Cardiovascular effects of the novel potassium channel opener bimakalim in conscious pigs after myocardial infarction: A comparative study with nicorandil

Woerkens, Leon J. van; Baas, Niels R. A.; Giessen, Willem J. van der; Verdouw, Pieter D.

doi:10.1007/bf00054190

Cited by 11 publications

(6 citation statements)

References 20 publications

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“…Thus, the discrepancy between the two studies regarding the infusion rate–coronary flow relationship was likely due to a higher plasma drug concentration in our study. In a previous study using conscious swine with myocardial infarction, 14 neither heart rate nor mean aortic pressure changed significantly over a wide range of nicorandil infusion rates (from 10 to 80 μg/kg per min, i.v.). Thus, it appears that heart rate and mean aortic pressure responses to nicorandil depend on drug concentration and anaesthesia status.…”

Section: Discussionmentioning

confidence: 70%

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Nicorandil Improves Myocardial High‐Energy Phosphates In Postinfarction Porcine Hearts

Murakami

Zhang

et al. 2002

Clin Exp Pharma Physio

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1. Nicorandil is a potent vasodilator combining the effects of a nitrate with an ATP-sensitive potassium channel (K(ATP)) opener. Because the postinfarct remodelled heart has increased vulnerability to subendocardial hypoperfusion, it is possible that the vasodilator effects of nicorandil could cause transmural redistribution of blood flow away from the subendocardium. Alternatively, the K(ATP) channel opening effects of nicorandil could exert a beneficial effect on mitochondrial respiration. Consequently, the present study was performed to examine the effect of nicorandil on energy metabolism in the postinfarct heart. 2. Studies were performed in swine in which myocardial infarction produced by proximal left circumflex coronary artery ligation had resulted in left ventricular remodeling. [(31)P] nuclear magnetic resonance spectroscopy (MRS) was used to examine the myocardial energy supply/demand relationship across the left ventricular wall while the transmural distribution of blood flow was examined with radioactive microspheres. Data were obtained during baseline conditions and during infusion of nicorandil (100 microg, i.v., followed an infusion of 25 microg/kg per min). 3. Nicorandil caused coronary vasodilation with a preferential increase in subepicardial flow; however, subendocardial flow also increased significantly. Nicorandil had no significant effect on the rate-pressure product or myocardial oxygen consumption. The ratio of phosphocreatine (PCr)/ATP determined with MRS was abnormally depressed in remodelled hearts (2.01 +/- 0.11, 1.85 +/- 0.10 and 1.59 +/- 0.11 for subepicardium, midwall and subendocardium, respectively) compared with normal (2.22 +/- 0.11, 2.01 +/- 0.15 and 1.80 +/- 0.09, respectively). Nicorandil had no effect on the high-energy phosphate content of normal hearts. However, nicorandil increased the PCr/ATP ratio in the subendocardium of remodelled hearts from 1.59 +/- 0.11 to 1.87 +/- 0.10 (P < 0.05). 4. Although nicorandil caused modest redistribution of blood flow away from the subendocardium of the postinfarct left ventricle, this was associated with an increase of the PCr/ATP ratio towards normal. These results suggest that nicorandil exerts a beneficial effect on energy metabolism in the subendocardium of the postinfarct remodelled left ventricle.

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Section: Discussionmentioning

confidence: 70%

“…In response to the infarct, the residual myocardium undergoes dilatation and hypertrophy, with an approximate 25% increase in LV mass despite the loss of myocardium in the region of the occluded coronary artery 10 . Hearts with postinfarct remodelling have been found to have increased vulnerability to subendocardial ischaemia 10,14 …”

Section: Discussionmentioning

confidence: 99%

Nicorandil Improves Myocardial High‐Energy Phosphates In Postinfarction Porcine Hearts

Murakami

Zhang

et al. 2002

Clin Exp Pharma Physio

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“… Comparison of the reflex‐tachycardia in response to systemic hypotension produced by Z1046 (○, present study), the dopamine receptor agonist epinine (□, Van Woerkens et al , 1992b), the calcium channel blocker nisoldipine (•, Duncker et al , 1987), and the K + atp channel activators nicorandil (▪, Verdouw et al , 1987) and bimakalim (▴, Van Woerkens et al , 1992a) in awake resting pigs. Data are presented as absolute changes in heart rate vs absolute changes in aortic pressure.…”

Section: Discussionmentioning

confidence: 83%

“…This hypothesis is supported by the observation that 100 μg kg −1 resulted in transient (< 5 min) increases in heart rate and cardiac output, that were absent when animals were pretreated with combined α‐ and β‐adrenoceptor blockade. It is important to note that in our awake swine model, Z1046 produced severe hypotension with considerably less reflex‐tachycardia than produced by pure vasodilators such as the dihydropyridine calcium channel blockers (Duncker et al , 1988) or K + ATP channel activators like nicorandil (Verdouw et al , 1987) and bimakalim (Van Woerkens et al , 1992a) that we have studied in the same model (Figure 7). The dopamine receptor agonist epinine, which also had some β 2 ‐adrenoceptor agonistic properties in this model, produces slightly greater increases in heart rate at a given reduction in mean aortic blood pressure (Van Woerkens et al , 1992b).…”

Section: Discussionmentioning

confidence: 93%

“…This attenuated hypotensive eect was not due to mitigation of the systemic vasodilator response but was the result of a maintained stroke volume and hence cardiac output following the second administration of 10 mg kg 71 (Figure 6). Figure 7 Comparison of the re¯ex-tachycardia in response to systemic hypotension produced by Z1046 (*, present study), the dopamine receptor agonist epinine (&, Van Woerkens et al, 1992b), the calcium channel blocker nisoldipine (*, Duncker et al, 1987), and the K + ATP channel activators nicorandil and bimakalim (~, Van Woerkens et al, 1992a) in awake resting pigs. Data are presented as absolute changes in heart rate vs absolute changes in aortic pressure.…”

Section: Haemodynamic Responses To Repeated Administration Of An Idenmentioning

confidence: 83%

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Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046

Duncker

Haitsma

Geest

et al. 1997

British J Pharmacology

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1 In view of the potential therapeutic application of speci®c dopamine receptor agonists in the treatment of hypertension and left ventricular dysfunction, we investigated the cardiovascular actions of the novel mixed D 1 /D 2 dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise. 2 Thirteen swine were chronically instrumented under sterile conditions for measurement of systemic, pulmonary, and coronary haemodynamics. Regional blood¯ows were determined with the radioactive microsphere technique. 3 Z1046 (1, 10, 100 mg kg 71 , i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27+3%, P40.05) in awake resting pigs which was accompanied by only minimal re¯ex activation of the sympathetic nervous system. The hypotensive response was principally the result of peripheral vasodilatation (system vascular resistance decreased up to 35+4%, P40.05), which was located in the cerebral, coronary, renal, mesenteric, adrenal, splenic and skeletal muscular vascular beds (vascular resistance decreased up to 30 ± 40% after the highest dose in these beds). Only in the cerebral and mesenteric bed was the vasodilatation suciently large to overcome the decrease in blood pressure and result in an increased blood¯ow; the vasodilatation in the coronary bed was most likely due to autoregulation as neither coronary blood¯ow nor myocardial oxygen demand were changed signi®cantly by Z1046. The systemic vasodilatation that was caused by the highest i.v. dose (100 mg kg 71 ) was accompanied by transient and minor increases in heart rate (15+5%, P40.05) and cardiac output (15+5%, P40.05) whereas after 10 mg kg 71 , i.v., a slight decrease in cardiac output also contributed to the hypotension. Z1046 had no eect on pulmonary vascular resistance. 4 The systemic vasodilator responses to Z1046 (100 mg kg 71 , i.v.) were sustained during treadmill exercise (2 ± 4 km h 71 which produced heart rates of up to 233+10 beats min 71 ), but with increasing treadmill speed attenuation of the exercise-induced increase in heart rate (711+3%, P40.05) and hence cardiac output (710+3%, P40.05) (as stroke volume was not altered by Z1046) contributed signi®cantly to a lower aortic blood pressure (720+3%, P40.05). Z1046 had no eect on pulmonary vascular resistance during exercise. 5 Oral administration of Z1046 (0.5, 1.5 mg kg 71 ) produced a fall in central aortic blood pressure (up to 15+3%, P40.05), which developed gradually during the ®rst 90 min and lasted up to 4 h after administration, again with negligible changes in heart rate and LVdP/dt max . 6 Neither non-selective a-and b-adrenoceptor blockade, nor selective a 2 -adrenoceptor blockade altered the vasodilator actions of Z1046, but non-selective a-and b-adrenoceptor blockade abolished the cardiac responses to dopamine receptor stimulation, suggesting that its cardiac actions were principally caused by D 2 -receptor-mediated inhibition of catecholamine release, whereas the vasodilator response was probably the result of vascular D 1 -receptor stimu...

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Is There a Potential Role for KATP Openers in the Treatment of Angina?

Opie

1995

Myocardial Protection and the KATP Channel

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Cardiovascular effects of the novel potassium channel opener bimakalim in conscious pigs after myocardial infarction: A comparative study with nicorandil

Cited by 11 publications

References 20 publications

Nicorandil Improves Myocardial High‐Energy Phosphates In Postinfarction Porcine Hearts

Nicorandil Improves Myocardial High‐Energy Phosphates In Postinfarction Porcine Hearts

Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046

Is There a Potential Role for KATP Openers in the Treatment of Angina?

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