Anti-ischemic Activity Research Articles

Synthesis and the antihypoxic and antiischemic activity of some 2-chloro-1,4-naphthoquinone derivatives

Synthesis and the antihypoxic and antiischemic activity of some 2-chloro-1,4-naphthoquinone derivatives

Increased cardiac workload by adrenoceptor agonists for the estimation of potential antiischemic activity in a conscious rabbit model

The antiischemic effect of drugs can be detected at a lower dose range if the cardiac workload is increased. A brief period of frequency-loading (ventricular overpacing = VOP) results in well-defined, reproducible changes in cardiac parameters in the conscious, chronically instrumented rabbit; however, rapid pacing frequently evoked ventricular tachycardia or even fatal ventricular fibrillation. Therefore, cardiac workload has been increased by i.v. administration of adrenoceptor agonists, such as isoproterenol (ISO), phenylephrine (PHE), and their combination, respectively. The doses applied (especially the combination of 2 μg/kg ISO and 16 μg/kg PHE, giving optimal changes) were sufficient to produce a marked elevation of both the ST segment in the intracavital electrogram and the left ventricular end-diastolic pressure, without evoking cardiac arrhythmias. We compared the effect of this adrenergic “test” stimulus with that of VOP on hemodynamic and electrophysiological parameters of the heart, and furthermore, on the modification of responses to both “test” stimuli by oral administration of the coronary vasodilator: Isosorbide-5-mononitrate (IS-5-N), given in a dose of 40 mg/kg. Both VOP- and ISO+PHE-induced changes were significantly attenuated by IS-5-N, and a temporal coincidence of the maximal effects was found as well. We reached the following conclusion: The combined administration of ISO and PHE not evoking fatal arrhythmias in the dose range applied can replace the more risky VOP as a “test” workload in the estimation of antiischemic action.

Facilitation of retinal function recovery by coumarin derivatives.

Ischemic retinopathy is a difficult disease to treat, although numerous drugs have been tried in the clinics. Coumarin was one of those tried as an anti-coagulant with a marginal efficacy. In this study, 15 coumarin derivatives were studied on the b-wave recovery in electroretinogram which is an indicator of the functional recovery of retina after ischemic insult. It was found that when positions 6, 7 and 8 were occupied by various functional groups, the b-wave recovery could be markedly enhanced. On the other hand, single occupation of position 3 with any functional group would cause damaging effects to the anti-ischemic activity. It is concluded that some coumarin derivatives with two or all of these positions at 6, 7 and 8 occupied by certain functional groups could result in useful drugs for the treatment of ischemic retinopathy.

HEMODYNAMIC CHANGES DO NOT MEDIATE THE CARDIOPROTECTION INDUCED BY THE A1, ADENOSINE RECEPTOR AGONIST CCPA IN THE RABBIT

Stimulation of adenosine A1receptors is known to reduce infarct size in the rabbit heart. The aim of the present study was to verify whether a protective activity similar to that of the selective A1receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), could also be obtained by inducing comparable hemodynamic effects with drugs having different mechanisms of action. The effects of theβ-adrenoceptor blocker atenolol, the calcium channel blocker felodipine, the A2A-selective adenosine receptor agonist 2-hexynyl-5′-N-ethyl-carboxamidoadenosine (2HE-NECA), and the non-selective adenosine receptor agonist 5′-N-ethyl-carboxamidoadenosine (NECA) were tested.Groups of 12–15 anesthetized open-chest rabbits received a 5-min infusion of CCPA (50gmgkg−1min−1), atenolol (1mgkg−1min−1), felodipine (50gmgkg−1min−1), 2HE-NECA (1gmgkg−1min−1), and NECA (1gmgkg−1min−1). Myocardial infarction was induced by a 30-min occlusion of a branch of the left coronary artery, followed by 3-h reperfusion. Infarct size was measured by tetrazolium staining.In controls, infarct size was about 40% of the zone at risk. Pretreatment with CCPA induced a marked decrease in heart rate (−40%) and blood pressure (−48%), and showed antiischemic activity (28% of the zone at risk). The other drugs tested produced similar effects on either heart rate (atenolol, −25%), or blood pressure (felodipine, 2HE-NECA and NECA, about −45%), but did not affect infarct size.In this model, the reduction in infarct size by CCPA is most likely mediated by A1receptors,since comparable hemodynamic effects, induced by other means, are not effective. A2Areceptor stimulation does not appear to exert a protective effect.

Secondary preventive potential of nitrates in ischaemic heart disease.

Nitrates exert their anti-anginal activity by a number of mechanisms. By reducing venous return and left ventricular end-diastolic pressure they lower myocardial oxygen demand and at the same time enhance blood flow to the sub-endocardium. They also directly increase myocardial oxygen supply by dilating the coronary artery stenoses and increasing collateral blood flow. These pharmacodynamic attributes are clinically efficacious in all the ischaemic myocardial syndromes. In stable angina pectoris, nitrates reduce myocardial ischaemia and ischaemic pain and increase exercise tolerance. In unstable angina, nitrates similarly reduce electrocardiographic evidence of myocardial ischaemia and relieve anginal pain. Following acute myocardial infarction, nitrates reduce ventricular dilatation and by so doing reduce pulmonary congestion and mitral regurgitation. The weak anti-aggregatory effect of nitrates on platelets may also play an adjuvant role in their anti-ischaemic activity. Early small-scale studies with both intravenous and oral nitrates demonstrated a trend to reduced mortality and reinfarction in survivors of acute myocardial infarction. However, the later and larger ISIS-4 and GISSI-3 trials have not confirmed this trend possibly due to the smaller doses of nitrates used and the diluting effect of the widespread use of open-label nitrates in the placebo group. In patients with congestive heart failure, including those of ischaemic aetiology, nitrates together with hydralazine have clearly demonstrated a significant reduction in the medium term mortality risk. Nitrates have the undoubted ability, probably greater than any other single anti-anginal drug, to rapidly and often completely relieve the pain and breathlessness associated with myocardial ischaemia. They are haemodynamically efficacious in reducing dilatation of the ischaemic left ventricle and enhancing coronary blood flow to ischaemic areas. Although their preventative impact in survivors of acute myocardial infarction awaits clarification, they have been shown in combination with hydralazine to extend survival in patients with congestive heart failure, including those of ischaemic origin.

Calcium channel blockers in heart failure: Help or hindrance?

Since their development, calcium channel blocking agents have stimulated interest intheir potential benefit for a variety of cardiovascular disorders, including heart failure. The rationale for the potential benefit of calcium channel blockers in heart failure is multi-factorial, including vasodilation, correction of perturbed diastolic relaxation, anti-ischemic action, and potential for inhibiting myocyte hypertrophy and injury. Despite these potential benefits, the degree of salutary influence has remained controversial, and a number of studies have suggested potential adverse action in patients with heart failure, perhaps linked to either negative inotropic action or to reflex neurohormonal activation. Diversity among different agents, particularly with regard to tissue selectivity and pharmacokinetics may imply substantial differences in the relative benefits and risks in various subgroups of patients with heart failure. One trial with the newer dihydropyridine agent, amlodipine, indicates benefit to survival in patients with moderate to severe heart failure and reduced ejection fraction. The reproducibility of this finding and the mechanism for this benefit deserves further investigation.

Myocardial Protection with the ATP-Sensitive Potassium Channel Openers

Abstract: The ATP-sensitive potassium channel (KArP) openers (e.g., Cromakalim) were originally developed for the treatment of hypertension, primarily due to their potent peripheral vasodilating properties. However, the clinical studies have failed to demonstrate any advantage of these compounds over the more established antihypertensive agents. Experimen­ tal studies have shown that the KArP openers may be effective for the treat­ ment of a variety of diseases (asthma, urinary incontinence, ischemia etc.) besides hypertension. However, their clinical utility is limited due to lack of tissue selectivity. We have shown that KArP openers have direct cardioprotective properties which do ,!lOt require contribution from vasodilation. However, the first generation agents offer a narrow window of safety for the treatment of myocardial ischemia due to their potent peripheral vasodilating properties which can compromise the tissue already at risk. Our efforts to find cardioprotective KArP openers with a lower degree of vasorelaxant potency relative to the first generation agents have resulted in the identification of a new class of agents (5). Their structure-activity relationships for antiischemic activity and efficacy in vivo are summarized in this review. The structure-activity studies show that an electron withdrawing group at C6 of the benzopyran ring, a gem-dimethyl at C2, a trans-hydroxyl at C3, an sp3 carbon at C3/C4 and an aryl ring attached to the nitrogen of the cyanoguanidine moiety are required for antiischemic activity. The mechanism of action of these compounds appear to involve opening of the KArP as structurally distinct KATP blockers abolish the cardioprotective effects of these compounds. Unlike the first generation compounds (e.g., cromakalim), the more selective KATP openers can be administered iv to observe antiischemic efficacy. The mechanism of antiischemic activity of KArP openers does not appear to involve the sarcolemmal KArP as their antiischemic activity is independent of action potential shortening. Progress at understanding the molecular mechanism of action of KArP openers and opportunities for future research are also discussed in this article.

The anti-ischemic drugs defibrotide and oligotide analogously inhibit leukocyte-endothelial cell adhesion in vitro

Abstract Defibrotide (a polydeox-yribonucleotide) and oligotide (an oligodeoxyribonucleotide) obtained from mammalian single-stranded DNA, have been demonstrated to have anti-ischemic activity in some experimental models of ischemia/ reperfusion of kidney in rats. We hypothesized that their anti-is chemic activity could be related to an inhibition of leukocyte-endothe lial cell adhesion and also the con sequent generation of oxygen free radicals by leukocytes. We studied the in vitro adhesion of neutrophils to human umbilical vein endothelial cells under basal conditions and following neutrophil or endothelial cell activation (using 10--7 fMLP and SO0 U/ml TNF-α, respectively). De fibrotide and oligotide significantly inhibited neutrophil adhesion to endothelial cells (after only 1 min of drug treatment). When the anti-LFA-1 70H12 F(ab)2 monoclonal antibody was used, the drugs exerted only slight additional inhibition of the adhesion of fMLP-acti-vated neutrophils to endothelium. These results, confirmed in NIH/ 3T3–ICAM-l-transfected cells, demonstrate that defibrotide and oligo tide interfere with leukocyte adhesion to endothelial cells by an LFA-1–dependent mechanism.

Inhibition of PAF synthesis by stimulated human polymorphonuclear leucocytes with cloricromene, an inhibitor of phospholipase A2 activation.

1. A phospholipase A2 (PLA2) represents the key enzyme in the remodelling pathway of platelet-activating factor (PAF) synthesis in human polymorphonuclear (PMN) leucocytes. 2. PLA2 activation is also the rate-limiting step for the release of the arachidonic acid utilized for the synthesis of leukotrienes in stimulated leucocytes; however, it is unknown whether the PLA2s involved in the two biosynthetic pathways are identical. 3. Cloricromene (8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxy- carbonylmethoxy coumarin) is an antithrombotic coumarin derivative which inhibits platelet and leucocyte function and suppresses arachidonic acid liberation by interfering with PLA2 activation. 4. The aim of the present study was to assess whether chloricromene inhibits PAF synthesis by stimulated human polymorphonuclear leucocytes (PMNs). 5. Cloricromene (50-500 microM) inhibited in a concentration-dependent manner the release of PAF, as measured by h.p.l.c. bioassay, from A23187-stimulated PMNs. Significant inhibition (45%) of PAF-release was obtained with 50 microM cloricromene and the IC50 was 85 microM. Mepacrine (500 microM), a non-specific PLA2 inhibitor, strikingly reduced PAF release. 6. The incorporation of [3H]-acetate into [3H]-PAF induced by serum-treated zymosan in human PMNs was also inhibited concentration-dependently by cloricromene, with an IC50 of 105 microM. Mepacrine also suppressed [3H]-acetate incorporation into [3H]-PAF. 7. Cloricromene did not affect the activities of the enzymes involved in PAF-synthesis acetyltransferase or phosphocholine transferase. 8. Our data demonstrate that cloricromene, an inhibitor of PLA2-activation in human leucocytes, reduces the synthesis of PAF by stimulated PMNs. This finding has a twofold implication: the PLA2s (or the mechanisms that regulate their activation) involved in PAF synthesis and arachidonate release in human leucocytes are either identical or else indistinguishable by their sensitivity to cloricromene; the inhibition of PAF release by activated leucocytes may contribute to the antithrombotic and anti-ischaemic activities exerted by cloricromene.

Antiischemic activity of immobilized cytochrome C

The antiischemic activity of polyethylene glycol- and dialdehyde dextran-immobilized cytochrome C is experimentally studied on rats. Immobilization of cytochrome C on these matrices enhanced the enzyme activity assayed by restriction of the necrotic zone 4 hours after coronary occlusion.

Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris

Spinal cord stimulation in angina pectoris increases exercise capacity and reduces both anginal attacks and ischemic electrocardiographic signs. This suggests an anti-ischemic action, perhaps through changes in myocardial blood flow. In 9 patients, regional myocardial blood flow was studied with positron emission tomography before and after 6 weeks of spinal cord stimulation, both at rest and during a dipyridamole stress test. Frequency of anginal attacks ana consumption of short-acting nitrates were assessed by patient diaries. Exercise duration and time to angina were measured with treadmill exercise tests. After 6 weeks of stimulation, both frequency of daily anginal attacks and nitrogen consumption decreased (3.7 ± 1.7 vs 1.4 ± 1.0 [p < 0.01] and 2.8 ± 2.2 vs 1.1 ± 1.2 tablets [p = 0.01], respectively); exercise duration and time to angina increased (358 ± 165 vs 493 ± 225 seconds [p < 0.01] and 215 ± 115 vs 349 ± 213 seconds [p = 0.02], respectively); and ST-segment depression during dipyridamole stress testing was reduced (0.17 [0 to 0.5] mV vs 0.09 [0 to 0.2] mV, p = 0.04) (all data mean ± SD). Total resting blood flow remained unchanged (115 ± 29 vs 127 ± 31 ml/min/100 g, p = 0.31), but flow reserve decreased (146 ± 43% vs 122 ± 39%, p = 0.04). The coefficient of variation of flow, representing flow heterogeneity, decreased after treatment, both at rest (20.1 ± 3.8% vs 17.4 ± 2.6%, p = 0.04) and after dipyridamole stress (26.2 ± 4.4% vs 22.9 ± 5.5%, p = 0.02). Thus, spinal cord stimulation is clinically effective due to homogenization of myocardial blood flow. Since flow reserve decreases despite clinical improvement, the dipyridamole effect may be blunted by spinal cord stimulation.

Comparative Effects of Idazoxan, Prazosin, and Yohimbine on Coronary Ligation-Induced Arrhythmias in Spontaneously Hypertensive Rats

We investigated whether certain drugs with alpha-adrenergic antagonist activity display anti-arrhythmic effects in hypertensive animals subjected to acute coronary artery ligation. The left anterior descending coronary artery (LAD) was ligated in open-chest pentobarbital-anesthetized spontaneously hypertensive rats (SHR); arrhythmias were subsequently recorded for 30 min. Drugs were administered intravenously, (i.v.) 5 min before ligation. The effects of yohimbine and idazoxan were compared with those of prazosin. Prazosin (100 mu g/kg) increased the occurrence of ventricular tachycardia (VT). In contrast, yohimbine 1.6 mg/kg decreased both the occurrence and the duration of VT and the occurrence and the duration of ventricular fibrillation, (VF). The results obtained with idazoxan 1 mg/kg were similar to those with yohimbine. The ECG alterations induced by coronary artery ligation in rats treated with yohimbine and idazoxan were more pronounced than in controls and in rats treated with prazosin, suggesting that the antiarrhythmic effects observed were not mediated by antiischemic activity. The protective effects against ligation-induced arrhythmias were preceded by a hypotensive effect and a decrease in the rate-pressure product in yohimbine-treated but not in idazoxan-treated animals. In rats treated with prazosin, more arrhythmic events were observed, although hemodynamics were similar to those in rats treated with yohimbine. Our results suggest that the yohimbine-induced antiarrhythmic action is not due to an alteration of conduction or repolarization rates. In this model, yohimbine and idazoxan appear to protect against ligation-induced arrhythmias. These data suggest that drugs with alpha-adrenergic properties might influence the nervous drive to the heart in SHR with cardiac ischemia. However, further investigations are needed to ascertain whether the alpha-adrenoceptor blockade participates in this effect.

The anti-ischemic drugs defibrotide and oligotide analogously inhibit leukocyte-endothelial cell adhesion in vitro.

Defibrotide (a polydeoxyribonucleotide) and oligotide (an oligodeoxyribonucleotide) obtained from mammalian single-stranded DNA, have been demonstrated to have anti-ischemic activity in some experimental models of ischemia/reperfusion of kidney in rats. We hypothesized that their anti-ischemic activity could be related to an inhibition of leukocyte-endothelial cell adhesion and also the consequent generation of oxygen free radicals by leukocytes. We studied the in vitro adhesion of neutrophils to human umbilical vein endothelial cells under basal conditions and following neutrophil or endothelial cell activation (using 10(-7) fMLP and 500 U/ml TNF-alpha, respectively). Defibrotide and oligotide significantly inhibited neutrophil adhesion to endothelial cells (after only 1 min of drug treatment). When the anti-LFA-1 70H12 F(ab)2 monoclonal antibody was used, the drugs exerted only slight additional inhibition of the adhesion of fMLP-activated neutrophils to endothelium. These results, confirmed in NIH/3T3-ICAM-1-transfected cells, demonstrate that defibrotide and oligotide interfere with leukocyte adhesion to endothelial cells by an LFA-1-dependent mechanism.

Cardioselective antiischemic ATP-sensitive potassium channel openers. 4. Structure-activity studies on benzopyranylcyanoguanidines: replacement of the benzopyran portion.

The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac selective antiischemic ATP-sensitive potassium channel (KATP) opener (4) are described. Systematic modification of the benzopyran ring of 4 resulted in the discovery of a structurally simpler acyclic analog (8) with slightly lower antiischemic potency than the lead compound 4. Further structure-activity studies on the acyclic analog 8 provided the 2-phenoxy-3-pyridylurea analog 18 with improved antiischemic potency and selectivity compared to the benzopyran-based compound 4. These data demonstrate that the benzopyran ring of 4 and its congeners is not mandatory for antiischemic activity and cardiac selectivity. The results described in this paper also show that, as for the benzopyran class of compounds, the structure-activity relationships for the antiischemic and vasorelaxant activities of KATP openers are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve KATP opening as their cardioprotective effects are abolished by pretreatment with the KATP blocker glyburide.

The antianginal agent ranolazine is a weak inhibitor of the respiratory Complex I, but with greater potency in broken or uncoupled than in coupled mitochondria

Ranolazine (RS-43285) has shown antianginal effects in clinical trials and cardiac anti-ischaemic activity in several in vivo and in vitro animal models, but without affecting haemodynamics. Its mechanism is thought to mainly involve a switch in substrate utilisation from fatty acids to glucose to, thus, improve efficiency of O 2 use; however, its precise molecular target(s) are unknown. In studies to investigate its action further, using isolated rat heart mitochondria, ranolazine was found to weakly inhibit (pIC 50, values > 300 μM) respiration by coupled mitochondria provided with NAD +-linked substrates but not with succinate. With broken mitochondrial membranes or submitochondrial particles, ranolazine inhibited NADH but not succinate oxidation and with pIC 50 values in the lower range of 3–50 μM. Studies with different electron acceptors and respiratory inhibitors indicated that it inhibits respiratory Complex I at a site between ferricyanide and menadione and ubiquinone-1 reduction ( i.e. at a similar locus to rotenone). However, unlike rotenone, ranolazine was an uncompetitive inhibitor with respect to ubiquinone-1. Ranolazine inhibition of Complex I was reversible and occurred also with mitochondria from pig, guinea pig, and human heart, and rat liver. Further studies using rat heart mitochondria in different energisation states ( i.e. broken, uncoupled, or coupled) showed a 50–100-fold shift to greater potency of ranolazine in the broken compared to the coupled; with the uncoupled it was about 2-fold less potent than the broken. These shifts in potency were not found with rotenone or amytal. Studies with radiolabelled ranolazine showed that it bound to mitochondrial membranes with greater affinity in the broken compared to the coupled or uncoupled conditions. Rotenone displaced radiolabelled ranolazine from its binding site. This property of ranolazine may play some role in its anti-ischaemic activity.

Coronary vasomotion during dynamic exercise: Influence of intravenous and intracoronary nicardipine

Our aim was to evaluate the influence of a calcium channel blocking agent of the dihydropyridine group (nicardipine) on coronary vasomotion during dynamic exercise. Coronary vasomotion plays an important role in the pathophysiology of myocardial ischemia. Twenty-nine patients with coronary artery disease were studied at rest and during bicycle exercise with the use of biplane quantitative coronary angiography. Twelve patients without pretreatment (group 1) served as control subjects. Seventeen patients (group 2) received nicardipine, either 0.2 mg by intracoronary injection (n = 9) or 2.5 mg intravenously (n = 8) before exercise. In the control group there was exercise-induced vasoconstriction (-29%, p < 0.001) of the stenotic segment but coronary vasodilation (+22%, p < 0.05) of the normal vessel segment. In group 2, nicardipine induced coronary vasodilation of both the normal (+16%, p < 0.001) and the stenotic vessel segment (+35%). During subsequent exercise there was some additional vasodilation of normal (+4%, p = NS) and stenotic arteries (+5%, p = NS). There was no difference between either intracoronary or intravenous nicardipine with regard to vasodilation. Application of sublingual nitroglycerin was associated with significant vasodilation of the normal vessel segment in groups 1 (+18%, p < 0.05) and 2 (+15%, p < 0.001). The stenotic vessels showed a significant increase in percent cross-sectional area after nitroglycerin in groups 1 (+12%, p = NS) and 2 (+51%, p < 0.001). Exertional angina pectoris occurred less frequently in group 2 (18%) than in group 1 (67% [p < 0.005 vs. group 2]); group 2 also had a smaller increase in mean pulmonary artery pressure (+14 vs. +21 mm Hg, p < 0.05). Exercise induces vasoconstriction of stenotic, but vasodilation of normal, coronary vessel segments. Intravenous and intracoronary nicardipine prevent vasoconstriction of stenotic coronary arteries during exercise and exert a significant anti-ischemic effect. The combination of two anti-ischemic drugs, nitroglycerin and nicardipine, has an additive effect on coronary vasomotion that is seen only in the stenotic vessel segment. Thus, the anti-ischemic action of nicardipine is mainly due to a primary effect on coronary vasomotor response rather than to secondary effects such as changes in loading conditions.

Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study

Objectives. We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina pectoris taking extended-release nifedipine.Background. Heart rate reduction is considered an important pharmacologic mechanism for providing anginal pain relief and anti-ischemic action in patients with chronic stable angina, suggesting a benefit for sinus node-inhibiting drugs.Methods. In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angina at baseline, and after randomization they performed a serial exercise test 3 h after each dose for 4 weeks.Results. Zatebradine reduced rest heart rate both at 4 weeks ([mean ± SEM] 12.9 ± 1.23 vs. 2.3 ± 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 ± 1.2 vs. 3.4 ± 1.2 [placebo] beats/min, p < 0.0001). Despite the significant effects on heart rate at rest and exercise, there were no additional benefits of zatebradine from placebo baseline in measurements of total exercise duration, time to 1-mm ST segment depression or time to onset of angina. Subjects taking zatebradine also had more visual disturbances as adverse reactions.Conclusions. Zatebradine seems to provide no additional anti-anginal benefit to patients already receiving nifedipine, and it raises questions regarding the benefit of heart rate reduction alone as an antianginal approach to patients with chronic stable angina.

Cardioselective anti-ischemic ATP-sensitive potassium channel openers. 3. Structure-activity studies on benzopyranyl cyanoguanidines: modification of the cyanoguanidine portion.

Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (KATP) opener (3) are described. The cyanoguanidine moity appears to be optimal since increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/selectivity. Similarly, unfavorable results are obtained by replacement of the aniline nitrogen with other linkers (CH2, S, O). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Constraining the urea moiety into a benzimidazolone or imidazolone ring retains anti-ischemic potency with significant improvement in cardiac selectivity. As shown by the ratio of vasorelaxant and anti-ischemic potencies, the cardiac selectivity in vitro varies over 3 orders of magnitude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally different KATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofenamic acid), the mechanism for the anti-ischemic actions of these compounds still appears to involve the opening of KATP.

Nitrovasodilators ITF 296 and isosorbide dinitrate exert antiischemic activity by dilating coronary penetrating arteries.

We examined the effect of the novel nitrovasodilator ITF 296 and isosorbide dinitrate (ISDN) on myocardial blood flow (BF) distal to a coronary artery stenosis. Eleven dogs with a Doppler velocity probe, hydraulic occluder, and indwelling microcatheter in the left anterior descending coronary artery (LAD) were studied during treadmill exercise in the presence of a coronary artery stenosis. On separate days, the effects of ITF 296 in doses of 4 and 20 micrograms/kg/min i.v. or ISDN 20 micrograms/kg/min i.v. were compared. Coronary pressure distal to the stenosis was maintained constant during the control period and after administration of either nitrovasodilator. Neither ITF 296 nor ISDN significantly altered heart rate (HR), arterial blood pressure (BP), or left ventricular end-diastolic pressure (LVEDP). In the presence of a stenosis that decreased distal coronary pressure to 58 +/- 4 mm Hg, mean myocardial BF measured with microspheres was 0.91 +/- 0.08 ml/min/g in the LAD-dependent region and 2.36 +/- 0.11 ml/min/g in the posterior control region, respectively. With no change in distal coronary pressure, ITF 296 increased mean BF in the LAD region to 1.25 +/- 0.05 ml/min/g (4 micrograms/kg/min i.v.) and 1.40 +/- 0.10 ml/min/g (20 micrograms/kg/min i.v.), whereas ISDN (20 micrograms/kg/min i.v.) increased flow to 1.28 +/- 0.18 ml/min/g (each p < 0.05). The increase in BF occurred exclusively in the deeper layers, with no change in subepicardial BF. Consequently, the endocardial/epicardial (endo/epi) BF ratio increased from 0.33 +/- 0.04 during control stenosis to 0.70 +/- 0.10 after ITF 296 (20 micrograms/kg/min), and to 0.56 +/- 0.08 after ISDN (each p < 0.05). Neither ITF 296 nor ISDN had an effect on myocardial BF in the normally perfused control region. Therefore, both ITF 296 and ISDN improved BF to the deeper myocardial layers distal to a coronary artery stenosis. This effect occurred without alterations in stenosis severity or diastolic intraventricular pressure, suggesting that these agents act by dilating the penetrating arteries which deliver BF to the subendocardium.

The negative inotropic and chronotropic effects of intravenous R 56865 during percutaneous transluminal coronary angioplasty.

The present study was designed to evaluate the potential anti-ischaemic activity of R 56865 in patients with coronary artery disease, scheduled to undergo percutaneous transluminal coronary angioplasty (PTCA). At baseline a complete haemodynamic profile, including cardiac output and coronary sinus blood flow (CSBF) was obtained. In addition, left ventricular pressure and contractility parameters were measured. These parameters were also measured before and after additional balloon inflations, preceded by placebo and R 56865 i.v. R 56865 was infused intravenously at three different dosages, namely: 20 mg (n = 8), 30 mg (n = 2), 40 mg (n = 2). No significant differences were observed between placebo and R 56865 (20 mg) concerning time to onset and duration of ST-segment changes and symptomatic angina pectoris, respectively. The other parameters did not show differences compared with the baseline values when R 56865 (20 and 30 mg) was infused. However, the two patients receiving a dose of 40 mg R 56865 developed a dramatic decrease in systolic and diastolic blood pressure, left ventricular (LV) systolic pressure, peak positive dP/dt and the CSBF (ranging from 30-50%), while the LV end-diastolic pressure increased by 100%. The two patients who received this dose became pale and cyanotic and did not respond to verbal commands. In summary, no anti-ischaemic effects of R 56865 were observed under these conditions, whereas at the highest dose (40 mg) R 56865 induced hypotension and a reduction in cardiac contractile force.