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The inhibitory effects of sodium 3-guanidinocarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ylmethyl sulfate monoethanolate (TY-51924) are selective for Na(+)/H(+) exchanger (NHE)-1 in PS120 cells expressing human NHE isoforms assayed by NH(4)Cl prepulse technique. The median inhibitory concentrations (micromolar) of TY-51924 were 0.095 ± 0.008 (NHE-1), 0.621 ± 0.093 (NHE-2), and >100 (NHE-3). In anesthetized dogs subjected to 90 minutes ischemia/300 minutes reperfusion, intravenous bolus TY-51924 at 5 and 10 mg/kg administered 5 minutes before reperfusion reduced infarct size. The infarct size reduction ratios of TY-51924 at 5 and 10 mg/kg versus vehicle were 32.8% and 52.4%, respectively. But TY-51924 at 10 mg/kg administered 10 minutes after reperfusion did not reduce infarct size. In 2-step intravenous infusion initiated 15 minutes before reperfusion, TY-51924 at low dose (3.8 mg/kg per 5 minutes, then 6.2 mg/kg per 20 minutes) and at high dose (7.6 mg/kg per 5 minutes, then 12.4 mg/kg per 20 minutes) reduced infarct size. The infarct size reduction ratios of TY-51924 at 10 and 20 mg/kg versus vehicle were 39.2% and 51.7%, respectively; plasma drug concentrations at reperfusion were 16.8 and 38.8 μg/mL, respectively. This indicates that maintaining a plasma drug concentration of >20 μg/mL at reperfusion enables TY-51924 to reduce infarct size by inhibiting the NHE, which is activated during the early period of reperfusion.

Animal data strongly support a role for inflammation in myocardial ischemia reperfusion injury. Attempts at cardioprotection by immunomodulation (such as with the specific C5 antibody pexelizumab) in humans have been disappointing. We hypothesized that a broader spectrum antiinflammatory agent might yield successful cardioprotection. The serine protease inhibitor nafamostat (FUT-175), which is already in clinical use, is a potent antiinflammatory synthetic serine protease inhibitor with anticomplement activity that we tested in a well-established rabbit model of 1 hour of myocardial ischemia followed by 3 hours of reperfusion. Compared to vehicle-treated animals, nafamostat (1 mg/kg of body weight) administered 5 minutes before reperfusion significantly reduced myocardial injury assessed by plasma creatine kinase activity (38.1 +/- 6.0 versus 57.9 +/- 3.7I U/g protein; P < 0.05) and myocardial necrosis (23.6 +/- 3.1% versus 35.7 +/- 1.0%; P < 0.05) as well as myocardial leukocyte accumulation (P < 0.05). In parallel in vitro studies, Nafamostat was a significantly more potent broad spectrum complement suppressor than C1 inhibitor. Nafamostat appears to have capability as an inhibitor of both complement pathways and as a broad-spectrum antiinflammatory agent by virtue of its serine protease inhibition. Administration of nafamostat before myocardial reperfusion after ischemia produced significant, dose-dependent cardioprotection. Reduced leukocyte accumulation and complement activity seem involved in the mechanism of this cardioprotective effect.

The aim of the study was to evaluate the cardioprotective and antiarrhythmic effects of intravenous Na+/H+ blockers (cariporide and SM-20550) in a rat model of ischemia and a long period reperfusion (14 days). This model allowed study of the role of Na+/H+ exchanger against late myocardial infarct expansion and left ventricular dysfunction. Each compound was administered 5 min before ischemia. Cariporide (from 0.16 mg/kg) and SM-20550 (from 0.04 mg/kg) significantly and dose-dependently reduced the number of ventricular premature beats during ischemia. The duration of ventricular tachycardia was importantly shortened in the presence of cariporide (0.63 mg/kg) and SM-20550 (0.16 mg/kg). Furthermore, cariporide (0.63 mg/kg) and SM-20550 (from 0.04 mg/kg) significantly reduced the infarct expansion: 43 +/- 2% in the cariporide group and 42 +/- 2% at 0.16 mg/kg SM-20550 versus 48 +/- 1% in the vehicle group. Cariporide and SM-20550 significantly prevented the left ventricular free wall thinning associated with the thickness ratio, suggesting a significant reduction of the ventricular dilation. Cariporide and SM-20550 significantly improved the negative dP/dtmax, suggesting a partial restoration of the cardiac relaxation. Collectively, Na+/H+ blockers administered before ischemia reduced arrhythmias and also prevented the remodeling process of the heart during postinfarction.

The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine), which possesses a strong cardioprotective effect to ischemia-reperfusion, was assessed for different pharmacological actions that may underlie its cardioprotective effect. In the living rat ME10092 decreased the blood pressure and heart rate in a dose-dependent manner. We found ME10092 to bind to alpha 1- and alpha 2-adrenoreceptors with moderate affinity (Ki values 1-4 microM), and to block adrenaline-elicited contractile responses in isolated guinea pig aortas. Our results indicate that ME10092 possesses a certain anti-oxidant profile. Thus, in a competitive manner and with low affinity it inhibited the bovine milk xanthine oxidase enzyme, as well as NAD(P)H oxidase driven oxyradical formation in membrane fractions isolated from the rat brain. By using electron paramagnetic resonance we here show that, after its systemic administration, ME10092 modulates the nitric oxide (NO) content in several tissues of the rat in a time-dependent manner. However, in vitro ME10092 inhibited the activities of nitric oxide synthases nNOS and eNOS, but not that of iNOS. Our data give evidence that the cardioprotective effect of ME10092 could be mediated through pharmacological mechanisms that include some modulation of NO production, as well as possible inhibition of radical formation during ischemia-reperfusion.

Adenosine triphosphate-sensitive potassium channel (KATP) openers protect ischemic myocardium by direct protection of cardiac myocytes, which is thought to be a result of activation of mitochondrial KATP (mKATP). KATP is expressed in skeletal muscle, and the purpose of this study was to determine the effect of the mKATP opener BMS-191095 on infarct size in an isolated gracilis model of ischemia and reperfusion in dogs. The right and left gracilis muscles were isolated in anesthetized dogs except for the artery and vein supplying these muscles (pedicle). BMS-191095 (0.4 mg) or vehicle were infused directly into the artery supplying each gracilis muscle (each animal had one drug-treated and one vehicle-treated muscle). The pedicle was completely occluded for 5 hours followed by 48 hours of reperfusion, after which infarct size was determined. In the vehicle-treated gracilis muscles, significant necrosis was observed (82% +/- 3% of gracilis muscle). BMS-191095 significantly reduced the infarct size in the contralateral gracilis muscle (55% +/- 6%). Reflow into the gracilis muscle was significantly greater in BMS-191095-treated muscles. BMS-191095 appears to reduce damage in ischemic/reperfused skeletal muscle, suggesting that mKATP activation is an important protective mechanism in this tissue.

Cold cardioplegia protects against reperfusion damage. Blocking Na+/H+ exchange may be as protective as cardioplegia by improving the left ventricular pressure (LVP)-[Ca2+] relationship after cold ischemia. In guinea pig isolated hearts subjected to cold ischemia (4 h, 17 degrees C) and reperfusion, the cardioprotective effects of a Krebs-Ringer (KR) solution, a cardioplegia solution, a KR solution containing the Na+/H+ exchange inhibitor eniporide (1 microM), and a cardioplegia solution containing eniporide were compared. Treatments were given before and initially after cold ischemia. Systolic and diastolic [Ca2+] were calculated from indo-1 fluorescence transients recorded at the LV free wall. During ischemia, diastolic [Ca2+] increased in each group but more so in the KR group. Peak systolic and diastolic [Ca2+] on initial reperfusion were highest after KR and smallest after cardioplegia + eniporide. After reperfusion, systolic-diastolic LVP (% of baseline) and infarct size (%), respectively, were KR, 47 +/- 3%, 37 +/- 4%; cardioplegia, 71 +/- 5%*, 20 +/- 2.2%*; KR + eniporide, 73 +/- 5%*, 11 +/- 3%* dagger; and cardioplegia + eniporide 77 +/- 3%*, 10 +/- 1.4%* dagger (*P

Using both 31P and 1H cardiac magnetic resonance techniques, it is possible to monitor the functional (ejection fraction [EF]) and biochemical (pH) status of the heart following a reperfused ischemic insult. This study assessed the effects of Na+/H+ exchange inhibition with cariporide in a closed-chest canine ischemia/reperfusion model. Dogs received 1-mg/kg cariporide treatments for 3 days after occlusion, but were monitored for 10 days. Baseline intracellular pH (+/-SEM) for the control and treated groups were 7.10 +/- 0.03 and 7.14 +/- 0.04, respectively, and dropped to 6.25 +/- 0.08 and 6.38 +/- 0.08 during occlusion. There was a significant increase in pH from occlusion to early reperfusion in the control group (P = 0.03) but, during the same time period, this increase was not seen in the cariporide group. There was a significant (P = 0.01) drug interaction in recovery of EF over the 10-day protocol. Individual time-point analysis revealed significant differences at immediate reperfusion through day 3 (73.9% +/- 2.5%, 84.5% +/- 3.1%; baseline normalized EF controls and cariporide, respectively). Neither pH nor EF measurements were significantly different between the groups at day 10. Despite early functional and metabolic benefits, infarct size, as measured at day 10, was 13.2% +/- 2.2% for the controls and 11.8% +/- 2.3% for the cariporide group (NS). Thus there were no long-term cariporide functional or biochemical benefits.

AMP 579, an adenosine A /A receptor agonist, is cardioprotective when administered at reperfusion. Pretreatment with the Na /H exchanger inhibitor cariporide or ischemic preconditioning (PC) also limits infarct size. To gain insight into the mechanism of AMP 579 we investigated whether its protection could be added to that from either cariporide or PC. rabbit hearts were subjected to 45 min of regional ischemia followed by 3 h of reperfusion. Infarct size in the control group was 55.8 +/- 3.9% of the risk zone. PC significantly reduced infarct size to 26.0 +/- 6.7% (p<0.05). AMP 579 (30 micro g/kg) given just before reperfusion followed by 3 micro g/kg/min infusion for 70 min also limited infarct size (32.1 +/- 1.8%,) but the combination of AMP 579 and PC showed a significantly greater limitation of infarct size (5.5 +/- 2.7%, p < 0.05). Because cariporide pretreatment was so protective (8.5 +/- 3.7% infarction), we had to increase the ischemic insult to 60 min to test for any additive effect of the combination of AMP 579 + cariporide. Infarct size in the untreated group was 66.0 +/- 4.9% of the risk zone. Cariporide (0.5 mg/kg) 5 min prior to ischemia significantly reduced infarct size to 41.5 +/- 7.7%. When cariporide pre-treatment was combined with AMP 579 at reperfusion, infarction was further limited (14.2 +/- 4.5%). Because AMP 579's protection can be added to that of either cariporide or PC, AMP 579's mechanism of protection probably differs from either of them. The combination of AMP 579 + cariporide was particularly efficacious and could be useful in the surgical setting.

Nitric oxide (NO) is a potent inhibitor of platelet aggregation. However, the benefits of NO-based therapies can be confounded by concomitant hypotension. Monophosphoryl lipid A (MLA) is a nontoxic derivative of endotoxin that purportedly increases nitric oxide synthase (NOS) activity and, presumably, NO production, yet has a hemodynamically benign profile. Thus our aims were to determine whether (a) MLA attenuates in vivo platelet aggregation in damaged and stenotic canine coronary arteries by a NO-mediated mechanism but without reductions in arterial pressure; and (b) the platelet inhibitory effects are manifest in vitro. To address the first aim, anesthetized dogs underwent coronary injury + stenosis, resulting in cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgement of platelet-rich thrombi. In protocol I, dogs received MLA (100 microg/kg + 40 microg/kg/h) or vehicle beginning 15 min before stenosis. Protocol II was identical, except the NOS inhibitor aminoguanidine was coadministered with MLA/vehicle. Coronary patency was assessed throughout the initial 3 h after injury + stenosis. Infusion of MLA did not result in hypotension. However, in protocol I, the median nadir of the CFVs was higher (2.1 vs. 0.8 ml/min; p < 0.05), median duration of total thrombotic occlusion tended to be reduced (0 vs. 10.4 min; p = 0.1), and mean flow-time area, expressed as a percentage of baseline flow, was increased (53 +/- 9% vs. 33 +/- 3%; p < 0.05) in MLA-treated versus vehicle-treated dogs. In contrast, in protocol II, vessel patency was comparable in both groups. Finally, whole blood impedance aggregometry (protocol HI) revealed a significant reduction in the in vitro platelet aggregation in blood samples receiving exogenous MLA, which was blocked by coadministration of exogenous aminoguanidine. Thus MLA attenuates platelet-mediated thrombosis in both damaged and stenotic canine coronary arteries and in vitro, possibly by an NO-mediated mechanism, but without concomitant hypotension.

Intracellular calcium ([Ca]i) overload on reperfusion may be one of the mechanisms responsible for ischemia-induced regional myocardial dysfunction. Because inhibiting the Na-H exchanger (NHE) limits intracellular sodium ([Na]i) and subsequent [Ca]i accumulation, we hypothesized that NHE inhibition would attenuate regional dysfunction in response to 25 cycles of ischemia (I, 2-min) and reperfusion (R, 8-min) of the left circumflex coronary artery (LCx) in conscious swine. Six animals were instrumented to measure arterial pressure, regional myocardial blood flow (colored microspheres), systolic wall thickening (WTh) in the normally perfused (left anterior descending, LAD) and LCx regions (sonomicrometry), LCx blood flow velocity (Doppler), and to reversibly occlude the LCx (hydraulic occluder). Each animal completed three protocols separated by 7 days: ISC, 25 I/R cycles; CAR, 25 I/R cycles + NHE inhibition (cariporide); and VEH, vehicle administration for 4.2 h. Regional myocardial blood flow was measured during LCx occlusion in the first protocol and 10 min after I/R 25 in all protocols. Systemic hemodynamics were similar among and within each protocol. Blood flow measured during LCx occlusion confirmed that perfusion was reduced (p < 0.05) to this compared with the LAD region. During ISC, LCx WTh was reduced (p < 0.05) after five IR cycles, and a stable reduction (approximately 55% of baseline; p < 0.05) was present after 20 I/R cycles. During CAR, LCx systolic WTh was reduced (p < 0.05) only after 15 and 25 I/R cycles (approximately 80 and 72%, respectively). The decrease in LCx WTh was greater in ISC than in CAR (p < 0.05). LCx WTh was not altered during VEH, while LAD WTh was similar within and among all protocols. Regional blood flow measured after 25 I/R cycles was not different among protocols. Our results indicate that NHE inhibition delays the onset and limits the degree of regional dysfunction in response to repeated bouts of ischemia and reperfusion.

We determined whether U-89232, a derivative of the ATP-sensitive potassium (KATP) channel opener cromakalim, is cardioselective and whether its action on the myocardium is still sensitive to glibenclamide. Experiments were performed in open-chest pigs subjected to a 60-min occlusion of the left anterior descending coronary artery (LADCA) and to 2 h of reperfusion. Four groups of animals were studied (n = 6 each). Animals received either U-89232, 3 mg/kg i.v. over a 15-min period (U), or glibenclamide, a selective KATP channel blocker, 1 mg/kg i.v. over a 15-min period (GLI) before the LADCA occlusion. In the GLI + U group, first glibenclamide (1 mg/kg/15 min) and then U-89232 (3 mg/kg/15 min) were infused before the 60 min of ischemia. Saline-treated animals served as controls (CON). Hemodynamic parameters were continuously monitored. Regional contractile wall function was quantified with ultrasonic crystals aligned to measure wall thickening. At the end of the protocol, infarct size (IS, as percentage of risk region) was determined by incubating the myocardium with p-nitrobluetetrazolium. With comparable myocardium at risk, infusion of U-89232 before 60 min of LADCA occlusion significantly reduced infarct size (IS, 18.5 +/- 3.7%; p < 0.001 vs. 63.2 +/- 3.3% for the controls), whereas glibenclamide had no effect on infarct size (IS, 69.5 +/- 4.4%). The administration of glibenclamide before U-89232 infusion blocked the infarct size-reducing effect of U-89232 [IS, 61.2 +/- 9.1 (NS) vs. controls and p < 0.001 vs. U]. Infusion of U-89232 had no effect on hemodynamic parameters or on regional wall function. At least in a pig model, U-89232 appears to be a cardioselective KATP channel opener, because in the absence of hemodynamic alterations, it exhibits a profound cardioprotective effect, which is fully reversible by blocking KATP channels.

ATP-sensitive potassium channel (KATP) openers have direct protective effects on ischemic myocardium that are independent of vasorelaxation. Because reference KATP openers (e.g., cromakalim, pinacidil) are potent relaxants of smooth muscle, their utility for treating myocardial ischemia may be limited by hypotension. Efforts aimed at development of a cardioprotective KATP opener with less vasorelaxant activity led to identification of the arylcyanoguanidine analogue BMS-180448. In globally ischemic rat hearts, BMS-180448 was cardioprotective (EC25 for increasing time to contracture = 2.5 microM), with potency equal to that of cromakalim (EC25 = 4.9 microM) despite being significantly less potent as a peripheral smooth muscle relaxant (methoxamine-constricted rat aorta). The cardioprotective effects of BMS-180448 in isolated perfused rat heart were abolished by the KATP blockers glyburide and sodium 5-hydroxydecanoate, indicating KATP involvement in its mechanism of action. Further confirmation was obtained by demonstration of single KATP opening by BMS-180448 in guinea pig cardiac myocytes. In anesthetized dogs, cromakalim was > 100-fold more potent than BMS-180448 in decreasing blood pressure (BP). In anesthetized dogs subjected to 90-min coronary occlusion/reperfusion, BMS-180448 reduced infarct size (IS) by 50% without hemodynamic effects. BMS-180448 provides the opportunity to explore the cardioprotective actions of this class of agents without the possible complications (hypotension, coronary steal) that may be caused by the currently available KATP openers.

Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) exist in cardiac tissue and a potential role in the pathogenesis of myocardial ischemia was hypothesized early after their discovery. Studies in in vitro models of myocardial ischemia and reperfusion have indicated that KATP openers, as a class, exert protective effects. This has been assessed by determination of recovery of contractile function, inhibition of contracture, or inhibition of necrosis. This protective effect appears to be exerted directly on the myocardium and is not dependent on peripheral or coronary dilator activities. These protective effects are uniformly abolished by blockers of KATP. The protective effects of KATP openers are accompanied by a conservation of myocardial energy during ischemia, and this occurs despite a relative lack of cardiodepressant effects. In vivo studies have shown more variable results with some investigators showing efficacy and others not showing efficacy. The lack of efficacy for some investigators may be related to the potent vasodilator activity of the KATP openers used. Efficacy for KATP openers has been shown in canine models of infarction and stunned myocardium. KATP blockers also appear to abolish the protective effects of KATP openers in these models. Future work on KATP openers is focused on the determination of the molecular mechanism of action for the cardioprotective effects of these agents, development of tissue selectivity, and the importance of action potential shortening in mediating cardioprotection.

KATP openers are recognized as having a therapeutic potential for the treatment of various cardiovascular and noncardiovascular diseases. However, the first-generation agents open KATP in a variety of tissues that limit their potential clinical utility. This review describes our studies aimed at the identification of a common pharmacophore among structurally diverse KATP openers and the discovery of tissue-selective agents that may offer advantages over the first-generation agents for the treatment of cardiovascular diseases. Compounds (e.g., BMS-182264) combining the structural features of KATP openers cromakalim and pinacidil, show smooth-muscle relaxing and antihypertensive activities comparable to their predecessors, indicating cromakalim and pinacidil may express their biologic effects through similar structural requirements. The hypothesis about common features is further supported by radioligand-binding studies showing cromakalim, pinacidil, and the combination compound BMS-182264 bind to a similar receptor site in rat aortic smooth-muscle cells. Regardless of having a pharmacologic profile similar to cromakalim and pinacidil in vascular smooth muscle, BMS-182264 had no effect on action potential duration in guinea pig papillary muscle, indicating smooth-muscle selectivity for BMS-182264. We demonstrate that no correlation exists between anti-ischemic and smooth-muscle relaxing potencies for a variety of structurally different KATP openers. Efforts to find KATP openers selective for the ischemic myocardium led to the identification of BMS-180448 which, despite having similar anti-ischemic potency to cromakalim, was significantly less active as a smooth-muscle relaxant. This compound was shown to be efficacious as an anti-ischemic agent in vivo without affecting hemodynamic variables, a potential liability of first-generation compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

We tested the hypothesis that opening myocardial ATP-dependent K+ (ATP-K) channels by administration of (-)-pinacidil or (-)-3-pyridyl pinacidil intracoronarily (i.c.) either during ischemia or as pretreatment could decrease infarct size in a canine model of ischemia-reperfusion injury in anesthetized male hounds subjected to 90-min left circumflex coronary artery (LCX) occlusion followed by 5-h reperfusion. Drugs were administered by one of two protocols. In the postocclusion treatment protocol (protocol post), either vehicle or (-)-3-pyridyl pinacidil [0.25 micrograms/kg/min (low dose) or 1 micrograms/kg/min (high dose)] was infused i.c. distal to the site of coronary artery occlusion, through LCX beginning 10 min after LCX occlusion and continuing until 10 min after the beginning of reperfusion. In the preocclusion treatment protocol (protocol pre), vehicle, low dose (-)-3-pyridyl pinacidil, or (-)-pinacidil (1 micrograms/kg/min) was infused i.c. distal to the site of coronary artery occlusion through the LCX beginning 10 min before occlusion and continuing until the end of the experiment. In both protocols, (-)-pinacidil and (-)-3-pyridyl pinacidil failed to demonstrate a decrease in infarct size from that of the vehicle-treated groups. In protocol post, the mean sizes of the infarcts in the vehicle, low-dose, and high-dose (-)-3-pyridyl pinacidil-treated groups were 26.4 +/- 5.0, 35.6 +/- 6.6, and 28.9 +/- 6.1% of the area at risk, respectively. In protocol pre, the mean sizes of the infarcts in the vehicle, (-)-pinacidil, and low dose (-)-3-pyridyl pinacidil-treated groups were 29.4 +/- 1.7, 27.0 +/- 3.9, and 35.6 +/- 4.1% of the area at risk, respectively. Neither subepicardial nor subendocardial blood flow in the ischemic zone, measured by radioactive microspheres, was significantly different among groups in either protocol. In protocol post, however, the endocardial/epicardial blood flow ration in the nonischemic zone was decreased by (-)-3-pyridyl pinacidil. In addition, the ischemic zone (LCX)/nonischemic left anterior descending coronary artery (LAD) zone blood flow ratio in the subepicardial region were decreased by (-)-3-pyridyl pinacidil. These observations suggest that the drug may shift blood flow away from the ischemic zone in general and away from the endocardium in particular. In protocol pre, the LCX/LAD ratio tended to decrease with both drugs, but the difference achieved statistical significance only with (-)-3-pyridyl pinacidil (low dose).(ABSTRACT TRUNCATED AT 400 WORDS)

P-1075 is a cyanoguanidine ATP-sensitive potassium channel opener (KATP) that relaxes smooth muscle and shortens myocardial action potential duration (APD) at concentrations in the nanomolar range. Most KATP openers have antiischemic potencies in the micromolar range. We wished to determine if the relatively high cardiac potency of P-1075 could be translated into high antiischemic potency. Isolated rat hearts were pretreated with 10-300 nM P-1075 followed by 25-min global ischemia and 30-min reperfusion. Before ischemia, P-1075 had little effect on cardiac function, although it did increase coronary flow. During ischemia, P-1075 significantly increased time to contracture in a concentration-dependent manner (EC25 = 57 nM). P-1075 also improved recovery of contractile function significantly and reduced lactate dehydrogenase (LDH) release during reperfusion (at concentrations > or = 60 nM). Treatment with 75 nM P-1075 both before and after ischemia did not add to the protective effects observed after preischemic treatment. Treatment with P-1075 only during reperfusion was not cardioprotective. The protective effects of P-1075 were completely abolished by the KATP blocker glyburide (100 nM). In addition, P-1075 relaxed methoxamine-constricted aorta with a higher potency relative to antiischemic potency. Thus, P-1075 has cardioprotective effects similar to that of other reference KATP openers, except that P-1075 is approximately 100-fold more potent relative to most other tested KATP openers. These results demonstrate that P-1075 is the first KATP opener that protects ischemic myocardium at nanomolar concentrations.

The quality of life (QL) was evaluated in a 6 month double-blind trial in six European countries. Patients with a sustained supine diastolic blood pressure (SDBP), phase V, of 95 mm Hg or more on bendrofluazide, 5 mg daily (or an equivalent dose of a thiazide diuretic) were randomised to additional pinacidil (n = 127), 25 mg up to 100 mg daily, or nifedipine (n = 130), 20 mg up to 80 mg daily. The treatment groups were similar at entry for QL scores, average DBP of 103 +/- 6 (SD) mm Hg, and average age of 56 +/- 10 (SD) years. Eighteen patients on pinacidil and 12 on nifedipine withdrew due to side effects, such as oedema (both drugs) and flushing (nifedipine). The maximum antihypertensive effect was achieved within 6 weeks and maintained, resulting in a significant fall in SDBP of 13.7 mm Hg on pinacidil and 15.5 mm Hg on nifedipine at the end of the trial. There was no significant difference in the antihypertensive effect. The target SDBP was achieved in 57% of pinacidil-and 63% of nifedipine-treated patients. The average number of symptomatic complaints fell in both groups, with significant decreases in the reporting of blurred vision and headaches on nifedipine. Complaints of growth of body and facial hair increased on pinacidil but there were no significant between-drug comparisons with respect to side effects. In measures of psychological well being, patients on pinacidil showed a significant (p less than 0.05) improvement in total and cognitive function scores compared to nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, TYB-3823 [1-(2,6-dimethylphenyl)-4,4-dimethyl-aminoguanidine hydrochloride], were investigated. To determine the antiarrhythmic effects, spontaneously occurring adrenaline-, digitalis-, and two-stage coronary ligation-induced arrhythmias were used. TYB-3823 suppressed these three arrhythmia models. The antiarrhythmic plasma concentrations, IC50, of TYB-3823 for digitalis-, coronary ligation-, and adrenaline-induced arrhythmias were 7.8, 16.8, and 5.0 micrograms/ml, respectively. In the blood perfused sinoatrial (SA) node and papillary muscle (PM) preparations, TYB-3823 decreased the sinoatrial rate (SAR) and contractile force following an initial small positive inotropic effect and increased the intraventricular conduction time and coronary blood flow. These results indicate that TYB-3823 is similar to other class I antiarrhythmic agents, such as aprindine and nicainoprol, in the antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

A single-blind, placebo-controlled study was conducted to determine the dose-response relationship of guanabenz, administered as single oral doses to patients with mild or moderate hypertension. Twelve hypertensive patients received ascending oral doses of 2, 4, 8, 16, 24, and 32 mg of guanabenz. Dose-response relationships were evaluated for the nine patients who received placebo and all six guanabenz doses. The greatest maximum response (40/24 mm Hg) was seen for the 16 mg guanabenz dose. Since eight of the nine patients had mild hypertension, they may have responded maximally to the lower guanabenz doses, precluding larger decreases with the 24 and 32 mg doses. The mean onset of satisfactory blood pressure reduction decreased from 4 to 2 h and the mean duration increased from 6 to 22 h as the oral dose was increased from 2 to 32 mg. In eight patients, the responses to 16 mg of guanabenz administered sublingually and orally were compared. The sublingual and oral routes produced similar mean (20/13 mm Hg) and maximum (33/24 mm Hg) blood pressure decreases as well as mean onset (2 h) and duration (16.5 h) of satisfactory response. Additional studies involving patients with more severe hypertension are needed to further characterize the dose-response relationship of oral guanabenz and to establish a dose-response relationship for sublingual guanabenz.

This retrospective study was undertaken to evaluate the effectiveness and clinical characteristics of guanabenz, a centrally acting agent, as monotherapy in hypertensive patients with coexisting diabetes mellitus. Of 113 patients with data available for analysis, 21 were receiving concurrent therapy with insulin, 31 were receiving oral hypoglycemic agents, and 61 were being treated by a diabetic diet alone. During treatment with guanabenz (4-64 mg daily) for up to 2 years (mean duration, 7 months), diastolic blood pressure (measured in the supine posture) decreased by an average of 10 mm Hg; the effects were similar among the three subgroups of patients receiving the different diabetic therapies. Clinically satisfactory treatment outcomes occurred in 52%, 77%, and 57% of patients, respectively. Body weight remained constant throughout the study. The antihypertensive efficacy of guanabenz in this study and the nature and frequency of side effects produced were similar to those reported previously in nondiabetic hypertensive patients. Neither plasma glucose concentrations nor the diabetic therapy requirements of the diabetic patients in this study were altered by guanabenz treatment. There also was a small decrease in serum total cholesterol concentration (mean decrease, 15 mg/dl, p less than 0.001) during the study. Thus, antihypertensive monotherapy with guanabenz is effective in the treatment of a majority of patients with coexisting diabetes mellitus. Since it does not appear to interfere with the concurrent treatment of diabetes or cause unwanted metabolic side effects, guanabenz may be a rational and safe agent for the management of hypertension in the diabetic patient.

The clinical pharmacology of potassium channel openers has been reviewed using pinacidil as a prototype drug. When administered acutely or chronically, the hemodynamic and neuroendocrine profile is that of a peripheral arterial vasodilator. The drug produces decreases in peripheral vascular resistance, and subsequent blood pressure decreases are associated with reflex increments in heart rate. When studied, plasma catecholamines increased about twofold during chronic therapy. Plasma renin activity, however, was not increased during chronic therapy with pinacidil monotherapy. When patients were treated with pinacidil doses ranging from 12.5 to 75 mg b.i.d., 66.9% of patients had a decrease in supine diastolic blood pressure to below 91 mm Hg and 10 mm Hg less than baseline, whereas only 23.9% of patients had similar falls during placebo treatment. During maintenance therapy with pinacidil, the average blood pressure during the daytime dosing interval was 137.8 +/- 1.2/83.4 +/- 0.7 mm Hg (mean +/- SEM). Titration of pinacidil as monotherapy resulted in a characteristic adverse event profile dominated by the presence of dose-related edema. Other characteristic events included tachycardia, palpitations and headache. When pinacidil was given to patients unresponsive to hydrochlorothiazide (25 mg b.i.d.), similar efficacy relative to placebo was noted with a change of post-dose supine diastolic blood pressure in the pinacidil group of 13.5 +/- 0.8 mm Hg and 7.3 +/- 0.9 mm Hg in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Fourteen adolescent patients, aged 12 to 21 years, with essential hypertension were treated on an open basis with guanabenz, a centrally acting antihypertensive agent. Guanabenz doses of 3-24 mg/day (0.08-0.20 mg/kg/day) given twice daily for 2 months effectively lowered mean supine blood pressure (p less than 0.05), standing blood pressure (p less than 0.01), and supine pulse rate (p less than 0.01). Body weight and standing pulse rate were unaffected. Adverse effects were mild, usually short lived, and did not interfere with therapy. No adverse effects were noted in laboratory test results or physical examinations. Baseline funduscopic photography revealed numerous but minor changes, including altered arteriovenous ratios and crossing changes. Prestudy echocardiograms revealed changes consistent with early hypertensive changes. Poststudy echocardiograms obtained in nine of the 14 subjects after 4-6 weeks of guanabenz therapy suggested that cardiac hypertrophy had regressed, but these changes did not reach statistical significance. These preliminary results suggest that guanabenz can be a safe and effective treatment for hypertensive children, that early hypertensive changes can be seen in the fundi and echocardiograms of mildly hypertensive adolescents, and that some echocardiographic changes may be reversed even after relatively short-term guanabenz therapy.

There is increasing interest in initial therapy of hypertension with sympatholytic agents and the influence of antihypertensive therapy on cardiac and renal function. We treated 26 men with essential hypertension with either guanabenz alone (n = 14) or propranolol alone (n = 12) and assessed blood pressure and renal perfusion before and after 5-7 weeks of treatment. Cardiac performance was evaluated for the guanabenz-treated patients. Both drugs substantially reduced blood pressure without weight gain. During guanabenz therapy, glomerular filtration rate and renal blood flow were preserved, with a fall in renal vascular resistance (from 12,100 +/- 1,500 to 9,300 +/- 1,190 dyne X s X cm-5, p less than 0.01). Propranolol decreased glomerular filtration rate (from 95 +/- 11 to 70 +/- 6 ml/min, p less than 0.05) without significant change in renal blood flow or renal vascular resistance. In guanabenz-treated patients, there was a decline in left ventricular mass (from 290 +/- 23 to 257 +/- 14 g, p = 0.067). Thus, both agents are effective initial therapy in hypertension. Guanabenz treatment also was associated with reduced renal vascular resistance and left ventricular mass.

The effects of guanabenz on serum lipids were assessed from data obtained in multicenter studies involving 483 patients treated for up to 2 years for essential hypertension. The mean age of the population was 50 years; 54% were male, and 61% were white. Dosage was titrated to maximize individual blood pressure response and was maintained at that level (mean final dosage 25 mg/day) for the remainder of the treatment period. After 4 weeks of treatment, mean total cholesterol levels decreased by 10 mg/dl (p less than 0.01), and the decrease was maintained throughout subsequent therapy. The decreases in cholesterol concentration were not affected by age, race, sex, previous diuretic therapy, previous antihypertensive therapy, smoking habits, or caffeine use. Complete lipid and lipoprotein profiles were obtained on serum specimens from 39 guanabenz-treated, overnight-fasted patients. Significant (p less than 0.01) mean decreases were observed for total cholesterol (-25 mg/dl) and low density lipoprotein cholesterol (-23 mg/dl) with no significant changes either in cholesterol levels of high density lipoproteins and very low density lipoproteins or in triglyceride levels. These changes indicate that guanabenz, given as monotherapy, has a favorable effect on the serum lipid profile with regard to cardiovascular risk.

N"-Cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine (P 1134) is a new vasodilating antihypertensive compound. In an open study, P 1134 was given in single oral doses of from 10 to 25 mg to 12 previously untreated patients with essential hypertension. All patients responded with decreases in mean arterial pressure (MAP) of at least 10 mm Hg and with almost equal blood pressure decreases in the supine and erect position. The increase of dose was significantly correlated with a progressive reduction of blood pressure. At a dose of 25 mg, the maximal decrease in supine MAP averaged 38 mm Hg, and the maximal increase in heart rate averaged 23 beats/min. Peak effect and serum concentration were seen about 1 h after tablet intake. The serum half-life from the peak concentration averaged 2.5 h. It is concluded that P 1134 is a fast-acting, effective antihypertensive agent.

The management of hypertension in patients with chronic obstructive pulmonary disease (COPD) may be complicated by the adverse effects of several antihypertensive agents on pulmonary function. The safety and antihypertensive efficacy of guanabenz, a centrally acting alpha-adrenergic agonist, were evaluated in 42 patients with asthma and 24 patients with other forms of COPD. Among the 64 patients with data evaluated for efficacy, pretreatment supine diastolic blood pressures (SDBP) were between 90 and 121 mm Hg (mean, 100 mm Hg). The patients were treated for 6 months with guanabenz as sole antihypertensive therapy in doses ranging from 8 to 64 mg/day (mean final dosage, 28 mg/day). At the end of the treatment period, a mean decrease in SDBP of 10 mm Hg was observed (p less than 0.001). Excellent or satisfactory blood pressure responses were obtained for 65% of the asthmatic patients and 83% of the patients with other forms of COPD. Mean supine pulse rate decreased by 7 beats/min (p less than 0.001), and mean body weight decreased by 2 lb. (p less than 0.05). Only one patient discontinued guanabenz treatment because of an exacerbation of asthma thought to be due to airway dryness. Because beta-adrenergic blocking agents, including the cardioselective drugs, have been known to exacerbate COPD, guanabenz treatment may be preferable as antiadrenergic antihypertensive therapy in patients with asthma and other forms of COPD.

Peripheral vasodilation has proved to be a successful method to control hypertension in recent years, as illustrated by the increasing number of marketed vasodilators like calcium antagonists, alpha-adrenergic antagonists, and angiotensin-converting enzyme inhibitors. A novel group of vasodilators showing excellent antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs has been discovered. The first compounds of the group were pyridylthioureas. Chemical modification based on structure-activity studies involving a substitution of N-cyanoguanidine for the less active thiourea function has led to the synthesis of pinacidil, N'-cyano-N-(4-pyridyl)-N"-(1,2,2-trimethylpropyl) guanidine, recently introduced as the new antihypertensive drug, Pindac. Preclinical studies showed that pinacidil does not relax vascular smooth muscle by any known mechanism, but recent investigations indicate that the compound opens potassium channels in the cell membranes. The hyperpolarization that follows is responsible for the relaxation. Pinacidil is rapidly and almost completely absorbed after oral administration and produces a dose-dependent blood pressure fall in hypertensive animals and humans. The therapeutic plasma concentrations are in the range of those producing relaxation of isolated, noradrenalin-contracted human blood vessels in vitro. In dogs, pinacidil decreases vascular resistance in most tissues proportionally to the blood pressure fall, but elicits a specific increase in coronary blood flow at antihypertensive doses. The compound shows a selectivity for precapillary vessels. It is mainly eliminated by hepatic metabolism to pinacidil-N-oxide followed by renal excretion, and the N-oxidation is partly reversible. Pinacidil is relatively free of toxicity, and action-related side effects such as fluid retention and tachycardia are readily controlled with diuretics and beta-blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

The antiarrhythmic and antifibrillatory actions of bethanidine were evaluated in two conscious canine models which are capable of developing ventricular tachyarrhythmias during the recovery phase of myocardial infarction. In the first model, nonsustained (n = 3) or sustained (n = 12) ventricular tachycardia (cycle length, 165 +/- 6 ms; mean +/- SD) was initiated by programmed electrical stimulation, 4-9 days after experimental myocardial infarction. Bethanidine was administered in cumulative doses of 2, 4, 8, and 16 mg/kg and programmed stimulation repeated. Bethanidine, in doses of 4, 8, and 16 mg/kg, slowed the cycle length of the tachycardia and allowed slower rates of ventricular pacing to produce equivalent delays at epicardial sites in the ischemic zone. Despite these changes, induction of sustained ventricular tachycardia was prevented in only two of 13 animals. Bethanidine (8 mg/kg i.v. every 8 h, n = 4; 16 mg/kg i.v. every 8 h, n = 5) failed to prevent the development of premature ventricular beats, ventricular tachycardia, and ventricular fibrillation which developed in response to a transient ischemic episode superimposed on the heart that had a previous acute myocardial infarction. No differences in survival at 24 h were observed between saline- (10%, n = 10) and bethanidine-treated (0%, n = 9) groups. These results suggest that bethanidine acts to increase the refractory period and depresses conduction velocity in ischemically injured tissue, slowing the rate of ventricular tachycardia. However, the drug fails to suppress the development of ventricular arrhythmias and ventricular fibrillation in both canine models.

Meobentine (sulfate) has antifibrillatory and antiarrhythmic activity in canine models. The antiarrhythmic, pharmacokinetic, and adrenergic neuronal blocking effects of meobentine were assessed in 15 patients with chronic, high-frequency ventricular ectopic depolarizations (VEDs). Eleven of the 15 patients had recurrent nonsustained ventricular tachycardia. The patients were given a series of gradually increasing single doses of meobentine; six received oral meobentine and nine had infusions. The antiarrhythmic efficacy of meobentine was assessed by a comparison of arrhythmia frequency during placebo given on days just prior to meobentine. Oral therapy with meobentine at dosages above 20 mg/kg caused diarrhea, and well-tolerated dosages achieved peak concentrations of 0.69 micrograms/ml (range 0.5-1.0 micrograms/ml). Antiarrhythmic activity was seen in only one patient with oral meobentine. In contrast, intravenous infusions (6.75-34.2 mg/kg) achieved concentrations ranging from 1.3-9.8 micrograms/ml. There was a linear relationship between pseudo-steady-state plasma concentrations and dosage, r = 0.82, p less than 0.01. Antiarrhythmic activity was seen in four of nine patients who received intravenous meobentine over a range of concentrations from 2.5-4.5 micrograms/ml. Four patients developed evidence of adrenergic neuronal blockage (loss of the venous reflex response); two at dosages of 16.2 mg/kg, one at 24.3 mg/kg, and one at 34.2 mg/kg. In one individual (24.3 mg/kg), the adrenergic neuronal blockade was associated with an acute episode of shortness of breath, orthopnea, and cough. With intravenous meobentine, there was a linear relationship between dosage and AUC, and the elimination half-life ranged from 11-27 h.(ABSTRACT TRUNCATED AT 250 WORDS)