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It has been claimed that Nigella sativa seeds (NSS), also known as black cumin, have antidiabetic and lipid-lowering properties. Our pilot study investigated the effects of powdered NSS on insulin secretion and lipid profile in healthy male volunteers. We conducted a double-blind, randomized, placebo-controlled 4-week trial in 30 subjects, receiving NSS powder (1 g/day) or placebo orally (15 subjects/group). Insulin secretion as determined by the hyperglycaemic clamp technique, insulin sensitivity as well as cholesterol and triglycerides serum concentrations, were measured before and after treatment. NSS powder administration was clinically well tolerated. It did not modify fasting glycaemia and insulinaemia, and was ineffective on glucose-induced insulin secretion and insulin sensitivity. No significant changes on serum lipids were observed after treatment in any treatment groups, nor between the two treatment groups. However, in the treated group only, there was a significant correlation between total cholesterol change after treatment and its baseline level (r = -0.71, P = 0.006, n = 13), and between low-density lipoprotein (LDL) cholesterol change after treatment and its baseline level (r = -0.74, P = 0.004, n = 13). No such correlations were found for high-density lipoprotein (HDL) cholesterol, and for triglycerides. These results do not confirm any NSS effect on glucose regulation; however, they suggest that NSS powder may be of interest in lowering lipid concentrations in hyperlipidaemic subjects., (© 2019 The British Pharmacological Society.)

Current antihypertensive strategies do not take into account that individual characteristics may influence the magnitude of blood pressure (BP) reduction. Guidelines promote trial-and-error approaches with many different drugs. We conducted the Identification of the Determinants of the Efficacy of Arterial blood pressure Lowering drugs (IDEAL) Trial to identify factors associated with BP responses to perindopril and indapamide. IDEAL was a cross-over, double-blind, placebo-controlled trial, involving four 4-week periods: indapamide, perindopril and two placebo. Eligible patients were untreated, hypertensive and aged 25-70 years. The main outcome was systolic BP (SBP) response to drugs. The 112 participants with good compliance had a mean age of 52. One in every three participants was a woman. In middle-aged women, the SBP reduction from drugs was -11.5 mm Hg (indapamide) and -8.3 mm Hg (perindopril). In men, the response was significantly smaller: -4.8 mm Hg (indapamide) and -4.3 (perindopril) (P for sex differences 0.001 and 0.015, respectively). SBP response to perindopril decreased by 2 mm Hg every 10 years of age in both sexes (P=0.01). The response to indapamide increased by 3 mm Hg every 10 years of age gradient in women (P=0.02). Age and sex were important determinants of BP response for antihypertensive drugs in the IDEAL population. This should be taken into account when choosing drugs a priori.

Background: Adequate pharmacologic cardiac support in acute myocardial infarction (MI), as well as in chronic MI patients under beta-blocker therapy, is problematic due to the impaired cardiac response to beta-adrenergic agonists. New therapeutic approaches could resolve this problem. Istaroxime (ISTA) is a new Na(+),K(+)-ATPase inhibitor and SERCA(2) agonist., Aims: To evaluate: 1) the effects of dobutamine (DOB) on left ventricular function in early (48-72 h) and late (14 days) phases of a post-MI canine model, compared to ISTA, and 2) the efficacy of DOB in chronic left ventricular dysfunction (6 months post-MI) in dogs pre-treated or not with a beta-blocker, compared with ISTA and milrinone (MIL)., Results: When compared to the effects in healthy animals, DOB increased contractility only slightly in the first 48-72 h post-MI, whereas its efficacy recovered partially by day 14 and fully by 6 months after MI. ISTA had a greater effect on contractility than DOB and improved relaxation, while DOB did not. Moreover, beta-adrenergic blockade inhibited the inotropic action of DOB, without altering the effect of ISTA. Surprisingly, beta-adrenergic blockade blunted the effects of MIL., Conclusion: ISTA may represent a novel strategy for enhancing left ventricular performance even in the context of acute MI and/or concomitant beta-adrenergic blockade.

Inotropic agents for acute decompensated heart failure are associated with a lack of efficacy or increased mortality. New compounds are needed to support patients with acute exacerbations of heart failure. This study examined the hemodynamic effects of a new inotropic agent (PST-2744) in dogs with chronic ischemic heart failure. Eight mongrel dogs at low risk for postmyocardial infarction (MI) sudden death entered the protocol. Dogs were studied after ischemic left ventricular dysfunction was induced by repeated injections of latex microspheres into the circumflex artery until the ejection fraction reached 35%. Hemodynamic parameters were measured at baseline and peak drug effect (PST-2744 5 microg.kg-1.min-1). In 5 animals, PST-2744 effects were compared with dobutamine. Heart rates, PR intervals and QT intervals were unchanged following PST-2744 administration. PST-2744 increased contractility (+dP/dt) by 56% from 1881 +/- 282 mm Hg/s to 2939 +/- 734 mm Hg/s (P < 0.01). The inotropic effect of PST-2744 was equal to that produced by 5-microg.kg-1.min-1 dobutamine (56% increase in +dP/dt), but peak heart rates were significantly higher with dobutamine (129 +/- 24 bpm PST-2744 versus 160 +/- 6 bpm 5-microg.kg-1.min-1 dobutamine, P < 0.002). No arrhythmias or conduction delays were seen with either compound. PST-2744 is an effective inotropic agent without positive chronotropic effect in subjects with stable moderate left ventricular dysfunction.

There is strong evidence that autonomic imbalance plays an important role in progression of heart failure. Analysis of heart rate variability (HRV) has achieved substantial acceptance as a noninvasive method for the assessment of autonomic tone. The purpose of this investigation was to study HRV in an experimental model of heart failure using cardiomyopathic (BIO TO.2) hamsters. Animals showed an autonomic imbalance of cardiac control that seems due to attenuation of parasympathetic activity and an enhanced sympathetic tone. The reduction of parasympathetic activity in BIO TO.2 hamsters is suggested by (a) the reduction of the high-frequency (HF) spectrum, and (b) the lack of atropine to generate a response. The increased sympathetic activity is indicated by (a) the decreased time-domain indexes, (b) the increased LF/HF ratio of the power spectrum, and (c) the alteration of HRV indexes induced by propranolol. These results support the notion that in heart failure, there is a similar autonomic imbalance in both human and hamster and suggest that the cardiomyopathic hamster is a suitable experimental model for studying the involvement of the autonomic nervous system in the progression of heart failure.

Although potassium channel openers have been demonstrated to induce arterial vasodilation and shortening of the QT interval, the complete in vivo hemodynamic and electrophysiologic profile of these drugs has not been fully established. We evaluated the effects of BRL 38227, the active enantiomer of cromakalim, on the electrophysiologic and hemodynamic parameters in anesthetized dogs. Four intravenous (i.v.) doses (0.01, 0.03, 0.1, and 0.3 mg/kg) of BRL 38227 (lemakalim) were given to four different groups of 6 anesthetized and mechanically ventilated dogs. Electrophysiologic and hemodynamic parameters were measured with bipolar catheters positioned in the right atria and the right ventricle and double micromanometers placed in the left ventricle and the aorta. Nine dogs died of ventricular fibrillation (VF; 6 of 6 after 0.3 mg/kg, 2 of 8 dogs after 0.1 mg/kg, and 1 of 7 dogs after 0.03 mg/kg BRL 38227). Three dogs had atrial tachycardia (1 had atrial flutter and 1 had atrial fibrillation after 0.03 mg/kg, and 1 had atrial fibrillation after 0.01 mg/kg BRL 38227). BRL 38227 did not modify heart rate (HR), corrected sinus recovery time (CSRT), and atrial or atrio-ventricular (A-V) conduction times. In contrast, PR interval, Luciani-Wenckebach cycle length (LW), HV interval, QRS duration, ventricular effective refractory period (VERP), QT interval, and monophasic action potential (AP) were significantly shortened in a dose-dependent manner. Left ventricular end-diastolic pressure (LVEDP) was not modified, whereas LVdP/dtmax decreased significantly at 0.1 mg/kg BRL 38227. Finally, there was a significant dose-dependent decrease in systolic, diastolic, and mean aortic blood pressure (SBP, DBP, MAP). We conclude that BRL 38227 shortens the ventricular parameters of conduction velocity and of repolarization and decreases BP, both in a dose-dependent manner. All doses were arrhythmogenic, suggesting that BRL 38227 has a low safety margin.

We have examined the ability of lemakalim to correct bupivacaine-induced cardiac electrophysiological impairment in an experimental electrophysiological model in closed-chest dogs. Two groups (n = 6) of pentobarbitone-anaesthetized dogs were given atropine 0.2 mg kg-1 i.v., and bupivacine 4 mg kg-1 i.v. over 10 s. Group 2 received also lemakalim 0.03 mg kg-1 i.v. Bupivacaine induced bradycardia, prolonged PR and His-ventricle (HV) intervals, QRS duration, QTc and JTc intervals, decreased left ventricular (LV) dP/dt max and increased LV end-diastolic pressure. Lemakalim reversed bupivacaine-induced PR, HV, QRS, QTc and JTc prolongation, and did not worsen bupivacaine-induced bradycardia and haemodynamic depression. We conclude that lemakalim can antagonize the main deleterious electrophysiological effects induced by a large dose of bupivacaine in anaesthetized dogs.

Bupivacaine is more cardiodepressant than lidocaine. Nevertheless, the marked depression of contractility induced by bupivacaine cannot be completely explained by its electrophysiologic properties alone. Biophysical differences such as the greater lipid solubility of bupivacaine versus lidocaine must be taken into consideration. Perhaps more bupivacaine enters the cardiac cells and interacts with contractile processes. To test this hypothesis, the entry of lidocaine into the cells was facilitated by a membrane-permeant lipophilic anion, tetraphenylboron. We compared the spontaneous atrial rate and the contractile force of rabbit right atria bathing in solutions containing either 0.5 microgram/mL lidocaine or bupivacaine. Group 1 (n = 8) served to test the stability of the preparation. In group 2 (n = 6), tetraphenylboron (17 micrograms/mL) was added to Tyrode's solution; atrial rate was decreased by 8% and contractile force by 1.7%. In group 3 (n = 6), bupivacaine (0.5 microgram/mL) was added; bupivacaine decreased atrial rate by 11.3% and markedly depressed contractile force by 68.3%. In group 4 (n = 6), lidocaine (0.5 microgram/mL) was added; lidocaine did not change atrial rate but decreased contractile force by 6.0%. In group 5 (n = 6), both lidocaine and tetraphenylboron were added; atrial rate was decreased by 15.5% and contractile force was markedly depressed by 81.1%. In group 6 (n = 6), 0.2 mM adenosine triphosphate, tetraphenylboron, and then lidocaine were added; the addition of adenosine triphosphate partially counteracted the cardiodepressant effects of the combination of lidocaine and tetraphenylboron. Atrial rate was decreased by 10.4% and contractile force was depressed by 13.6%.(ABSTRACT TRUNCATED AT 250 WORDS)

The ability of clonidine and dobutamine to correct bupivacaine-induced cardiac electrophysiologic and hemodynamic impairment was evaluated in an experimental electrophysiologic model on closed-chest dogs. Five groups (n = 6) of pentobarbital-anesthetized dogs were given atropine (0.2 mg/kg IV). Group 1 was given a saline solution; all other dogs were given bupivacaine (4 mg/kg IV) over a 10-s period. Group 2 was given only bupivacaine. Group 3 was given clonidine (0.01 mg/kg IV) over a 1-min period. Group 4 was given a dobutamine infusion at 5 micrograms.kg-1.min-1. Group 5 was given the combination of clonidine and dobutamine. Bupivacaine induced bradycardia, prolonged atrioventricular conduction time (PR interval), atrioventricular node conduction time (AH interval), His-Purkinje conduction time (HV interval), and QRS duration. Bupivacaine decreased left ventricular (LV) dP/dt max and increased LV end-diastolic pressure (LVEDP). Clonidine improved QRS duration and HV interval but enhanced AH interval, bradycardia, and hemodynamic depression induced by bupivacaine. Dobutamine infusion improved LV dP/dt max but did not modify bupivacaine-induced ventricular electrophysiologic impairment. The combination of clonidine and dobutamine corrected not only the electrophysiologic impairment induced by bupivacaine but also the hemodynamic depression. As the HV interval and the QRS duration could be correlated with ventricular conduction velocities, we conclude that (a) clonidine reversed the slowing of ventricular conduction velocities induced by bupivacaine, and (b) the combination of clonidine and dobutamine was able to correct the cardiac disturbances induced by bupivacaine in anesthetized dogs.

Hemodynamic changes following intravenous administration of SR 42128A (SR), a potent renin inhibitor, were evaluated in normal (N) and sodium-depleted (SD) anesthetized baboons. SR, at 9 mg/kg, decreased arterial pressure (AP) only in the SD group. This effect persisted for at least 2.30 h. At this dose, SR decreased the systemic vascular resistance (SVR) and increased the cardiac output in the SD group more than in the normal group. In both groups, heart rate was slightly increased. However, in the normal group, the highest dose (12 mg/kg) induced the same hemodynamic responses as the dose of 9 mg/kg in the SD group. Every time, plasma renin activity (PRA) was inhibited. Thus, in SD baboons, SR produced a hypotensive effect more pronounced than in the normal group. The dose-related effect on AP seemed to be correlated with the change in SVR. We can conclude that total inhibition of PRA is necessary but not sufficient, under normal conditions, to get an adequate lowering of SVR and a hypotensive effect.

Although several mechanisms have been proposed to explain bupivacaine cardiotoxicity, the predominant effect remains to be determined. In this study, we used an isolated rabbit right atrial model that reproduces the effects on inotropic and chronotropic functions induced by 0.5 micrograms/mL bupivacaine; then we tried to counteract these events by electrical stimulation or by addition of CaCl2 or adenosine triphosphate (ATP) to the bathing solution. Contractile force was dramatically depressed by bupivacaine alone (-68%), even when the preparation was paced (-59%). CaCl2 partially counteracted this decrease (-37%). Inotropic function was almost completely restored (-9%) when ATP was added before administration of bupivacaine. Inhibition of energy metabolism seems to be a major explanation for bupivacaine cardiotoxicity.

Five insulin treated diabetics were studied on three consecutive days. Overnight variable intravenous insulin infusions were used before each study to maintain normoglycaemia and to calculate the optimal basal insulin infusion rate (1.1 +/- 0.1 U/h) which ws then kept constant throughout the study day. A standard 400 kCal breakfast with 25 g xylose was given at 0800 h. When the blood glucose rose above 4.1 mmol/l, an external artificial pancreas was used to infuse either extra insulin (day INS) or somatostatin for either 3h (day som) or the entire 8h experimental period (day SOM). Peak post-prandial blood glucose values were similar on all three days. The blood glucose rebounded after the cessation of the somatostatin infusion on day som. Post-prandial blood xylose peaks were lowered by somatostatin on both days but rebounded after the cessation of the somatostatin infusion on day som. The area under the plasma and urinary xylose curves was lowered by somatostatin only on day SOM. Growth hormone and glucagon levels were not statistically different on all 3 days. Thus somatostatin, when added to an optimal insulin infusion, minimised the insulin requirements by slowing intestinal absorption, but led to rebound hyperglycaemia if not feed-back controlled.

The interaction between human renin and a potent pepstatin analog, SR 42128, has been investigated using binding studies. Binding and enzymatic assays were performed at pH 5.7 and pH 7.4. We found one specific inhibitor binding site per molecule of renin at both pH's. The dissociation constant (KD) obtained at equilibrium was 14-fold lower at pH 5.7 than at pH 7.4, showing a pH effect on binding of [3H]SR 42128. A similar decrease was measured in enzymatic studies. In nonequilibrium conditions, we demonstrated that only association kinetic constants have been affected by pH variations. Radioligands provided interesting tools to investigate enzyme-inhibitor relationships.

A new potent renin inhibitor, Iva-Phe-Nle-Sta-Ala-Sta-OH (SR 42128), and its arginine salt (SR 42128A) have been synthesized. This compound had a concentration required to displace 50% of ligand binding of 2.8 X 10(-8) M toward human plasma renin at pH 7.4 and was 2,000 times more potent than pepstatin. All primate renins tested were inhibited within the same order of magnitude whereas other animal renins were much less inhibited. The effect in vivo of SR 42128A was studied in sodium-depleted conscious monkeys. A single dose of SR 42128A produced a dose-dependent blood pressure decrease as well as a dose-dependent inhibition of plasma renin activity (PRA). Blood pressure was still significantly lowered 3 h after a single administration of 3 or 10 mg/kg whereas PRA was still completely inhibited. SR 42128 is a potent and long-acting tool for studying the role of the renin angiotensin system in primates and humans.

The intracellular electrophysiologic properties of a new antiarrhythmic substance, penticainide, were studied in isolated rabbit, dog, and guinea pig myocardial preparations superfused or perfused with oxygenated Tyrode's solution. "Therapeutic" concentrations of penticainide (1.5 to 3 X 10(-5) M) had little effect on sinus node automaticity; sinoatrial conduction was slightly delayed. In atrial, Purkinje and ventricular fibers, amplitude, and maximal rate of rise of phase O (dV/dtmax) were decreased by penticainide; Purkinje-ventricle conduction velocity was depressed. Penticainide did not significantly modify action potential duration (APD) of rabbit atria and dog ventricle and reduced APD and effective refractory period (ERP) of dog Purkinje and guinea pig ventricular fibers. Penticainide reduced APD heterogeneity of Purkinje-ventricle junction with a preferential effect at the gate and decreased tension amplitude of perfused papillary muscle in dog heart. The effect of penticainide on dV/dtmax was voltage and rate dependent; the resting block was weak. Thus, penticainide is a class 1 antiarrhythmic agent with properties of class 1B agents such as APD reduction and properties of class 1C agents such as slow recovery kinetic of rate-dependent block.