal lesion. In a subsequent experiment either NNZ-2591 (0.2, 1 and 5 mg·day⁻¹, s.c.) or saline was administered daily for 14 days starting 2 weeks after the lesion. Behavioural and neurochemical outcomes were examined using the adjusting step test and immunohistochemical staining.

Key results:

Cyclo-L-glycyl-L-2-allylproline given 2 h after the lesion reduced the degree of motor deficit compared with the saline-treated group. Delayed treatment with NNZ-2591, initiated after the onset of motor deficit, significantly improved motor function from week 7 onwards compared with the saline-treated group. Neither treatment regime altered nigrostriatal dopamine depletion. NNZ-2591 significantly enhanced the expression of doublecortin-positive neuroblasts in the sub-ventricular zone.

Conclusions and implications:

These studies reveal that early treatment with NNZ-2591 protects against the motor deficit induced by 6-OHDA and that treatment initiated after the establishment of motor impairment significantly improves long-term motor function. These effects of NNZ-2591 on functional recovery were independent of dopamine depletion and also appeared not to be symptomatic as the improved motor function was long-lasting. NNZ-2591 has potential as a therapeutic agent for neurodegenerative disorders.     

Ventricular pressure-heart rate product before induction of ischemia as a determinant of the reperfusion-induced accumulation of calcium within myocardium

Using the product of heart rate (HR) and left ventricular developed pressure (LVP) as a measure of the total mechanical energy required for contraction (TMEFC), experiments were performed with isolated perfused heart preparations of the guinea pig to establish the importance of TMEFC before induction of ischemia for induction of calcium accumulation within ischemic reperfused myocardium. Two calcium antagonists, diltiazem and nicardipine, and prazosin produced a dose-related suppression of the calcium accumulation when given prior to induction of ischemia (except for the highest dose of nicardipine), while they were ineffective when given only during the period of reperfusion, and the suppression was found to be closely correlated with the decrease in HRxLVP before induction of ischemia. The failure of the highest dose of nicardipine to suppress calcium accumulation (while producing a dose-related decrease in HRxLVP) was not associated with an increase in cyclic AMP. These findings are compatible with the idea that TMEFC before induction of ischemia is a prime determinant of calcium accumulation within the ischemic reperfused myocardium.     

The administration of alpha-melanocyte-stimulating hormone protects the ischemic/reperfused myocardium

The contribution of alpha-melanocyte-stimulating hormone (alpha-MSH) treatment, an active fragment of adrenocorticotropic hormone (ACTH), to the recovery of postischemic cardiac function, infarct size, the incidence of reperfusion-induced ventricular fibrillation and apoptotic cell death was studied in ischemic/reperfused isolated rat hearts. Rats were subcutaneously injected with 40, 200 and 400 microg/kg of alpha-MSH, and 12 h later, hearts were isolated, perfused and subjected to 30 min of ischemia followed by 120 min of reperfusion. Thus, after 120 min of reperfusion, with the concentration of 200 microg/kg alpha-MSH, coronary flow, aortic flow and left ventricular developed pressure were significantly improved from their control values of 14.6+/-0.6 ml/min, 7.5+/-0.5 ml/min and 9.1+/-0.4 kPa to 20.2+/-0.4 ml/min (p<0.05), 31.5+/-0.9 ml/min (p<0.05) and 15.9+/-0.6 (p<0.05) kPa, respectively. With the doses of 40, 200 and 400 microg/kg of alpha-MSH, infarct size was reduced from its control value of 38+/-5% to 33+/-6% (NS), 17+/-3% (p<0.05) and 19+/-4% (p<0.05), respectively. The reduction in the incidence of reperfusion-induced ventricular fibrillation followed the same pattern. It is reasonable to assume that a reduction in infarct size, in the alpha-MSH-treated myocardium, resulted in a reduction as well in apoptotic cell death. Although we did not specifically study the exact mechanism(s) of alpha-MSH-afforded postischemic protection, we assume that this protection may be related to alpha-MSH-induced corticosterone release and corticosterone-induced de novo protein synthesis, which reflected in the recovery of postischemic cardiac function in isolated hearts. Thus, interventions that are able to increase plasma corticosterone or glucocorticoid release may prevent the development of ischemia/reperfusion-induced damage.     

The effect of chemical sympathectomy on mitochondrial function in the ischaemic and reperfused myocardium.

1 Isolated rabbit hearts were perfused aerobically for 120 min, made ischaemic for 90 min, or made ischaemic for 90 min and then reperfused for 30 min. 2 Some rabbits were pretreated with 6-hydroxydopamine (6-OHDA), given as three separate intravenous doses of 30, 20 and 20 mg/kg, 20 to 48 h before they were killed; others (controls) received saline according to the same regime. 3 Mitochondria were harvested from left ventricular homogenates and their function assessed by measuring state 3O2 consumption (state 3 QO2), respiratory control index (RCI), phosphate: oxygen ratio (ADP:O), Ca2+ content, and ATP-producing activity. In other experiments peak left ventricular developed tension was recorded. 4 In hearts from saline-treated animals, mitochondrial state 3 QO2, RCI and ATP producing activities were reduced after global ischaemia, with or without reperfusion. There was a small gain in mitochondrial Ca2+ after ischaemia, and a large gain upon reperfusion. 5 6-OHDA pretreatment provided some protection against the effects of ischaemia and reperfusion on mitochondrial function and on peak developed tension. 6 It was concluded that chemical sympathectomy with 6-OHDA does not duplicate the effect of prolonged beta-adrenoceptor blockade in protecting mitochondrial function against the deleterious effects of ischaemia and reperfusion.     

The calcium channel antagonist nifedipine causes confusion when used to treat opiate withdrawal in morphine-dependent patients.

Several animal studies have suggested that calcium channel antagonists may be clinically effective in the treatment of opiate withdrawal. In this study we aimed to examine whether the alpha 2-adrenoceptor agonist clonidine and the calcium channel antagonist nifedipine were equally effective in attenuating the naltrexone-precipitated opiate withdrawal syndrome. We planned to study 16 morphine-dependent in-patients in a double-blind trial. However, the study had to be abandoned after only four patients were entered into it because the first two patients treated with nifedipine became severely confused following naltrexone. The mechanism underlying the development of delirium in these two patients is uncertain, but might possibly relate to a large unopposed release of noradrenaline within the central nervous system. These findings suggest that the calcium channel antagonist nifedipine is not effective in the clinical treatment of opiate withdrawal. Whether other calcium channel antagonists also cause confusion when used in this clinical condition is uncertain at present, but in any future studies investigating their efficacy considerable care is required in their use.     

The interaction of the NK1 receptor antagonist CP-96,345 with L-type calcium channels and its functional consequences.

1. We investigated the effects of the non-peptide NK1 receptor antagonist, CP-96,345, its inactive enantiomer CP-96,344, and the racemic mixture (+/-)-CP-96,345, on the binding of [3H]-nimodipine and [3H]-diltiazem to L-type calcium channels in rat cerebral cortex membranes. In isolated peripheral tissues containing tachykinin receptors, the effects of (+/-)-CP-96,345 have been compared with those of diltiazem. 2. In guinea-pig trachea, (+/-)-CP-96,345 produced antagonism of responses to the selective NK1 agonists [Sar9, Met(O2)11]SP and substance P-methyl ester that was apparently competitive in nature (pKB 7.0-7.5), while in guinea-pig ileum the antagonism was not surmountable. 3. The reduction of maximum responses by (+/-)-CP-96,345 in the guinea-pig ileum was not selective; it was obtained with muscarinic agonists and other agents, and was also observed in the portal vein of the rat where NK1 receptors are not present. 4. The tissue-specific reduction of maximum responses by (+/-)-CP-96,345 in ileum was reproduced by diltiazem. 5. (+/-)-CP-96,345 produced a concentration-dependent enhancement of [3H]-nimodipine binding to rat cerebral cortex membranes with a maximal stimulation of 186 +/- 29% above control (EC50 83.2 nM). Scatchard analysis revealed that (+/-)-CP-96,345 increased the affinity of [3H]-nimodipine for its binding sites without affecting Bmax (control: KD = 0.32 nM; with 100 nM (+/-)-CP-96,345: KD = 0.074 nM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Central effects of the calcium antagonist, nifedipine.

1. Central effects of the calcium antagonist, nifedipine retard (10, 20 and 40 mg) and nifedipine capsules (10 mg) were studied in 14 healthy male subjects. Two placebos and an active control drug, oxazepam (15 mg), were included. Medication was administered double-blind at 10.00 h. The effects of drugs on performance and subjective feelings were assessed before and from 1.5-2.5 h and 3.5-4.5 h after ingestion, and recordings of the electrical activity of the brain (EEG) and body sway carried out. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, together with critical flicker fusion and two flash fusion. The EEG was recorded with eyes open while the subjects carried out a mental arithmetic task, and with eyes closed, when they were required to relax. Body sway was recorded with eyes open and with eyes closed. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. 3. Nifedipine did not alter performance levels on any of the skills tested, while oxazepam (15 mg) increased the number of errors (P less than 0.01) and reduced accuracy at continuous attention (P less than 0.01). 4. Nifedipine (10 mg) reduced total power of the EEG in the frequency range (0.5-30 Hz), and nifedipine (20 mg) increased total alpha power (7.5-13 Hz) (P less than 0.05). Oxazepam reduced alpha and increased beta 1 power (13.5-21 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)     

S-adenosyl-L-methionine improves the changes of calcium content and glucose metabolism after transient ischemia in the rat

Effects of S-adenosyl-L-methionine on Ca accumulation as well as the changes of electrolytes contents and glucose metabolism after transient ischemia were investigated. In the 4-vessel occlusion model of rats, brain Ca content increased to 200-250% of that in sham operated rats 1 day after 60 min transient ischemia. The change in the striatum was more severe than that in the cortex or hippocampus. Na content increased and K content decreased, and glucose, pyruvate and lactate contents increased significantly in the striatum 1 day after transient ischemia. SAM (100 mg/kg, i.p.) was injected at the end of occlusion and every hour for 5 hr thereafter. Treatment with SAM reduced Ca accumulation, decrease of K, and increase of lactate and pyruvate in the striatum significantly. The present results suggest that the inhibition of Ca accumulation might partly explain the beneficial effects of SAM on the cerebral dysfunction following ischemia.     

Cardioplegic arrest of the myocardium with calcium blocking agents.

This study was designed to compare the effects of the calcium slow channel blocking agents verapamil (0.15 mg/kg), diltiazem (0.15 mg/kg), and nifedipine (50 micrograms/kg) on the myocardium after global ischemia and reperfusion in the in situ canine model. Animals were subjected to 120-min normothermic global ischemia, followed by 45-min reperfusion. Cardioplegic arrest of the myocardium was achieved by administering one of the three calcium antagonists in a multidose fashion. Superior preservation (p less than 0.01) of left ventricular (LV) systolic function was achieved in group I (verapamil cardioplegia). dP/dt, at an intraventricular balloon volume of 25 cc, was 83% of control after reperfusion in group I. Group II (diltiazem) and group III (nifedipine) achieved only 55 and 63% of their preischemic dP/dt values. LV chamber stiffness was increased in hearts protected with nifedipine. The exponential constant m was increased from 0.04 +/- 0.01 to 0.08 +/- 0.01. Coronary blood flow after reperfusion increased from 120 to 184 cc/100 gr/min in group I (p less than 0.01). The hyperemic response in group III was negligible. The O2 consumption of the reperfused myocardium was not significantly altered in any of the treatment groups. Lactate metabolism during ischemia and after reperfusion was similar in all groups. ATP values were markedly reduced in all groups (p less than 0.05). Immediately after ischemia, ATP was 50, 28, and 44% of control in group I, II, and III, respectively. The excellent preservation of systolic function and a physiologic hyperemic response by verapamil could not be correlated with improved preservation of high-energy compounds or with significant changes in myocardial O2 consumption.(ABSTRACT TRUNCATED AT 250 WORDS)     

新生儿窒息心肌酶谱的变化

目的研究新生儿窒息时心肌酶谱的变化。方法对25例新生儿窒息心肌酶谱作统计学处理。结果重度窒息组乳酸脱氢酶（LDH）、谷草转氨酶（GOT）、肌酸激酶（CK）较对照组差异有非常显著性（P〈0．01），轻度窒息组与对照组GOT、CK差异有显著性（P〈0．05）而LDH无明显差异（P〉0．05）。重度窒息组与轻度组GOT、CK差异有显著性（P〈0．05）而LDH无明显差异（P〉0．05）。结论新生儿窒息心肌酶谱的变化与窒息程度呈正相关。     

The interaction of the calcium antagonist RO 40-5967 with digoxin.

1. The interaction of the newer calcium antagonist Ro 40-5967 with digoxin was investigated in 42 healthy subjects under steady state conditions. 2. After an adequate loading dose digoxin 0.375 mg once daily was given alone for 1 week. Afterwards three different doses (50, 100, 150 mg daily) of the calcium antagonist Ro 40-5967 were administered to three groups of 14 subjects each for 1 week concurrently with digoxin 0.375 mg daily. 3. Ro 40-5967 led to an increase of mean maximum digoxin plasma concentrations (Cmax) and AUC. For AUC this effect was significantly dose-dependent. 4. Increasing doses of the calcium antagonist led to a stepwise rise of the PQ-time in ECG. 5. A slight fall of heart rate was seen after a 7 day treatment of digoxin alone. This effect was more pronounced when Ro 40-5967 was added to the medication. No significant changes of stroke volume and blood pressure were noted. 6. In conclusion Ro 40-5967 led to a significant elevation of the plasma concentration-time curve (AUC) of digoxin. This effect was dose-dependent.     

药物干预对大鼠脑缺血后神经再塑及功能恢复的实验研究

目的 研究大鼠脑缺血后,损伤区域及相关部位的神经再塑与运动行为恢复之间的相互关系;以及哌醋甲酯对神经再塑以及肢体功能恢复的影响.方法 线栓法建立大鼠的大脑中动脉缺血模型,术后第3天起,对手术给药组及假手术给药组的大鼠口服灌注哌醋甲酯;于术后第7、14、21、28天,触觉刺激试验作行为测试,记录其撕去胶布所使用的时间.采用免疫组织化学方法观察突触素(SYN)及突触后致密物质(PSD-95)在大鼠皮层缺血灶的内侧、外侧、对侧的表达.结果 SYN及 PSD-95的免疫反应产物于术后第7天在3个观察部位都显著减少,在14 d以后明显增加,与此相对应的肢体活动在第21天明显恢复.手术给药组前肢功能恢复较之假手术给药组及手术对照组于第14天即有显著进步(P<0.01),至第28天甚至超过假手术对照组(P<0.05).结论 哌醋甲酯对大鼠脑缺血后神经再塑以及肢体功能恢复有促进作用.     

Neutrophil infiltration into the ischaemic/reperfused rabbit isolated myocardium: effect of PF-5901 and cycloheximide.

The Langendorff-perfused rabbit heart preparation has been used to study the interaction of isolated rabbit neutrophils with regionally ischaemic myocardium. Short durations of regional ischaemia (10-60 min) and subsequent reperfusion (30 min) of the hearts with neutrophils resulted in a significant time-dependent accumulation of neutrophils (as assessed by myeloperoxidase activity) in the area at risk. Pre-activation of neutrophils with zymosan-activated serum prior to their infusion into the myocardium potentiated neutrophil accumulation in the area at risk. Pretreatment of the myocardium with a lipoxygenase inhibitor, PF-5901 (10 microM), or a de novo protein synthesis inhibitor, cycloheximide (10 microM), significantly reduced the accumulation of neutrophils in the ischaemic/reperfused myocardium. In contrast, pretreatment of neutrophils with cycloheximide (10 microM, for 15 min) prior to their infusion had no significant effect on neutrophil accumulation in the area at risk. The cyclooxygenase inhibitor, indomethacin (10 microM), had no effect on neutrophil accumulation in the area at risk following ischaemia and reperfusion. These results suggest the involvement of de novo protein synthesis and the lipoxygenase products in the infiltration of neutrophils following ischaemia and reperfusion in vitro.     

Characterization in rat aorta of the binding sites responsible for blockade of noradrenaline-evoked calcium entry by nisoldipine.

1. The effectiveness of the calcium antagonist, 1,4-dihydropyridine nisoldipine, as an inhibitor of contraction and 45Ca entry evoked by noradrenaline in rat aorta has been investigated and correlated with binding characteristics in intact artery. 2. Contractions evoked by noradrenaline were concentration-dependently depressed by nisoldipine (0.3-300 nM). About 60% of the response was resistant to inhibition, while KCl-induced contractions could be completely blocked. Noradrenaline-induced contractions were also less sensitive to nisoldipine inhibition than were KCl-induced contractions. 3. Preincubation of the aorta with nisoldipine in high KCl depolarizing solution increased the inhibition of the contraction evoked by a short application of noradrenaline or KCl to a similar extent. 4. The inhibition by nisoldipine of 45Ca influx evoked either by KCl depolarizing solution or by noradrenaline correlated well with the inhibition of the contractile responses. However, while KCl-stimulated 45Ca influx was totally abolished by nisoldipine (300 nM), 38% of the noradrenaline-stimulated 45Ca influx was resistant to inhibition by nisoldipine (300 nM). 5. The study of [3H]-(+)-PN 200-10 ([3H]-(+)-isradipine) binding in intact aorta showed the presence of a homogeneous population of specific binding sites. KD values were dependent on the KCl concentration in the bath while Bmax was unaffected. Binding of [3H]-(+)-isradipine was also increased in tissue exposed to noradrenaline; in the presence of 10(-5) M noradrenaline, binding parameters of [3H]-(+)-isradipine were close to the values obtained in aorta bathed in 20 mM KCl solution. 6. Displacement of [3H]-(+)-isradipine specific binding by nisoldipine was determined in segments of mesenteric artery and of aorta. The potency of nisoldipine was dependent on the incubation conditions applied to the vessel, as follows: KCl (100 mM) depolarizing solution greater than noradrenaline (10(-5) M) = KCl (25 mM) solution greater than physiological solution. The Ki value measured in aorta exposed to noradrenaline (10(-5) M) was close to the IC50 value of nisoldipine on the noradrenaline-evoked contraction. 7. The membrane potential value of rat aorta was estimated by the distribution of [3H]-tetraphenylphosphonium bromide ([3H]-TPP+), [3H]-TPP+ uptake concentration-dependently decreased when the KCl concentration in the bath was increased from 5.9 to 130 mM. Noradrenaline also concentration-dependently decreased [3H]-TPP+ uptake; the maximum effect (1-10 microns noradrenaline) was comparable in amplitude to the effect of 25 mM KCl solution.(ABSTRACT TRUNCATED AT 400 WORDS)     

Anti-ischemic activity of the novel benzazepine calcium antagonist SQ 31,486.

We tested the benzazepine, SQ 31,486 for its ability to selectively block the voltage-dependent calcium channel and to protect the ischemic myocardium. SQ 31,486 was found to be a selective calcium antagonist in vascular tissue with an IC50 value of 1.5 microM in KCl-contracted rabbit aorta. SQ 31,486 decreased contractile function and increased coronary flow in nonischemic isolated rat hearts in a concentration-dependent manner. SQ 31,486 also significantly reduced postischemic lactate dehydrogenase (LDH) release and end-diastolic pressure (EDP) compared to vehicle. Reperfusion double product [heart rate (HR) x left ventricular developed pressure (LVDP)] was also significantly improved by SQ 31,486. Diltiazem was a less potent anti-ischemic agent and was significantly more cardiodepressant relative to its anti-ischemic efficacy than was SQ 31,486. Thus, SQ 31,486 should have a larger therapeutic index. In a model of pacing-induced myocardial ischemia in anesthetized, open chest dogs, SQ 31,486 reduced pacing-induced ST-segment elevation approximately 50% at 10, 40, and 70 min after drug administration. This protective effect occurred despite a lack of effect of SQ 31,486 on ischemic regional blood flow and peripheral hemodynamic status.     

Effect of vitamin E on the energy allowance of functional and plastic processes in the myocardium during ischemia and reoxygenation

It was found that preliminary (before ischemia) administration of vitamin E in a dose of 200 mg/kg to albino rats causes the changes in energy support of the ischemic myocardium leading to prolonged maintenance of synthesis processes: energy production, cGMP concentration, unsaturation of cell membrane lipids increase. The combination of all these factors probably determines the anti-ischemic effect of vitamin E providing adequate restoration of the myocardial function in the postischemic period.     

Differential effects of the calcium antagonist, nisoldipine, versus the arterial vasodilator, minoxidil, on ventricular anatomy, intravascular volume, and sympathetic activity in rats

Opposite effects on cardiac volume load or sympathetic activity by calcium-antagonists versus classical arterial vasodilators may be responsible for their different effects on ventricular anatomy, [i.e., left ventricular (LV) and right ventricular (RV) weights and LV internal diameter and wall thickness.] Therefore, we evaluated the time course of changes in intravascular volume and ventricular anatomy in unanesthetized normotensive rats, following treatment for 1, 2, 14, 35, or 70 days with minoxidil (120 mg/L drinking water) or nisoldipine (0.3 and 1.0 mg/g food). Tissue-specific sympathetic activity was assessed by the norepinephrine turnover rate (NE TR) after 14 and 35 days of treatment. Minoxidil produced RV hypertrophy and eccentric LV hypertrophy (i.e., increased LV diameter with unchanged wall thickness) and increased intravascular volume. Nisoldipine did not alter LV anatomy, but the high dose produced a small, significant increase in RV weight, associated with a tendency (p less than 0.1) to increase blood volume. Minoxidil increased NE TR in the LV (after 14 and 35 days), in the RV (after 14 days), as well as in the superior mesenteric artery (after 14 and 35 days), but not in the kidney. Nisoldipine decreased cardiac NE TR, but did not affect NE TR in the other tissues, suggesting a central effect of nisoldipine. We conclude that an increase in blood volume caused by arterial vasodilators may contribute to cardiac volume overload resulting in cardiac hypertrophy. These volume and cardiac changes are largely absent during treatment with calcium-antagonists. Changes in cardiac sympathetic activity possibly modulate (i.e., potentiate or blunt) the extent of cardiac hypertrophy induced by cardiac overload.