Simvastatin and atorvastatin enhance hypotensive effect of diltiazem in rats.

Effects of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin, on diltiazem-induced hypotension were examined in anaesthetized rats and compared to that of pravastatin. Vehicle, 2 mg/kg/day simvastatin, 2 mg/kg/day atorvastatin, or 4 mg/kg/day pravastatin was administered orally for 4 days. Diltiazem at 3 mg/kg was given orally 2 hours after the final administration of the inhibitors. Arterial blood pressure was measured via a cannula introduced into the left carotid artery, and heart rate was counted from the pulse pressure. In all groups, diltiazem significantly decreased the mean arterial blood pressure without any changes in heart rate. Pretreatment with simvastatin and atorvastatin significantly enhanced the hypotensive effect of diltiazem, while that with pravastatin did not. Heart rate was not modified by pretreatment with the inhibitors. The results indicate that concomitant use of diltiazem with simvastatin or atorvastatin enhances diltiazem-induced hypotension, probably by competitive inhibition of diltiazem metabolism with simvastatin and atorvastatin metabolisms.

Vascular smooth muscle cell proliferation is effectively suppressed by the non-specific growth factor inhibitor suramin.

The purpose of this study was to investigate the effects of the non-specific growth factor inhibitor suramin on smooth muscle cell proliferation in vitro and in vivo. Cultured vascular smooth muscle cells (VSMC) were stimulated by platelet-derived growth factor (PDGF) and cellular DNA synthesis assessed by [3H]-thymidine uptake. Suramin dose-dependently inhibited DNA synthesis in VSMC, and 100 microM of suramin completely suppressed the PDGF-AB-induced cellular DNA synthesis. Rabbit carotid arteries were injured by the balloon catheter, and then suramin locally delivered using a porous balloon catheter over ten minutes. Three weeks after the vascular injury, the extent of intimal thickening was compared between the suramin-treated and control rabbits. The neointimal formation triggered by balloon-mediated vascular injury was suppressed significantly and dose-dependently by locally infused suramin, and the intima to media area ratios of the control and 1 mM suramin-treated animals were 48.8+/-14.9 and 12.2+/-6.0%, respectively (p < 0.01. n = 6 for each group). These results suggest that one time local administration of suramin was sufficient to suppress neointimal formation after balloon-mediated vascular injury, and that pharmacological intervention targeting the growth factor's signaling pathways could be a promising approach to prevent smooth muscle cell proliferation in various proliferative vascular diseases.

Renal carbonic anhydrase activity in DBA/2FG-pcy/pcy mice with inherited polycystic kidney disease.

DBA/2FG-pcy/pcy (D2-pcy) mice are a hereditary murine model of slowly progressive polycystic kidney disease (PKD) and characterized by the persistent excretion of acidic urine, in association with polyuria, after weaning. In this study, the activity of carbonic anhydrase (CA) and it histological distribution in the kidney of D2-pcy mice were investigated by immunohistochemistry. Significantly higher CA activity was detected in the cytosolic, but not membrane, fraction of kidney homogenates in 5-week-old D2-pcy mice than in age-matched, control DBA/2 (D2) mice, and a more rapid rate of urine acidification was noted in 11-week-old mice when acetazolamide, an inhibitor of the enzyme, was administered orally. By immunohistochemistry for the major renal CA isoenzyme (CA II), epithelial cells in the distal straight tubules and the cortical collecting ducts were stained intensely, whereas those of the proximal convoluted tubules had only weak and diffuse staining. The glomeruli, the proximal straight tubules and the ascending thin limb of Henle's loop were almost free from staining. In the cells lining cysts and/or dilated tubules, CA II activity was well preserved, although the staining intensity was considerably reduced in fully-flattened, lining cells of cysts, but no difference was found between D2-pcy and D2 mice in any segmental localization of renal CA II activity. From these results it seems that D2-pcy mice in the early stages of the cystic disease continue to secrete excess protons through the CA-mediated reaction that is stimulated for regulation of acid-base balance in the distal portion of the nephron and the collecting duct in kidney. It also suggests that monitoring urine pH may be useful in predicting the effects of early interventions on the progression of slowly developing renal cysts.

Enhanced GRK5 expression in the hearts of cardiomyopathic hamsters, J2N-k.

GTP binding protein-coupled receptor kinase 5 (GRK5) cDNA was cloned from the hearts of Syrian hamsters. The hamster GRK5 cDNA contained 1770 nucleotides encoding 590 amino acids, and the nucleotide sequence had 89.6% homology to the human homologue. An inbred cardiomyopathic hamster strain, J2N-k, was used to investigate the alteration of GRK5 mRNA expression in the setting of congestive heart failure. M-mode echocardiography revealed significant dilatation of the left ventricle and a decrease of left ventricular contractility in 20-week-old J2N-k hamsters compared with age-matched control hamsters, J2N-n. Semi-quantitative RT-PCR showed that GRK5 mRNA expression in the hearts of J2N-k was significantly higher than in those of J2N-n (J2N-k 60.3 +/- 13.3, J2N-n 25.8 +/- 17.2 arbitrary units, p < 0.005, n = 6 in each group). These results suggest that an enhanced GRK5 expression might play a role in the reduced responsiveness to catecholamines in failing hearts via beta-adrenergic receptor phosphorylation.

The effect of paclitaxel on the progression of polycystic kidney disease in rodents.

Woo et al (Nature 368:750-753) reported that parenteral administration of paclitaxel arrested the striking renal enlargement and prolonged life in C57BL/6J-cpk/cpk mice with a rapidly progressive form of polycystic kidney disease (PKD). In the current study, we sought to determine whether paclitaxel could alter the progression of other forms of hereditary PKD in rodents. Paclitaxel was administered by intraperitoneal injection to C57BL/6J-cpk/cpk mice and Han:SPRD-Cy/Cy rats with rapidly progressive PKD and to DBA/2FG-pcy/pcy mice and Han:SPRD-Cy/+ rats with slowly progressive PKD. Paclitaxel (150 micrograms/wk) prolonged the survival of cpk/cpk mice from 24.5 days to more than 65 days and decreased kidney weight relative to body weight from 16.5% at 21 days of age to 8.2% at more than 65 days of age. Mortality attributable to paclitaxel was 12%. By contrast, the administration of paclitaxel (0.1 to 15 mg/kg/wk) to 7- to 10-day-old Han:SPRD-Cy/Cy rats with rapidly progressive PKD had no effect on the course of the disease; moreover, paclitaxel caused severe side effects and premature death in all the Cy/Cy animals. Heterozygous male Cy/+ rats develop slowly progressive renal enlargement and azotemia. Paclitaxel, administered at 7, 15, or 27 mg/kg/wk to male Cy/+ rats from 4 until 10 weeks of age, reduced body weight gain, had an inconsistent effect on kidney weight relative to body weight, and had no effect on the serum urea nitrogen concentration. Mortality associated with the 7, 15, and 27 mg/kg/wk doses of paclitaxel was 0%, 15.4%, and 28.5%, respectively. DBA/2FG-pcy/pcy mice of either sex developed slowly progressive renal enlargement and azotemia. The administration of paclitaxel (100 to 150 micrograms/wk) from 2 to 10 weeks of age to DBA/2FG-pcy/pcy mice with cystic disease had no effect on the increase in kidney weight or on the level of serum urea nitrogen in comparison to untreated cystic animals. Mortality associated with 100- and 150-micrograms/wk doses of paclitaxel was 0% and 20%, respectively. We conclude that paclitaxel diminished the rate of renal enlargement and increased the life span of cpk/cpk mice but not Cy/Cy rats with rapidly progressive forms of PKD. Paclitaxel had no apparent benefit in Cy/+ rats nor pcy/pcy mice with slowly progressive PKD. On the basis of these studies in rodents, it appears that paclitaxel has limited potential usefulness as a therapeutic agent in the treatment of PKD.

Effects of KRN4884, a novel K channel opener, on the cardiovascular system in anesthetized dogs: a comparison with levcromakalim, nilvadipine, and nifedipine.

Pharmacological profiles of KRN4884, 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine+ ++, were evaluated in in vitro and in vivo experiments. In rat isolated aorta, KRN4884 (10(-10)-10(-5) M) produced a concentration-dependent relaxation. Pretreatment with glibenclamide (10(-7)-10(-6) M) produced a rightward shift of the concentration-response curve for KRN4884. In anesthetized dogs, KRN4884 (3 and 10 micrograms/kg intravenously, i.v.), levcromakalim (3 and 10 micrograms/kg i.v.), nilvadipine (1-10 micrograms/kg i.v.), and nifedipine (1-10 micrograms/kg i.v.) produced decreases in mean blood pressure (MBP), total peripheral vascular resistance (TPR), and coronary vascular resistance (CVR), and increases in aortic blood flow (AoF) and coronary blood flow (CBF). The percentage decrease in CVR was greater than that in TPR with KRN4884 and levcromakalim, but nilvadipine and nifedipine showed no significant differences between CVR and TPR in percentage decreases. Heart rate (HR) was slightly increased by KRN4884 but was not affected by levcromakalim, nilvadipine, or nifedipine. Left ventricular dP/dt (LVdP/dt) was reduced only by nifedipine in a dose-dependent manner. The duration of the hypotensive action of KRN4884 was longer than those of levcromakalim and nifedipine and was similar to that of nilvadipine. The duration of the decreases in TPR and CVR induced by KRN4884 was longer than those induced by levcromakalim and nifedipine and shorter than that induced by nilvadipine. These results suggest that the cardiovascular effects of KRN4884 are very similar to those of the K channel opener levcromakalim and Ca channel blockers such as nilvadipine and nifedipine. However, the hypotensive effects of KRN4884 are long-acting in comparison with those of levcromakalim and the selective effect of KRN4884 on coronary vasculature is greater than those of nilvadipine and nifedipine.

Cardiovascular effects of KRN2391, nitroglycerin and cromakalim in dihydroergotamine-treated pithed rats.

1. The effects of KRN2391 on the cardiovascular system were compared with those of nitroglycerin and cromakalim in pithed rats treated with dihydroergotamine (DHE) in order to examine the effects of these drugs on venous blood vessels. 2. DHE (100 micrograms/kg, i.v.) produced increases in mean blood pressure (MBP), cardiac output (CO) and central venous pressure (CVP) without changes in total peripheral vascular resistance (TPR) and heart rate (HR) based on venoconstriction. The DHE-treated pithed rats, nitroglycerin (30 micrograms/kg, i.v.) decreased CO and CVP whereas cromakalim (30 micrograms/kg, i.v.) produced a slight increase in CO followed by a decrease and did not affect CVP. KRN2391 (30 micrograms/kg, i.v.) produced a decrease in CVP without affecting CO. Decreases in MBP and TPR were induced by all drugs. 3. These results suggest that nitroglycerin acts predominantly as a venodilator and KRN2391 and cromakalim showed a venodilating action in addition to an arterial dilating action in DHE treated pithed rats. However, the venodilating action of KRN2391 in this condition is more potent than that of cromakalim.

Comparison of coronary dilating effects of Ki1769, a new K channel opener of the pyridinecarboximidamide type, and nifedipine in anesthetized dogs.

The coronary dilating effect of a new type of K channel opener, N-cyano-N'-(2-phenethyl)-3-pyridinecarboximidamide (Ki1769), was examined in anesthetized dogs in comparison with that of nifedipine. Administration of Ki1769 (30 and 100 micrograms/kg, i.v.) and nifedipine (1 and 3 micrograms/kg, i.v.) produced a dose-dependent decrease of mean blood pressure with a concomitant increase in heart rate. Ki1769 and nifedipine dose-dependently increased coronary blood flow and aortic blood flow and decreased coronary vascular resistance and total peripheral vascular resistance. The percentage decrease of coronary vascular resistance was greater than that of total peripheral vascular resistance with Ki1769 and nifedipine, but Ki1769 showed a greater specificity in the decrease of coronary vascular resistance than nifedipine. Glibenclamide (5 mg/kg, i.v.) inhibited these hemodynamic effects of Ki1769 but did not affect those of nifedipine. These results suggest that the preferential effect of Ki1769 on the coronary vascular bed is greater than that of nifedipine. Such a profile of Ki1769 is based on its K channel-opening action.

Cardiovascular effects of KRN2391 in anesthetized dogs: a comparison with cromakalim and nitroglycerin.

The cardiovascular effects of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridine carboximidamide monomethanesulfonate, were compared with those of cromakalim and nitroglycerin in anesthetized dogs. KRN2391 (3-30 micrograms/kg, i.v.), cromakalim (3-30 micrograms/kg, i.v.) and nitroglycerin (1-10 micrograms/kg, i.v.) produced a dose-related decrease of the mean blood pressure with concomitant increase in heart rate. The increase in heart rate caused by cromakalim was lower than that caused by KRN2391 and nitroglycerin. Left ventricular end-diastolic pressure was decreased by all doses of KRN2391 and nitroglycerin. Cromakalim at 3 and 10 micrograms/kg decreased this end-diastolic pressure but increased it at 30 micrograms/kg. Left ventricular dP/dt was increased by KRN2391 and nitroglycerin but was decreased by cromakalim. KRN2391 and cromakalim produced a dose-dependent increase in aortic and coronary blood flow. Nitroglycerin showed biphasic changes in aortic and coronary blood flow, i.e., an initial increase followed by a decrease. At equipotent hypotensive doses, the increase in coronary blood flow induced by KRN2391 was greater than that by cromakalim and nitroglycerin, and total peripheral and coronary vascular resistances were decreased by KRN2391 and cromakalim. Nitroglycerin showed biphasic changes in total peripheral and coronary vascular resistances, i.e., these resistance showed an initial decrease followed by an increase. The relative decrease of coronary vascular resistance compared to the total peripheral vascular resistance was greater for KRN2391 than for cromakalim and nitroglycerin. The changes in hemodynamic parameters caused by KRN2391 were inhibited by pretreatment with glibenclamide (5 mg/kg, i.v.). These results suggest that the hemodynamic profile of KRN2391 is closer to that of cromakalim than to that of nitroglycerin, but that the selectivity for the coronary vascular bed is higher for KRN2391 than for cromakalim. In addition, it is considered that, compared with KRN2391 and nitroglycerin, cromakalim has a low selectivity for the vasculature vs the myocardium.

Effect of KRN2391 on canine ventricular arrhythmia models.

1. KRN2391 (3-30 micrograms/kg, i.v.) produced a decrease in mean blood pressure (MBP) with concomitant increase in heart rate (HR) and change in electrocardiogram (ECG) such as the shortening of PP and PQ intervals and the prolongation of QTc and these changes in HR and ECG were attenuated by pretreatment with propranolol (1 mg/kg) in normal dogs. 2. KRN2391 at 30 micrograms/kg induces neither suppression nor aggravation of ventricular arrhythmias caused by adrenaline and digitalis. 3. In two-stage coronary ligation-induced arrhythmia, KRN2391 inhibited arrhythmia at 48 hr. 4. These results suggest that KRN2391 may be effective on arrhythmia related to ischemia. In addition, it is considered that arrhythmia is not induced even by a high dose of KRN2391 in the normal condition.

Mechanism of action of KRN2391 in canine coronary vascular bed.

The present studies were performed to clarify the mechanism of action of KRN2391 in various sizes of canine coronary artery. We used the responses of isolated large and small coronary arteries and the changes in coronary blood flow (CBF) as indicators reflecting the responses of conductive arteries and resistive arterioles, respectively. In isolated small coronary artery, the effect of KRN2391 (10(-8)-10(-5) M) was antagonized by either methylene blue or glibenclamide. In isolated large coronary artery, the vasorelaxant effect of KRN2391 (10(-8)-10(-5) M) and nicorandil (10(-7)-10(-4) M) were antagonized by methylene blue (10(-5) M) but not by glibenclamide (10(-6) M). The relaxant effect of cromakalim was antagonized by glibenclamide but not by methylene blue in isolated large coronary artery. Intracoronary arterial injection of KRN2391, nicorandil or cromakalim produced an increase in CBF dose-dependently. Glibenclamide (5 mg/kg, i.v.) attenuated the increase in CBF caused by KRN2391, nicorandil and cromakalim. ED20, the dose that produced an increase in CBF by 20 ml/min, increased about 5-fold for KRN2391 and nicorandil and about 12-fold for cromakalim after administration of glibenclamide. These results suggest that the mechanism of action of KRN2391 and nicorandil depends on the segment of coronary arteries; i.e., they show a nitrate action alone in large coronary artery, and a K-channel opening action in addition to a nitrate action as the size of the coronary artery decreases.

[Alcohol-related problems in mortality in middle-aged urban-dwelling men from cerebro-cardiovascular diseases].

A survey was performed of the life-styles and medical histories of men, who died of cerebro-cardiovascular diseases at ages between 40 and 64 years in Hirakata, Neyagawa, Moriguchi and Kadoma cities in Osaka prefecture. Data was available on 127 of 172 men who died in 1988. Of these, 28 had histories of alcohol-related problems. Analysis showed that the amount of alcohol consumed was associated with disease history and serious alcohol-related problems. 1) Histories of hypertension, cerebrovascular and liver disease were found more often in heavy drinkers with a daily alcohol intake exceeding the equivalent of 46 g pure ethanol compared to either moderate drinkers with a daily alcohol intake of less than 46 g or abstainers. 2) Of 28 subjects with alcohol-related problems, one had been treated at a specialized alcoholic-clinic, two had been admitted to psychiatric hospitals and one subject had consulted a physician at a mental health clinic of the public health center in his community. 3) Although 18 of the 28 subjects with alcohol-related problems had their own regular doctors, they did not appear to have received adequate care. 4) Subjects with alcohol-related problems had histories of cerebrovascular and liver diseases more often than those without alcohol-related problems. 5) Subjects with alcohol-related problems were confronted with unemployment, divorce and housing problems more often than those without alcohol-related problems. With the increasing amount of alcohol consumption in Japan, alcohol-related problems need more attention. There is an urgent need to establish community-based strategies for prevention of alcohol-related problems and to organize a network of multi-disciplinary support teams for those with problems such as alcoholics in urban communities.

Effect of KRN2391, a novel vasodilator, on various experimental anginal models in rats.

The antianginal effect of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethanesulfonate, on various anginal models in rats was compared with those of nifedipine and nicorandil. Angina pectoris was induced by methacholine or isoproterenol, and the change in the ST-segments in the electrocardiogram (ECG) was used as the parameter to indicate angina pectoris. The intracoronary administration of methacholine (3 micrograms) produced an elevation in the ST-segment of the ECG. This ST-elevation was inhibited by the intravenous administration of KRN2391 (30 and 100 micrograms/kg), nifedipine (100 and 300 micrograms/kg) and nicorandil (1000 and 3000 micrograms/kg). The administration of isoproterenol (10 micrograms/kg/min, i.v.) produced a depression of the ST-segment of the ECG. The intravenous administration of KRN2391 (100 micrograms/kg), nifedipine (100 micrograms/kg) and nicorandil (3000 micrograms/kg) inhibited the ECG changes induced by isoproterenol. These results suggest that KRN2391 exerts a potent protective effect on angina pectoris models compared with nifedipine and nicorandil. KRN2391 appears to be useful as an antianginal drug.

Effect of KRN2391 on venous return: comparison with other vasodilators.

We compared the cardiohemodynamic effects of KRN2391, a novel coronary vasodilator, with those of nicorandil, nifedipine, cromakalim, and nitroglycerin (NTG) administered intravenously (i.v.) to anesthetized open-chest dogs. KRN2391 (10 and 30 micrograms/kg) decreased mean blood pressure (MBP) and superior vena cava flow (SVCF), and increased inferior vena cava flow (IVCF), total venous return (TVR), pulmonary artery blood flow (PAF), and right atrial pressure (RAP). Administration of KRN2391 (30 micrograms/kg) decreased heart rate (HR). Nicorandil (100 and 300 micrograms/kg) decreased MBP and SVCF, and produced transient increases followed by decreases in IVCF, TVR, PAF, and RAP. HR was decreased by administration of nicorandil (300 micrograms/kg). Nifedipine (1 and 3 micrograms/kg) decreased MBP and increased SVCF, IVCF, TVR, PAF, and RAP. HR was not affected by either dose of nifedipine. Cromakalim (10 micrograms/kg) decreased MBP, SVCF, and increased HR, IVCF, TVR, PAF and RAP. Nitroglycerin (3 micrograms/kg) decreased MBP, SVCF, IVCF, TVR, PAF, and RAP. In dogs that received glibenclamide (5 mg/kg, i.v.), the changes in MBP, SVCF, IVCF, TVR, PAF, and RAP caused by KRN2391 were reduced in comparison with those in dogs that received vehicle for glibenclamide. The decreases in IVCF, TVR, and PAF induced by nicorandil were not affected by glibenclamide, but the decrease in MBP was diminished and the decrease in RAP was augmented. The hemodynamic changes caused by cromakalim were almost inhibited by glibenclamide, whereas those caused by NTG were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of KRN2391, nicorandil and diltiazem on the changes in the electrocardiogram caused by endothelin-1 in anaesthetized rats.

1. The effect of KRN2391, a novel vasodilator, on the changes of electrocardiogram caused by endothelin-1 (ET-1) was studied in anaesthetized rats and compared with the effects of nicorandil and diltiazem. In addition, the effect of KRN2391 on the action potential of guinea-pig papillary muscle was studied. 2. The intracoronary administration (i.c.) of ET-1 (5 micrograms) induced not only ST segment elevation of the electrocardiogram due to contraction of the coronary artery, but also arrhythmias involving atrioventricular block (A-V block), ventricular premature contraction (VPC) and ventricular fibrillation (VF), and resulted in death in most animals. However, the administration of methacholine (3 micrograms, i.c.) produced ST segment elevation alone without developing arrhythmias. 3. Pretreatment with intravenous administration of KRN2391 (30 micrograms kg-1) inhibited the ST segment elevation and the development of arrhythmias induced by ET-1, and decreased the incidence of death. 4. Nicorandil (1000 micrograms kg-1) prevented the ST segment elevation without suppression of the occurrence of VF. Diltiazem (100 micrograms kg-1) suppressed both the ST segment elevation and the occurrence of VF but not other arrhythmias. Nicorandil at 3000 micrograms kg-1 and diltiazem at 300 micrograms kg-1 produced not only a suppression of ST segment elevation and VF incidence but also a decrease in the occurrence of arrhythmias. These doses of nicorandil and diltiazem produced a decrease in death in a dose-dependent manner. 5. KRN2391 (10 and 30 micrograms kg-1), nicorandil (1000 and 3000 micrograms kg-1) and diltiazem (100 and 300 micrograms kg-1) significantly decreased mean blood pressure in a dose-dependent manner. Heart rate was decreased by nicorandil (3000 microg kg-1) and diltiazem (100 and 300 microg kg-1) but was not affected byKRN2391 (10 and 30 microg kg-1).6. KRN2391 (30 microM) significantly shortened the action potential duration of guinea-pig ventricle at 50% and 90% repolarization (APD50 and APD90). The effect of KRN2391 was inhibited by a K+channel blocker, glibenclamide (30 microM).7. These results suggest that the occurrence of ST segment elevation and arrhythmias induced by ET-1 are due to a dual direct action on both coronary vascular smooth muscle and myocardium. Therefore,the protective effects of KRN2391, nicorandil and diltiazem on ET-l-induced heart disorders appear to be due to their direct actions on coronary vascular smooth muscle and the myocardium.

Vasorelaxant mechanism of KRN2391 and nicorandil in porcine coronary arteries of different sizes.

1. The relaxant mechanisms of action of KRN2391, a novel vasodilator, and nicorandil on epimyocardial coronary artery (2.5- 3.0 mm outer diameter) and mid-myocardial coronary artery (0.8-1.0 mm outer diameter) were investigated in porcine isolated coronary arteries. In addition, the vasorelaxant responses of KRN2391 and nicorandil were compared with those of nitroglycerin and cromakalim, a K+ channel opener, in epi- and mid-myocardial coronary arteries. 2. Nitroglycerin showed a more potent relaxant effect on epi-myocardial coronary arteries than on mid-myocardial coronary arteries, whereas cromakalim produced greater relaxation responses in mid-myocardial coronary arteries. There was no difference between epi- and mid-myocardial coronary arteries in terms of the relaxant effect of KRN2391 and nicorandil. 3. Relaxation induced by KRN2391 in epi- and mid-myocardial coronary arteries was inhibited by oxyhaemoglobin, a pharmacological antagonist of nitrovasodilators, and glibenclamide, a pharmacological antagonist of K+ channel opening drugs. However, the inhibitory effect of glibenclamide on KRN2391-induced relaxation was greater in mid-myocardial coronary artery than in epi-myocardial coronary artery. 4. Relaxation induced by nicorandil was inhibited by oxyhaemoglobin alone in epi-myocardial coronary arteries and by both oxyhaemoglobin and glibenclamide in mid-myocardial coronary arteries. 5. In epi- and mid-myocardial coronary arteries, relaxation induced by cromakalim was inhibited by glibenclamide but not by oxyhaemoglobin, whereas relaxation induced by nitroglycerin was inhibited by oxyhaemoglobin but not by glibenclamide. 6. These results suggest that KRN2391 and nicorandil exhibit a dual mechanism of action acting partly as a nitrate and partly as a K+ channel opener. The mechanism of action of these drugs depend on the segment of coronary artery studied. Furthermore, the dual mechanism of action of KRN2391 and nicorandil seems to contribute to the equipotent relaxant effect between epi- and mid-myocardial coronary arteries.

Hemodynamic profile of KRN2391, a novel vasodilator, in anesthetized dogs.

In the present study, we compared the effects of KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethanesulfonate), a novel vasodilator, with those of nicorandil and nifedipine on hemodynamic profiles. KRN2391 (1-30 micrograms), nicorandil (10-300 micrograms), and nifedipine (0.1-3 micrograms) increased coronary, mesenteric, renal and femoral blood flows in a dose-dependent manner when intraarterially administered. KRN2391 was approximately 18 times more potent than nicorandil and about five times less potent than nifedipine in increasing coronary blood flow. Intravenous (i.v.) administration of KRN2391, nicorandil, and nifedipine produced increases in coronary and mesenteric blood flows and decreases in these vascular resistances. Although nicorandil i.v. had no significant effect on renal blood flow (RBF), nifedipine i.v. decreased RBF whereas KRN2391 i.v. increased it. Femoral BF (FBF) decreased only at the highest i.v. dose of KRN2391 and decreased after an initial increase with nicorandil. Nifedipine i.v. had no significant effect on FBF. The effects of these three agents in increasing BF and in decreasing vascular resistance were most prominent in coronary vasculature. The duration of the effect of KRN2391 in increasing coronary BF (CBF) was longer than that of nicorandil but was similar to that of nifedipine. The hypotensive effect of KRN2391 was also weaker than its effect in increasing CBF in comparison with nicorandil and nifedipine. Thus, KRN2391 was demonstrated to possess a preferential activity on coronary vasculature.

Comparison of the effects of KRN2391 and other coronary dilators on porcine isolated coronary arteries of different sizes.

The present study was performed to determine whether KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethanesulphonate), a novel vasodilator, shows different effects on porcine isolated coronary arteries of different sizes. The vasodilating effects of KRN2391 on porcine large (2.5-3.0 mm outer diam.) and small (0.8-1.0 mm) coronary arteries were also compared with those of cromakalim, nicorandil, nifedipine, nitroglycerin and adenosine. The relaxant effects of these drugs were examined in coronary arteries contracted by 25 mM KCl. Nitroglycerin caused greater relaxation in large vessels than in small vessels. In contrast, adenosine, nifedipine and cromakalim caused greater relaxation in small vessels. However, there was no difference between large and small vessels in the relaxing effects of KRN2391 and nicorandil. These unique features of KRN2391 and nicorandil appear to be beneficial in ischaemic heart disease.