Renal failure in haemorrhagic shock in dogs: Salutary effects of the calcium entry blocker felodipine

Summary The efficacy of felodipine, a dihydropyridine calcium entry blocker to restore renal function was investigated in Wiggers model of haemorrhagic shock. Mongrel dogs were anaesthetized with sodium pentobarbital and subjected to haemorrhagic shock by allowing the animals to bleed into a reservoir. After maintaining the hypotensive state (mean blood pressure 40–45 mm Hg) for a period of 150 min, the blood was reinfused and the recovery of the various parameters were monitored for an additional 120 min. These studies were conducted in three different groups of dogs: (A) Solvent control, (B) Felodipine 0.01 mol/kg i. v., administered 10 min prior to reinfusion of the blood, and (C) Felodipine 0.01 mol/kg i. v., administered prior to haemorrhage. In all the three groups arterial blood pressure returned to similar basal levels following reinfusion. Felodipine administration prior to haemorrhage or before reinfusion (Group B and C) resulted in a 80–95% recovery in the renal blood flow, 60–65% in the glomerular filtration rate, 15–300% in the urine volume and 80–100% in the urinary sodium and potassium excretions. In the vehicle-treated control group, despite a 45% recovery in the renal blood flow, renal function was not restored following reinfusion.The observations made in these studies suggest that felodipine, an arteriolar dilator which also possesses natriuretic properties, could be clinically useful in the treatment of renal failure in haemorrhagic shock. Prevention of cellular calcium overload during ischaemia and reperfusion by this dihydropyridine derivative, may account for its ability to preserve vascular as well as tubular function. Send offprint requests to B. S. Jandhyala at the above address     

糖尿病多形核白细胞吞噬功能的改变

目的 研究正常人及糖尿病患者多形核白细胞（polymorphonuclear leukocytes,PMNLs)吞噬功能的改变及钙通道阻滞剂对其的影响。方法 应用过氧化氢释放法测定白细胞吞噬功能,同时研究PMNLs细胞外不同浓度糖环境及钙通道阻滞剂对细胞吞噬功能的影响。结果 糖尿病患者的PMNLs吞噬功能较正常人低下。体外培养基葡萄糖浓度增高,吞噬功能越差,硝苯啶可明显改善糖尿病患者PMNLs的吞噬功能。结论 推测葡萄糖可能是通过激活L型钙通道引起细胞内游离钙浓度升高,从而影响吞噬功能,而硝苯啶可阻断该通道,恢复吞噬功能。     

Effect of Oral Administration of Dotarizine on Cerebrovasculature Subjected to Constriction Followed by Dilatation in Rabbits

In the study presented the effect of Dotarizine on blood flow velocity in cerebral arteries - in middle cerebral artery (MCA), and basilar artery (BA)- was investigated and compared utilising transcranial Doppler sonography during normoventilation, 15 min hyperventilation with subsequent 3 min anoxia in anaesthetized rabbits. In the Dotarizine treated group (12 rabbits) 25 mg/kg of Dotarizine dissolved in 0,25% agar was administered orally for five days twice daily. In the control group (9 rabbits) animals were fed with agar of the same concentration. The results revealed that decrease of flow velocity caused by hyperventilation and increase during anoxia were less pronounced in the Dotarizine treated group than in control group of animals. A difference between changes of flow velocity in MCA and BA during anoxia was found and the different reactivity of both vessels was established.     

Changes in optic nerve head blood flow and retrobular hemodynamics following calcium-channel blocker treatment of normal-tension glaucoma

Background: Because calcium channel blockers reduce vascularresistance, they may have a clinical application in the treatment ofnormal-tension glaucoma (NTG). This study investigates changes inboth the optic disc blood flow and the hemodynamics of retrobulbarvessels in NTG patients after the systemic administration of a calcium channel blocker. Methods: Twelve eyes of 12 NTG patients (meanage 57 6 ± 15.3 years) were examined before and after a 4-weektreatment with 2 mg b.i.d. oral nilvadipine, an L-typc calcium channel blocker. By scanning laser-Doppler flowmetry (SLDF), we obtained the velocity, flow, and volume from within a 10 × 10 pixel windowplaced on the temporal rim region of the optic disc perfusion map. Byultrasound color Doppler imaging (CDI), we measured the peak systolicvelocity (PSV) and the end diastolic velocity (EDV) of the ophthalmicartery (OA), central retinal artery (CRA), nasal posterior ciliary artery (NPCA), and temporal posterior ciliary artery (TPCA). We then calculated a resistance index (RI) for each vessel. Results: After treatment, the flow and velocity of the optic disc blood flow significantly increased (P < 0.05).Nilvadipine also significantly reduced RIs of the CRA, NPCA, and TPCA(P <0 .05), and increased both the PSV of the NPCA and the EDVs of the CRA, NPCA, and TPCA. The percent change in velocity correlated significantly with the percent changes of the CRA RI and NPCA RI. Conclusions: Oral nilvadipine appears to reduce orbital vascular resistance, which consequentlyincreases the optic disc blood flow. Abbreviations.BP – blood pressure;CRA – central retinal artery;CDI – ultrasound color Doppler imaging;EDV – end diastolic velocity;NPCA – short posterior ciliary arteries located nasal to optic nerve;NTG – normal-tension glaucoma;OA – ophthalmic artery;PP – perfusion pressure;PSV – peak systolic velocity;RI – resistance index;SLDF scanning laser-Doppler flowmetry;TPCA – short posterior ciliary arteries locatedtemporal to optic nerve.     

Total Ischaemic Burden European Trial (TIBET): Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina

OBJECTIVES: To study the relationship between presence or absence of ischaemicevents on Holter monitoring and occurrence of a hard or hard+softendpoint. DESIGN: A randomized double-blind parallel group study of atenolol,nifedipine and their combination, with ambulatory monitoringoff-treatment and after 6 weeks of randomized treatment andprospective follow-up of 2 years on average. SETTING: Europe. SUBJECTS: 682 men and women with a diagnosis of chronic stable anginaand who were not being considered for surgery. MAIN OUTCOME: Hard endpoints were cardiac death, nonfatal myocardial infarctionand unstable angina; soft endpoints were coronary artery bypasssurgery, coronary angioplasty and treatment failure. RESULTS: The study showed no evidence of an association between the presence,frequency or total duration of ischaemic events on Holter monitoring,either on or off treatment, and the main outcome measures. Therewas a non-significant trend to a lower rate of hard endpointsin the group receiving combination therapy. Compliance, as measuredby withdrawal from trial medication, was clearly poorest inthe nifedipine group with similar with drawal rates in the atenololand combination therapy groups. CONCLUSION: The recording of ischaemic events in 48 h Holter monitoringfailed to predict hard or hard+soft endpoints in patients withchronic stable angina.     

The effect of trimethyltin on acetylcholine release in the guinea-pig trachea

The purpose of the present work was to characterise the effects of trimethyltin on the release of acetylcholine from parasympathetic nerves and its effect on the postjunctional cholinergic stimulation of a smooth muscle. The guinea-pig trachea has been used as a model. Prejunctionally, trimethyltin (3.0 × 10⁻³ M) significantly enhanced in a reversible manner the high K⁺ (75 mM) evoked release of endogenous acetylcholine and [³H]acetylcholine. The evoked release of endogenous acetylcholine and [³H]acetylcholine was released from a pool of acetylcholine being independent of extraneuronal Ca²⁺ in the presence, but not in the absence of trimethyltin. The effect of trimethyltin on the release was not inhibited by low Ca²⁺ (0 mM and 1.0 × 10⁻⁴ M) or by Ca²⁺ channel blockers (verapamil, 1.0 × 10⁻⁴ M, flunarizine, 1.0 × 10⁻⁴ M, ω-conotoxin GVIA, 2.0 × 10⁻⁷ M and ω-agatoxin, 2.0 × 10⁻⁷ M). The present results also demonstrate that trimethyltin induce emptying of a non-vesicular, probably a cytoplasmic storage pool of acetylcholine, since AH5183 (2.0 × 10⁻⁵ M), an inhibitor of the translocation of acetylcholine into synaptic vesicles, and -latrotoxin (1.0 × 10⁻⁸ M), a toxin from black widow spider venom inducing vesicle depletion, had no inhibitory effects on the release of [³H]acetylcholine evoked by trimethyltin (3.0 × 10⁻³ M). The release of [³H]acetylcholine was moreover enhanced by trimethyltin when the vesicular uptake of [³H]acetylcholine was inhibited by AH5183, probably as a result of a higher cytoplasmic concentration of [³H]acetylcholine. Trimethyltin also reduced the neuronal uptake of [³H]choline and this was probably due to a depolarising effect of trimethyltin on the cholinergic nerve terminals. A similar depolarisation induced by trimethyltin was observed during patch clamping of GH₄ C₁ neuronal cells. Postjunctionally, trimethyltin had no effect by itself or on the carbachol-induced smooth muscle contraction, indicating that trimethyltin did not have a general depolarising effect on smooth muscle cells or an effect on muscarinic receptors. Furthermore, the reduced electrical field-induced contraction and the subsequent increase in the basal smooth muscle tension that was observed by addition of trimethyltin was activity-dependent, and was most probably due to emptying of a nervous non-vesicular storage pool of acetylcholine, followed by rapid hydrolysis of acetylcholine by acetyl- and pseudocholinesterases.     

Antihypertensive effect of E-643, a new alpha-adrenergic blocking agent

Summary To determine whether E-643, a new -blocking agent, would reduce the blood pressure, regardless of the posture, a 1 mg dose was given 3 times daily for 7 consecutive days, to 8 male and 7 female inpatients, aged 37–73 years, with essential hypertension. Blood pressure and pulse rate were measured daily in the supine, sitting and standing positions. Before and after the treatment with E-643, plasma levels of noradrenaline, adrenaline, dopamine--hydroxylase, renin and aldosterone were determined, samples being obtained with the subjects recumbent and after standing upright for 60 min. A significant reduction in the systolic and diastolic blood pressures was evident in the supine (172±31/100±12 151±28/89±14 mmHg), sitting (158±22/101±11 138±28/89±15 mmHg) and standing (153±32/103±21 129±31/89±20 mmHg) positions. The reduction in blood pressure remained unchanged throughout the period of administration of E-643. Pulse rate was not affected when the subjects were supine (67±10 69±10 beats/min), but was increased in the sitting (68±10 73±9 beats/min) and standing (73±10 81±11 beats/min) positions. The increased pulse rate tended to decline during continued administration of E-643. Treatment with E-643 produced no significant change in plasma levels of adrenaline, noradrenaline, dopamine--hydroxylase, renin and aldosterone. The antihypertensive effect of treatment was more prominent in the patients with higher levels of plasma catecholamines and dopamine--hydroxylase, and was less prominent in those with higher plasma renin and aldosterone. Two patients had temporary bouts of dizziness and visual disturbances, but there were no subjective complaints during treatment.     

Mechanisms underlying the slow onset of action of a new dihydropyridine,NZ-105, on a cultured smooth muscle cell line

Summary The inhibitory effect of a new dihydropyridine derivative, (±)-2-[benzyl(phenyl)amino]ethyl-1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride (NZ-105), on whole cell Ca²⁺ current (I_Ca) in cultured vascular smooth muscle cells was investigated with the patch clamp technique. NZ-105 blocked I_Ca in a concentration-dependent manner when the command pulse ranged from +10 mV to –50 mV. The inhibitory effect of NZ-105 appeared at concentrations higher than 10 mol/l and it blocked I_Ca completely at a concentration of 1 nmol/l. The concentration which produced the half-maximal inhibitory effect was estimated to be around 20 mol/l. NZ-105 (500 pmol/l) completely blocked I_Ca elicited by depolarization to + 10 mV at a holding potential of –40 mV, whereas it blocked I_Ca by only 67% at a holding potential of –90 mV. NZ-105 (100 mol/l) shifted the steady-state inactivation curve by 40 mV to more negative potentials without affecting its slope factor. The blocking time constant of 500 mol/l NZ-105 was 57.6 + 9.9 s at a holding potential of –70 mV. These results indicate that NZ-105 has characteristics typical of dihydropyridines and binds to Ca²⁺ channels of vascular smooth muscle cells with a high affinity. They also suggested that the slow onset of its action is due to the slow binding of the drug to Ca²⁺ channels. Send offprint requests to S. Kokubun at the above address     

Penfluridol: An open phase III study in acute newly admitted hospitalized schizophrenic patients

An open study was carried out in 17 acutely ill, newly admitted, floridly psychotic schizophrenic patients to a city hospital in New York. Penfluridol was given on a daily basis up to doses of 120 mg and patients were rated objectively by means of different psychometric evaluations; vital signs were monitored daily as were side effects.The drug was found to be a rapid acting, well-tolerated, and highly effective antipsychotic agent within the population of patients explored and within the dose range used. It was particularly effective in acutely agitated floridly paranoid schizophrenics; a statistically significant impact was achieved by 7 days and usually within 72 h after initiating treatment. The drug appears unique in that (1) its effects are realized without the untoward and usually trouble-some effects of nonspecific sedation attendant upon the use of many other neuroleptic medications, and (2) even within the relatively high doses used it produces no hypotensive effects. It is concluded that this appears to be a unique antipsychotic agent and a potentially important addition to the treatment armamentarium of both acute and chronic schizophrenic individuals.Dr. Klein was a research fellow who has since returned to the University of Munich, West Germany. Dr. Selzer was also a research fellow who is now in private practice     

Beneficial effect of verapamil added to chronic ACE inhibitor treatment on renal function in hypertensive elderly patients

This study analysed the effect of low doses ofverapamil added to chronic treatment withangiotensin-converting enzyme (ACE) inhibitors onblood pressure and serum creatinine levels in eightelderly hypertensive patients who had a steadyincrease of serum creatinine while on ACE inhibitors.The study was performed in eight elderly hypertensivesubjects, five men and three women (mean age 70 ±2 years; systolic blood pressure 173 ± 4 mmHg; diastolic blood pressure 99 ± 1 mm Hg) andserum creatinine of 1.60 ± 0.27 mg/dl beforetreatment. During an average of 25 weeks, ACEinhibitors significantly reduced both systolic anddiastolic blood pressures, but serum creatinine levelswere increased over basal levels (0,68 ± 0,20 mg/dl, p < 0.05). During an average of 10 weeks,the addition of verapamil did not decrease bloodpressure further, but serum creatinine levels werereduced to baseline. Our study suggests that theaddition of verapamil to ACE inhibitors can reverseACE-induced increase in creatinine levels in elderlyhypertensive patients in whom this side effect isobserved. This revised version was published online in August 2006 with corrections to the Cover Date.