Pentaerythritol trinitrate and glyceryl trinitrate on myocardial oxygen consumption and haemodynamics in the dog

1. The effects of pentaerythritol trinitrate (pentrinitrol) and glyceryl trinitrate on myocardial oxygen consumption and myocardial and systemic haemodynamics were studied in anaesthetized open-chest dogs. An in vivo oximeter in the coronary sinus permitted continuous determination of arteriovenous oxygen difference and myocardial oxygen consumption. All parameters were determined simultaneously at various intervals after drug administration. 2. Myocardial oxygen consumption was diminished by both nitrates for more than 16 min. Changes in arteriovenous oxygen difference and coronary sinus oxygen content were variable between drugs. Following an initial transient increase, coronary blood flow was reduced by both nitrates. Aortic blood pressure, aortic blood flow, left ventricular end-diastolic pressure and left ventricular dP/dt were also reduced. Heart rate and contractile force were not appreciably altered by either nitrate. 3. The decrease in myocardial oxygen consumption appears to be associated with the haemodynamic profile of these drugs. Both nitrates produced comparable reductions in preload (left ventricular end-diastolic pressure) and afterload (aortic pressure) as well as dP/dt.     

A COMPARISON OF THE CARDIAC ACTIONS OF DOPAMINE AND NORADRENALINE IN ANAESTHETIZED DOGS AND GUINEA-PIG ATRIA

1. The positive chronotropic and inotropic actions of dopamine and noradrena-line have been compared in anaesthetized dogs and isolated guinea-pig atria. 2. Inotropic activity was measured with a strain-gauge arch in vagotomized dogs or estimated from max (dp/dt) in dogs with denervated hearts. 3. The effects of propranolol and haloperidol on the concentration-response curves to both amines were studied in isolated atria. 4. In anaesthetized vagotomized dogs noradrenaline was more potent than dopamine but dopamine appeared to have a selective inotropic action, less apparent with noradrenaline. In denervated hearts, doses of noradrenaline and dopamine which caused similar increases in max (dp/dt) also caused similar increases in heart rate. 5. In isolated atrial preparations, concentrations of dopamine and noradrenaline which produced similar increases in force of contraction also had similar chronotropic effects. 6. Propranolol produced a shift to the right of the concentration-response curves to both dopamine and noradrenaline but the antagonism of noradrenaline was quantitatively greater. Haloperidol had no effect in concentrations below those found to cause general tissue depression. 7. It is concluded that neither dopamine nor noradrenaline show any real difference in their relative inotropic and chronotropic activities in the absence of autonomic innervation.     

EVIDENCE OF AN ADENOSINE-DEPENDENT MECHANISM IN THE HYPOTENSIVE EFFECT OF l-ARGININE IN MAN

1. The hypothesis that endogenous adenosine could play a role in the haemodynamic response to l-arginine is investigated. 2. The study has been divided into two parts. The first part was a single blind, randomized, placebo-controlled study in which L-arginine i.v. infusion (0.07 mmol/kg per min) in five healthy volunteers caused a significant fall in systolic (-14.2%, from 129.0 ± 8.2 to 110.6 ± 8.5 mmHg; F= 62.89, P<0.0l), diastolic (-16%, from 80.0 ± 7.9 to 67.2 ± 7.0 mmHg; F= 18.97, P < 0.0l) and mean (-15.5%, from 96.4 ± 6.7 to 81.4 ± 6.5 mmHg; F= 28.78, P< 0.01) arterial blood pressure, with a concomitant increase of plasma adenosine concentration (from 244.0 ± 32.2 to 637.0 ± 43.4 nmol/L; F= 79.3 P<10.01). Maximal effects were obtained at the end of L-arginine infusion: haemodynamic parameters returned to basal values in about 30 min while adenosine concentrations normalized in about 15 min. Saline infusion had no effect on these parameters. 3. In the second study the effect of L-arginine i.v. infusion on arterial blood pressure, lower limb blood flow and plasma adenosine, before and after theophylline treatment (1000 mg/day for 3 days, p.o.) was examined. In 10 healthy volunteers the i.v. infusion of l-arginine (0.07 mmol/kg per min) was followed by the same haemodynamic changes as reported above and by a Significant increase in lower limb blood flow (+ 36.7%, from 2.18 ± 0.40 to 2.98 ± 0.71mL/min/lOOmL;t = 4.61, P< 0.01). Pretreatment with theophylline, an adenosine-receptor antagonist, did not affect basal values of arterial pressure, lower limb blood flow and adenosine concentration. The pretreatment with theophylline reduced maximal decrease in systolic pressure (- 8.2 vs -15%), in mean pressure (- 9.9 vs -13.7%) and maximal increase in lower limb blood flow (+19 vs + 37%) caused by i.v. infusion of l-arginine (0.07 mmol/kg per rnin). Such a treatment allowed a progressive restoration of basal blood pressure values and of blood flow, during the second half of l-arginine infusion. This observation was confirmed by the analysis of the area under the curves (AUC). A significant difference in AUC values before and after treatment was obtained for systolic pressure (t = 8.25, P< O.Ol), mean pressure (t= 6.67, P<0.0l) and blood flow (t= 2.31, P<0.05). 4. Theophylline study suggested that the endogenous adenosine increase is sufficient to participate at least in part in the haemodynamic changes caused by l-arginine and that it is involved in a secondary response to l-arginine.     

蝙蝠葛酚性碱对离体大鼠心肌顿抑的保护作用

目的　探讨蝙蝠葛酚性碱(PAMD)对离体大鼠心肌顿抑的作用。方法　采用缺血10min后再灌注30min造成心肌顿抑模型(S) ,灌流液中加0.5mg·mL^-1 PAMD(P)组同样缺血再灌注。结果　灌注末S组LVSP ,+dp/dt_max和-dp/dt_max分别降至预灌末的49% ,53%和58% ,LVEDP则增至422% ;心肌钙含量为(514±142 ) μg·g^-1 (干重) ;出现可逆性心肌超微结构损伤。而P组再灌注末LVSP ,LVEDP ,+dp/dt_max和-dp/dt_max恢复为预灌末值的70% ,205% ,78%和79% ;心肌钙为(316±84) μg·g^-1 (干重) ;以上变化均有显著差异。结论　PAMD对离体大鼠顿抑心肌有保护作用     

Role of endothelium in ischaemia‐induced myocardial dysfunction of isolated working hearts: cardioprotection by activation of adenosine A2A receptors

1 This study aimed to determine the role of the vascular endothelium on recovery of contractile function following global low‐flow ischaemia of guinea‐pig isolated working hearts and the effects of adenosine analogues on this recovery. 2 Guinea‐pig isolated spontaneously beating or paced working hearts were set up and coronary flow (CF), aortic output (AO) (as an index of cardiac function), heart rate (HR), left ventricular pressure (LVP) and dP/dt max recorded. The endothelium was either intact or removed by a blast of oxygen. 3 In spontaneously beating hearts, low‐flow ischaemia for 30 min reduced CF and cardiac contractility (LVP, dP/dt max) but not AO. On reperfusion, CF, LVP and dP/dt max recovered, while AO fell precipitously followed by a gradual recovery, indicative of myocardial stunning. The effects of ischaemia did not differ between endothelium‐intact and ‐denuded hearts, indicating no role of the endothelium in the changes observed. 4 The adenosine analogues, N⁶‐cyclopentyladenosine (CPA, A₁ selective), 5'‐N‐ethylcarboxamidoadenosine (NECA, two‐fold A₂ selective over A₁) and 2‐p‐((carboxyethyl)‐phenethylamino)‐5'carboxamidoadenosine (CGS21680, A_2A selective) were infused (3 × 10^?7 M ) from 10 min into the 30‐min low‐flow ischaemia of denuded hearts and during reperfusion. 5 CGS21680 increased CF and improved the postischaemic functional recovery, as measured by the AO. NECA and CPA were not cardioprotective. The A_2A selective antagonist, ZM241385, attenuated the coronary vasodilatation by CGS21680 and abolished the improved recovery of AO on reperfusion. 6 Reperfusion of paced working hearts caused a dramatic fall in AO which failed to recover. Infusion of CGS21680 from 15 min into the ischaemic period produced vasodilatation but failed to restore AO, presumably because the ischaemic damage was irreversible. 7 Thus, the endothelium plays no role in myocardial dysfunction following low‐flow global ischaemia and reperfusion of guinea‐pig working hearts. The A_2A adenosine receptor‐selective agonist but not the non‐selective A₂ receptor agonist, NECA, attenuated ischaemia‐ and reperfusion‐induced stunning. This was attributed to increased CF and was independent of the endothelium.     

Digital pulse plethysmography as a non-invasive method for predicting drug-induced changes in left ventricular preload

Objective: Changes in the contour of the plethysmographically recorded digital pulse curve after nitrate ingestion are well known, but it has not been fully established whether these changes reflect nitrate action on left ventricular (LV) preload or afterload. Therefore, we compared the pulse wave contour after administration of equieffective doses of nitroglycerin and nifedipine. Methods: In 20 patients with coronary artery disease we measured aortic blood pressure curve in the aorta ascendens, digital volume pulse curve with a photoelectric pulse pickup, Riva Rocci blood pressure and heart rate after administration of either 0.8 mg nitroglycerin or 10 mg nifedipine. Results: Peak plasma concentrations of nitroglycerin and nifedipine were achieved 5 min and 20 min after ingestion of the drugs. Systolic aortic blood pressure decreased after both nitroglycerin and nifedipine to 19.4 mmHg, but diastolic blood pressure decreased only after nifedipine by 10.5 mmHg (P < 0.05). Riva Rocci blood pressures showed a similar time course. Heart rate increased from 67.4 to 70.9 beats⋅min⁻¹ after nitroglycerin and from 58.9 to 69.4 beats⋅min⁻¹ after nifedipine. The calculated a/b ratio of the aortic pressure curve increased after both medications (nitroglycerin, from 1.66 to 1.99; nifedipine, from 1.66 to 1.93) and its time course mimicked that of the systolic blood pressure. The a/b ratio of the digital pulse curve did not change after nifedipine, but showed a pronounced rise after nitroglycerin from 1.29 to 1.84. With regard to pharmacological actions, nitroglycerin causes a reduction in LV preload and afterload, whereas nifedipine has only LV-afterload-reducing activity. Conclusion: We conclude, that the reduction in afterload did not cause the typical changes in wave contour of the peripheral pulse curve which occur with organic nitrates. Most likely changes in the a/b ratio reflect changes in LV preload. Received: 16 May 1995/Accepted in revised form: 9 November 1995     

CARDIOVASCULAR EFFECTS OF NEUROMUSCULAR BLOCKADE DURING INDUCED HYPOTHERMIA

Young lambs were used to study the effects of progressive cooling and rewarming on cardiovascular function during neuromuscular blockade induced by gallamine. Initially, it was shown that gallamine exerted no immediate, direct haemodynamic effect in normothermic or hypothermic lambs (cooled by 10 degrees C). By comparison with hypothermic controls, neuromuscular blockade was associated with increases in left ventricular (LV) max dP/dt (153%; P less than 0.02) as cooling progressed, and even greater increases (232%; P less than 0.001) during rewarming. It was concluded that these changes seem likely to represent enhanced myocardial contractility since preload did not closely follow LV max dP/dt (heart rate and mean aortic pressure fell gradually during cooling but values were restored in the rewarming phase). LV max dP/dt in lambs given gallamine only after cooling also showed a similar response during rewarming. Results of this study may have clinical relevance relating to the mechanical recovery of the hypothermic heart in patients receiving neuromuscular blockade during cardiac surgery, and they argue against using gallamine as such an agent.     

ABNORMALITY OF THE GLOMERULAR ANGIOTENSIN II RECEPTOR IN EXPERIMENTAL DIABETIC NEPHROPATHY

1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII-R) relationship in streptozotocin-induced diabetes was investigated as well as the effect of glycaemic control on this relationship. 2. Diabetes was induced in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with streptozotocin 60 mg/kg and blood sugars maintained between 18–21 mmol/L (uncontrolled diabetes) and 4–8 mmol/L (controlled diabetes). Rats were killed on days 1 and 7. Angiotensin II receptor was estimated by saturation analysis and plasma AII by radio-immunoassay. 3. Angiotensin II receptors were significantly higher in non-diabetic SHR than WKY rats (708 ± 62 and 388 ± 36 fmol/mg protein, respectively, P = 0.0008). Plasma AII were comparable in both groups (47 ± 2.7, 38 ± 3.5 pg/mL, respectively) and a significant inverse relationship between AII/AII-R was observed (WKY P = 0.02 and SHR P = 0.004). 4. On day 7, plasma AII and AII-R levels in diabetic groups were comparable with those of their non-diabetic controls. Diabetic WKY rats maintained an inverse correlation between AII and AII-R (controlled P= 0.04 and uncontrolled P= 0.015), but this did not occur in the SHR. 5. Absence of receptor response to varying ligand concentrations in the diabetic SHR may contribute to the development of nephropathy. Glycaemic control does not appear to reverse this abnormality in the SHR, so that co-existent hypertension may have a more direct influence on renal function.     

EFFECTS OF AMIODARONE AND L8040, NOVEL ANTIANGINAL AND ANTIARRHYTHIC DRUGS, ON CARDIAC AND CORONARY HAEMODYNAMICS AND ON CARDIAC INTRACELLULAR POTENTIALS

1. The effects on the coronary and systemic haemodynamics of intravenous and intracoronary injections of two benzfuran derivatives, amiodarone and its brominated analogue (L8040), were studied in open-chest anaesthetized dogs. The effects of L8040 on cardiac intracellular potentials after 6 weeks of 20 mg/kg intraperitoneal injections in rabbits were also investigated. 2. Both compounds produced dose-related and quantitatively similar decreases in coronary vascular resistance following their intracoronary administration; threshold effects occurred with about 0.25 mg of each drug and maximal effects with 4 mg. Larger intracoronary doses produced measurable systemic effects. 3. Intravenous injections of amiodarone and L8040 (2·5·10 mg/kg) produced dose-related decreases in heart rate and aortic pressure with a fall in total peripheral resistance. The left ventricular output was either unaffected or increased with a consistent augmentation in stroke volume. 4. The bradycardia produced by both drugs was associated with prolongation of the P–R interval of the electrocardiogram with no significant effect on the QRS duration or the Q–T interval. 5. Each drug produced a decrease in the total peripheral vascular resistance with no change in left ventricular end diastolic pressure except after 10 mg/kg doses which led to an increase in this parameter. 6. Cardiac contractile force and peak LV dp/dt were reduced by both drugs in a dose-related manner. 7. Chronic intraperitoneal administration of L8040 in rabbits caused a prolongation of the duration of the atrial and ventricular intracellular potential without an effect on the maximal rate of depolarization. 8. The effects of amiodarone or L8040 on the coronary circulation and arterial pressure may be attributed to their vasodilator properties but their depressant actions on cardiac contractile force and peak LV dp/dt with an increase in left ventricular end diastolic pressure at high doses, also suggest intrinsic negative inotropic propensity for both compounds. 9. It is concluded that the overall effects on coronary and systemic haemodynamics of amiodarone and its brominated analogue are likely to permit a favourable influence on the balance of oxygen supply and demand in myocardial ischaemia; in addition, their actions on sinoatrial and atrio-ventricular conduction as well as those on cardiac repolarization suggest potential antiarrhythmic properties which merit investigation.     

In vivo demonstration of α-adrenoceptor-mediated positive inotropy in pithed rats: evidence that noradrenaline does not stimulate myocardial α-adrenoceptors

1 This study examines whether positive inotropy via α-adrenoceptors could be observed in vivo in pithed rats. Cardiac contractility was measured as the maximum rate of rise of left ventricular pressure (dP/dt_max). Heart rate and aortic blood pressure were also recorded. 2 The selective α₁-adrenoceptor agonists, methoxamine, cirazoline, amidephrine and phenylephrine caused dose-related increases in dP/dt_max. This response was progressively reduced by increasing doses of the α₁-adrenoceptor antagonist prazosin. However, since the concomitant increase in diastolic blood pressure (DBP) was also blocked, the changes in dP/dt_max may have been a consequence of increased after load. 3 Adrenaline and noradrenaline also increased dP/dt_max, accompanied by pressor responses. Propranolol (1 mg kg^??1) antagonized the increase in dP/dt_max in response to noradrenaline, suggesting β-adrenoceptor involvement, but not that to adrenaline. The additional presence of prazosin (1 mg kg^??1) further shifted the dose–response curves for both noradrenaline and adrenaline to the right. 4 Analysis of the increases in dP/dt_max at predetermined increases in DBP by each agonist revealed three groups of regression lines. Adrenaline in the presence of propranolol and the four selective α₁-adrenoceptor agonists occupied a common central position. Above this group were adrenaline and noradrenaline in the absence of antagonists; their additional effects on contractility were β-adrenoceptor-mediated since the regression lines were lowered by propranolol. Clearly below the main group of agonists was noradrenaline in the presence of propranolol. 5 Thus, for a given increase in DBP, adrenaline (in the presence of β-blockade) and the α₁-adrenoceptor agonists exert an additional inotropic effect to noradrenaline (also in the presence of β-blockade). This is concluded to be an α-adrenoceptor-mediated increase in cardiac contractility which is not shared by noradrenaline.     

ROLE OF NITRIC OXIDE IN TUBULOGLOMERULAR FEEDBACK: EFFECTS OF DIETARY SALT

1. The tubuloglomerular feedback (TGF) response operates primarily by vasoconstriction of the afferent arteriole and a fall in glomerular capillary pressure (P_GC) and single-nephron glomerular nitration rate (SNGFR) during increased NaCl reabsorption in the macula densa (MD). Numerous studies have suggested that nitric oxide (NO) is synthesized by the MD and acts to suppress TGF. As a high-salt (HS) diet has been found to blunt TGF, we tested the effects of salt intake on NO-dependent changes in TGF. 2. In the first series of experiments, values of SNGFR were contrasted from samples of tubular fluid taken from the proximal tubule (PT; MD delivery interrupted) and the distal tubule (DT; MD delivery intact). Compared with HS rats, the difference between PT and DT values of SNGFR was increased in low-salt (LS) diet rats (4.3 ± 0.4 vs 10.3 ± 1.2 nL/min, respectively; P < 0.001). Intravenous infusion of iV^G-monomethyl-L-arginine (L-NMMA), in pressor doses increased the difference between PT and DT values of SNGFR of HS rats (4.3 ± 0.4 vs 9.5 ± 1.2 nL/min before and during L-NMMA, respectively; P < 0.001) without significantly affecting values in LS rats (10.3 ± 1.2 vs 12.3 ± 1.4 nL/min before and during L-NMMA, respectively; NS). 3. A second series of experiments assessed TGF responses directly. Changes in stop-flow pressure (PSF; an index of P_GC) were measured in response to graded perfusion of the loop of Henle (LH) with artificial tubular fluid. Loop perfusion with 10_-3 mol/1. L-NMMA did not affect the PSF responses of LS rats but did reduce (P < 0.01) the PSF of HS rats during perfusion at 20 nL/min (-1.5±0.4mmHg; P<0.01), 30nL/min (-1.8 ± O.5 mmHg; P < 0.01) and 40 nL/min (-2.2 ± 0.5 mmHg; P < 0.001). 4. We conclude that the TGF response is increased by suppression of NOS activity during HS but not LS intake.     

细辛对狗左室功能的作用及其与去甲乌药硷、异丙肾上腺素的比较

实验表明细辛可使狗左室泵功能和心肌收缩性能明显改善。在心肺制备狗,主要表现为LVSP↑,LVEDP↓,MAP↑,CO↑,HR↑,SV↓,dp/dt_max↑,-dp/dt_max↑,t—dp/dt_max↓,V_px↑,V_ce-cpip↑,V_max↑;在麻醉开胸狗,除MAP降低和SV增加外,对其它指标的作用方向与心肺制备实验结果基本一致;两个实验中测取的Lissajous图形的正向前降支均向右上方移位。从而排除了前、后负荷的影响,说明泵功能的改善似由于细辛增强心肌收缩性能所致。通过细辛与去甲乌药硷、异丙肾上腺素的比较研究,提示三者的作用基本相似,唯SV显示不同的结果。细辛使SV增加,去甲乌药硷、异丙肾上腺素却使SV减少,这可能与细辛增加HR的比率较二者为低密切相关。肾上腺素能β受体阻滞后,细辛增加CO的作用仍然存在,值得进一步研究。     

THE RELATIVE BIOAVAILABILITY OF TWO MARKETED CONTROLLED RELEASE DILTIAZEM DOSAGE FORMS AT STEADY STATE IN HEALTHY VOLUNTEERS

This study was conducted to determine the relative bioavailability of Dilacor^TM XR capsules compared to Cardizem^® CD capsules at both low (180 mg d⁻¹) and high (540 mg d⁻¹) dose levels. Trough and serial plasma samples were obtained and pharmacokinetic parameters were calculated from the steady state concentration—time profiles. Mean steady state plasma diltiazem concentrations (AUC_ss(0–24)) of Dilacor XR were 19% and 26% lower than those of Cardizem CD for the 180 mg d⁻¹ and 540 mg d⁻¹ dose levels, respectively. In addition, Dilacor XR had lower mean C_max,ss, T_max,ss, C_min,ss, and trough values than Cardizem CD with percentage differences ranging from 17% to 29%. The variability (%CV) in the data from the Dilacor XR treatments was higher for each calculated pharmacokinetic parameter compared to the Cardizem CD treatments. The %CV for Dilacor XR ranged from 34% to 104% while the %CV for Cardizem CD ranged from 21% to 49%. From these results, it may be concluded that Dilacor XR is not bioequivalent to Cardizem CD at steady state doses of 180 mg d⁻¹ and 540 mg d⁻¹.     

The effect of heart rate on indices of myocardial contractility in the dog

1. Changes in heart rate were evoked by atrial pacing in anaesthetized dogs with no pretreatment and in dogs given reserpine or guanethidine for 72 h. The effect of alterations in heart rate were related to two indices of myocardial contractility: the maximal rate of change of left ventricular pressure (dp/dt), and an index which was independent of initial fibre length (dp/dt)/IIT, where IIT is integrated isometric tension. 2. An increase in heart rate in control dogs was accompanied by a rise in both dp/dt and (dp/dt)/IIT confirming that the Bowditch staircase does exist in the intact ventricle. The regression line relating heart rate to (dp/dt)/IIT was significantly steeper than that relating heart rate to dp/dt because the reduction in left ventricular preload at high heart rate tends to attenuate the rise in dp/dt. 3. Reserpine, but not guanethidine pretreatment was accompanied by either a slight decrease or no change in (dp/dt)/IIT during pacing. 4. Acute elevation of (dp/dt)/IIT by either calcium or isoprenaline infusion in reserpine pretreated dogs did not restore the Bowditch effect. 5. Acute depression of (dp/dt)/IIT by propranolol and pentobarbitone was accompanied by a greater rise in (dp/dt)/IIT with pacing in control dogs and a rise rather than a fall in reserpine-pretreated dogs.     

RESPONSE TO ORTHOSTATIC STRESS PREDICTS OFFICE-DAYTIME BLOOD PRESSURE DIFFERENCE, BUT NOT NOCTURNAL BLOOD PRESSURE FALL IN MILD ESSENTIAL HYPERTENSIVES: RESULTS OF THE HARVEST TRIAL

1. The aim of the present study was to evaluate whether postural blood pressure (BP) change could predict office-daytime BP disparity and the nocturnal BP fall in young, mild essential hypertensives. We investigated 411 males aged between 18 and 45 years with never treated borderline to mild hypertension. BP was measured three times after a 5 min rest in the supine position and thereafter three times after 2 min of standing. The mean of six BP measurements obtained during two visits in the lying position was defined as office BP. 2. Twenty-four hour ambulatory BP monitoring was performed with either the A and D TM-2420 model 7 or the ICR Spacelabs 90207. BP values were averaged for day—and nighttime periods. The nocturnal BP fall was defined as the difference between the average day—and night-time BP. 3. The standing-lying difference was significantly inversely correlated with the office-daytime difference for both systolic blood pressure (SBP) (r = -0.34, P 0.001) and diastolic blood pressure (DBP) (r = -0.24, P 0.001). These correlations did not change when the obese subjects (body mass index > 30 kg/m²) were excluded from the analysis. No significant correlation between standing-lying difference and nocturnal BP fall was found. 4. Our results indicate that white coat hypertension assessed as the office-daytime BP disparity is partially related (in a negative fashion) to the BP reaction to standing. The postural BP change does not predict nocturnal BP fall in young, mild essential hypertensives.     

Upregulation of cardiac NOS due to endotoxemia and vagal overactivity contributes to the hypotensive effect of chronic ethanol in female rats

We previously reported that chronic ethanol lowers blood pressure in female rats. In this study, hemodynamic, biochemical, and immunoblot analyses were performed to investigate: (i) the roles of cardiac contractility and autonomic activity in the hypotensive action of ethanol, and (ii) whether endotoxemia-induced upregulation of cardiac and/or vascular nitric oxide synthase (NOS) isoforms underlies the hypotensive and cardiac effects of ethanol. Telemetric monitoring of blood pressure, heart rate, and myocardial contractility (dP/dt_max) was performed in female rats receiving liquid diet with or without ethanol (5% w/v, 13 weeks). Autonomic control was assessed by frequency domain analysis of interbeat intervals (IBI) and systolic blood pressure (SBP). Compared with pair-fed controls, ethanol caused sustained reductions in blood pressure, heart rate, and + dP/dt_max. Ethanol feeding increased the spectral power of high-frequency band (IBI_HF, 0.75–3 Hz) and decreased the low-frequency band (IBI_LF, 0.25–0.75 Hz) and IBI_LF/HF ratio, suggesting increased cardiac parasympathetic dominance. In contrast, vascular tone was not affected by ethanol because SBP spectral bands and plasma norepinephrine remained unchanged. Myocardial expressions of eNOS and its upstream regulators, phosphatidylinositol 3-kinase (PI3K) and Akt, and plasma endotoxin and nitrite/nitrate were increased by ethanol. Myocardial iNOS was also increased by ethanol whereas nNOS remained unchanged and aortic levels of all NOS isoforms were not altered by ethanol. These findings suggest that facilitation of myocardial PI3K/Akt/eNOS and iNOS pathways, due possibly to ethanol-induced endotoxemia and/or increased cardiac parasympathetic dominance, might constitute a cellular mechanism for the reduced myocardial contractility and hypotension caused by ethanol in female rats.     

EFFECT OF CATIONIC DRUGS ON THE RENAL SECRETION OF RANITIDINE IN THE RAT ISOLATED PERFUSED KIDNEY

1. The rat isolated perfused kidney (IPK) was used to determine whether the renal tubular secretion of ranitidine is influenced by clinically relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubular secretion. 2. Ranitidine and [³H]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a constant infusion to maintain clinically relevant perfusate ranitidine concentrations in the range 400–700 ng/mL. The renal clearance of ranitidine (CL_R) was calculated, as was glomerular filtration rate (GFR), from the renal clearance of [¹⁴C]-inulin. 3. A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 min. In four control IPK, no drug other than ranitidine was administered. In the remaining IPK, amantadine, pseudoephedrine, triamterene or trimethoprim (n= 4 in each case) were administered to achieve low, medium and high concentrations during the 20–40, 40–60 and 60–80 min periods, respectively. 4. The mean (± SD) unbound fraction of ranitidine in the perfusion medium was 0.889±0.046 and was not altered (P>0.05) by the presence of the other drugs. 5. The CL_R/GFR ratio for ranitidine in all kidneys was substantially greater than unity and had a mean value of 10.65 or greater in control kidneys, indicating extensive net tubular secretion. 6. The CL_R/GFR was not affected (P>0.05) by amantadine, pseudoephedrine or triamterene at any concentration or by trimethoprim at the low concentration. However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reductions in CL_R/GFR of 20 and 28%, respectively (P<0.05). 7. The results indicate that at clinically relevant concentrations the renal tubular secretion of ranitidine is inhibited by trimethoprim, but not by amantadine, pseudoephedrine or triamterene.     

EFFECT OF ATRIAL NATRIURETIC PEPTIDE ON CELLULAR ELEMENT CONCENTRATIONS IN RAT PROXIMAL TUBULES: EVIDENCE FOR INHIBITION OF THE SODIUM PUMP

1. In order to further define the action of atrial natriuretic peptide (ANP) on proximal tubular (PT) transport, combined clearance and electron microprobe X-ray (EMPX) experiments were performed on five male Wistar rats infused with ANP (0.16 nmol/kg per h) and nine control animals. 2. Electron microprobe X-ray analysis of PT cell electrolytes (mmol/ kg wet weight) revealed a similar [Na]_i in both the control and ANP treated groups (16.4 ± 0.4 vs 16.5 ± 0.4; P= 0.894). [Cl]_i was lower in the ANP treated animals (14.8 ± 0.3 vs 12.0 ± 0.3; P<0. 0001) as was [K]_i (131.4 ± 1.4 vs 114 ± 1.7; P<0.0001). The PT cells in the ANP treated group had a significant reduction in dry weight (20.1 ± 0.3 g%vs 19.0 ± 0.3 g%; P<0.024), indicating significant cell swelling. Thus, despite a normal [Na]_i, there was net accumulation of Na_i following ANP treatment. 3. These results are consistent with accumulation of Nai due to inhibition of the Na pump followed by cell swelling and subsequent regulatory volume decrease with exit of K and Cl. These results are the first to show the effect of ANP on PT intracellular electrolytes.     

INTERACTIONS BETWEEN THE CIRCULATORY EFFECTS OF CENTRAL HYPOVOLAEMIA AND ARTERIAL HYPOXIA IN CONSCIOUS RABBITS

1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12–14 and 8–10% O₂, with and without the addition of 3–4% CO₂, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between Pao₂ (but not Pao₂) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of Pao₂, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of Pao₂, on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O₂), Phase II occurred later than during normoxia (21% O₂); and (b) across the normoxic and hypoxic gas mixtures (21–8% O₂, with and without added CO₂), there was an independent linear relationship between Pao₂ (but not Pao₂ or Pao₂×Pao₂) and the level of CI at which Phase II occurred. That is, the lower the level of Pao₂, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.     

DETERMINANTS OF THE KINETICS OF VERY LOW-DENSITY LIPOPROTEIN APOLIPOPROTEIN B-100 IN NON-OBESE MEN

1. Apolipoprotein B-100 (ApoB) is the principal structural and functional protein of the pro-atherogenic lipoproteins. Elevated plasma apoB is an independent risk factor for coronary artery disease. In the present study we aimed to assess the factors that determine the kinetics of apoB in the very low-density lipoprotein (VLDL) in healthy men. 2. We studied 17 non-obese men who were consuming an ad libitum diet and had the following characteristics: mean (± SD) age 45.5 ± 9.7 years, body mass index (BMI) 25.1 ± 1.4 kg/m², waist: hip ratio 0.91 ± 0.04, serum cholesterol 5.2 ± 0.6 mmol/L, triglycerides 1.08 ± 0.53 mmol/L and high-density lipoprotein-cholesterol 1.24 ± 0.31 mmol/L. Daily dietary intake was as follows: total fat 76 ± 26 g, carbohydrate 238 ± 67 g, protein 103 ± 33 g and alcohol 20 ± 16 g. 3. The kinetics of VLDL ApoB were studied using a primed, constant infusion (1 mg/kg per h) of l-[¹³C]-leucine over 8 h with measurement of isotopic enrichment of ApoB using gas chroma-tography/mass spectrometry. The fractional turnover rate of VLDL ApoB was estimated using a monoexponential function. The mean (± SD) absolute hepatic secretion rate (ASR) of ApoB was 8.5 ± 4.6 mg/kg per day and the fractional catabolic rate (FCR) was 7.9 ± 5.6 pools/day. The ASR was significantly correlated with the waist: hip ratio (r= 0.60; P= 0.04), but not with age, BMI, weight or nutrient intake. The FCR was significantly and inversely correlated with plasma triglycerides (r =—0.53; P= 0.03) and alcohol intake (r = -0.48; P= 0.05). 4. In conclusion, the hepatic secretion of VLDL ApoB in non-obese, healthy men is primarily determined by the waist: hip ratio, a measure of visceral fat. This is consistent with the hypothesis that the rate of lipid substrate supply to the liver regulates the output of ApoB. The fractional catabolism of VLDL ApoB may, however, be inversely related to alcohol intake and appears to determine the plasma concentration of triglycerides.