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)     

K+ channel-opening action contributes to the preventive effects of nicorandil on U46619-induced vasoconstriction of canine large coronary arteries in vivo

The antispasmogenic effects of nicorandil on epicardial coronary artery vasoconstriction were compared with those of a K+ channel opener, cromakalim, and a nitrovasodilator, nitroglycerin, in open-chest dogs. Intracoronary administration of U46619 (0.5-1.0 micrograms), a stable thromboxane A2 analogue, reduced the external diameter of the left circumflex coronary artery with no marked alternations in systemic hemodynamics. This U46619-induced vasoconstriction of large epicardial coronary arteries was dose-dependently prevented by the intracoronary infusion of nicorandil (1-10 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min). After pretreatment with glibenclamide (3 mg/kg, i.v.), and ATP-sensitive K+ channel blocker, these effects of nicorandil and cromakalim were inhibited significantly, whereas the response to nitroglycerin remained unchanged. Nicorandil (3 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min) increased coronary blood flow. However, the inhibitory effects of each drug on the U46619-induced vasoconstriction were not influenced by the partial occlusion of the left circumflex coronary artery, which kept coronary blood flow constant. This indicates a direct antispasmogenic effect of K+ channel openers, which is independent of that mediated by the response to flow. Furthermore, our results suggest that, by this effect, nicorandil protects large coronary arteries from U46619-induced vasoconstriction.     

Vasorelaxant action of Ki1769, a new pyridinecarboximidamide, in isolated porcine coronary artery

The characteristics of KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethansulfonate) and its phenethyl and 2-hydroxyethyl derivatives (Ki1769 and Ki3315) were studied in isolated porcine coronary arteries. KRN2391, Ki1769 and Ki3315 produced concentration-dependent relaxation of coronary arteries contracted by 25 mM KCl and the order of relaxant potency was KRN2391 > Ki1769 > Ki3315. At the maximum effect, KRN2391 produced nearly complete relaxation but Ki1769 produced about 66% relaxation. The maximum effect of Ki3315 could not be obtained because of its solubility. The relaxation induced by KRN2391 was antagonized by glibenclamide and methylene blue but relaxations caused by Ki1769 and Ki3315 were antagonized by glibenclamide alone. The antagonistic effect of glibenclamide on Ki1769- and Ki3315-induced relaxations was more potent than that on KRN2391-induced relaxation. KRN2391 induced relaxation of coronary arteries contracted by 40 mM KCl in a concentration-dependent manner but the effect of KRN2391 was smaller against 40 mM KCl-induced contractions than against 25 mM KCl-induced contractions. Ki1769 had almost no effect on coronary arteries contracted by 40 mM KCl. These results suggest that pyridinecarboximidamide derivatives which do not possess a nitroxyl group have vasodilating ability based on a K+ channel opening action.     

Effects of carperitide (alpha-human atrial natriuretic peptide) on acute congestive heart failure in dogs

Effects of carperitide (alpha-human atrial natriuretic peptide) on hemodynamics and renal function in dogs with congestive heart failure (CHF) produced by volume expansion and ligation of the left anterior descending coronary artery were compared with those of various anti-heart failure agents (cardiotonic, vasodilator and diuretic). Carperitide (0.1-1 microgram/kg/min) dose-dependently decreased the elevated left ventricular end-diastolic pressure (LVEDP). No significant changes in cardiac contractility (LV dP/dtmax) and heart rate (HR) were noted, although cardiac output (CO) tended to reduce during the infusion of carperitide. Nitroglycerin (NG; 3 micrograms/kg/min) and furosemide (1 mg/kg) also decreased LVEDP, but the potency was less than that of carperitide. Sodium nitroprusside (SNP; 10 micrograms/kg/min) and dobutamine (10 micrograms/kg/min) caused a reduction in LVEDP and increased CO with an increase in HR. Hydralazine (H; 100 micrograms/kg/min) increased CO without reduction in LVEDP and induced a pronounced increase in HR. Double product (systolic blood pressure x HR), an index of myocardial oxygen consumption, was significantly reduced by carperitide, but significantly increased by DB and H. Carperitide, unlike NG, SNP, H and DB, increased urine volume and urinary electrolyte excretion. These results suggest that carperitide will be an useful therapeutic agent for the treatment of CHF.     

The haemodynamic effects of milrinone HCl in halothane anaesthetised horses

The haemodynamic effects of milrinone hydrochloride were determined in halothane-anaesthetised horses. Six healthy adult horses were anaesthetised with guaifenesin and thiamylal and maintained with halothane in oxygen (end-tidal halothane concentration of 1.15%). Baseline haemodynamic data were recorded after a 45 min stabilisation period. All 6 horses received a single loading dose of milrinone HCl, 0.2 microgram/kg i.v., followed by progressively increasing infusions of 2.5, 5, 10 and 20 micrograms/kg bwt/min. Each infusion lasted for 15 min and produced dose related increases in heart rate, mean arterial blood pressure, cardiac output, maximum rate of increase and decrease of left ventricular pressure (+/- dP/dtmax) and ejection fraction in halothane anesthetised horses. Median artery blood flow increased following milrinone administration. Right atrial and pulmonary artery pressures, systemic vascular resistance and left ventricular end-diastolic and end-systolic volumes decreased. Most haemodynamic changes were sustained throughout the infusion period and for 30 min following the termination of milrinone infusion. Systemic vascular resistance was increased above baseline values at 30 min following the termination of milrinone infusion. No adverse side effects were observed during this study although a milrinone infusion rate of 20 micrograms/kg bwt/min increased heart rate to values greater than 50 beats/min. The results of this study suggest that milrinone produces beneficial haemodynamic effects in halothane anaesthetised horses and is potentially useful in the treatment of patients with a reduced cardiac output.     

Zaprinast, but not dipyridamole, reverses hemodynamic tolerance to nitroglycerin in vivo

Hemodynamic tolerance to nitroglycerin was developed in spontaneously hypertensive rats following 2-3 days of pretreatment with 100 mg/kg of nitroglycerin administered s.c. 3 times/day. Tolerance was evaluated both in vivo, by administering ascending bolus doses of nitroglycerin of 1-300 micrograms/kg i.v., and ex vivo in isolated, denuded aortic vascular rings by exposure to ascending concentrations of nitroglycerin of 0.0003-100 microM. Tolerance was observed as a significant blunting of the hypotensive and vasorelaxant effect of nitroglycerin. Co-incubation of tolerant aortic rings and pretreatment of tolerant SHR with 10 microM and 0.1-10 mg/kg zaprinast, respectively, resulted in full restoration of the vasorelaxant and hypotensive effect of nitroglycerin. Zaprinast partially reversed hemodynamic tolerance at 0.01 mg/kg. Conversely, dipyridamole (10 microM) reversed tolerance ex vivo, but was ineffective in reversing tolerance in vivo at pretreatment doses of 30 and 60 mg/kg. Following a 100-micrograms/kg i.v. challenge dose of nitroglycerin, aortic cyclic guanosine monophosphate (cGMP) levels were lower in nitroglycerin tolerant SHR when compared to non-tolerant SHR. Pretreatment of tolerant SHR with 10 mg/kg zaprinast restored the increase in cGMP levels to nitroglycerin to that seen in non-tolerant SHR. Conversely, dipyridamole (30 mg/kg) pretreatment was not effective in restoring cGMP levels. These data therefore suggest that reversal of hemodynamic tolerance in vivo is related to restoration of changes in vascular cGMP levels. Zaprinast, a selective cGMP phosphodiesterase inhibitor, effectively reverses tolerance and dipyridamole, a rather non-selective inhibitor, does not.     

Pharmacological profile of valsartan, a non-peptide angiotensin II type 1 receptor antagonist. 5th communication: hemodynamic effects of valsartan in dog heart failure models

Hemodynamic effects of valsartan ((S)-N-valeryl-N-?[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl?valine, CAS 137862-53-4, CGP 48933), a non-peptide angiotensin II type 1 receptor antagonist were examined in dogs with heart failure induced acutely by coronary artery ligation and chronically by rapid-ventricular pacing. Coronary artery ligation induced decrease in cardiac output and increase in left ventricular end-diastolic pressure. Valsartan at 10 mg/kg i.v. reduced blood pressure, heart rate, left ventricular pressure, left ventricular end-diastolic pressure and total systemic resistance. Similar changes were observed with enalaprilat at 0.1 mg/kg i.v. Rapid left ventricular pacing for 2 weeks reduced cardiac contractility. Valsartan, administered at a dose of 100 mg/kg/d p.o. for 2 weeks, lowered left ventricular end-diastolic pressure. Valsartan reduced preload and afterload in these two dog heart failure models.     

Comparison of haemodynamic responses to cilnidipine and nicardipine in an experimental model of acute congestive heart failure

1. The haemodynamic effects of cilnidipine, a new calcium channel blocker, were examined in a canine model of acute congestive heart failure and were compared with those of nicardipine at equihypotensive doses. 2. The model was prepared by injections of saponin into coronary arteries of anaesthetized open-chest dogs followed by volume loading and continuous i.v. infusion of methoxamine. After the treatment, aortic blood flow (AoF) and left ventricular dP/dt markedly decreased, while left ventricular end-diastolic pressure (LVEDP), right atrial pressure and systemic vascular resistance (SVR) increased. Cilnidipine (0.3, 1.0 and 3.0 micrograms/kg per min), nicardipine (0.3, 1.0 and 3.0 micrograms/kg per min) or the respective vehicle was given i.v. after accomplishment of heart failure. 3. These drugs both produced a comparable reduction in aortic pressure and an increase in AoF associated with profound decreases in LVEDP, SVR and coronary vascular resistance. In contrast, administration of nicardipine was associated with significant increases in heart rate and cardiac contractility but that of cilnidipine was not. 4. These results indicate that cilnidipine as well as nicardipine can exert beneficial haemodynamic effects in a model of acute heart failure probably through lessening afterload and cilnidipine may moderate reflex-induced sympathetic stimulation.     

Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310

The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450 > SKP-818 > Lemakalim > SKP-310 (EC50: 0.12, 0.55, 0.71 and 5.89 mumol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3-100 micrograms/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED20: 9.8, 11.7 and 22.4 micrograms/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3-1,000 micrograms/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED20: 2.6, 4.2 and 588.8 micrograms/kg, respectively). They slightly increased left ventricular positive dP/dtmax with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (Emax: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.     

Effects of a K+ATP channel opener, lemakalim, on systemic, coronary and regional vascular dynamics in conscious dogs: comparison with nifedipine, adenosine, nitroglycerin and acetylcholine

The systemic, coronary and regional vascular responses to the K+ATP channel opener lemakalim were compared to other potent vasodilators (i.e., nifedipine, adenosine, nitroglycerin and acetylcholine). Experiments were performed in 12 conscious dogs 2 to 4 weeks after implantation of aortic catheters and flow probes on the ascending aorta, left circumflex coronary, celiac, mesenteric, renal and iliac arteries, and solid-state miniature pressure gauges in the left ventricular cavity. Dose-response curves induced by bolus injection (i.v.) were examined. For doses that reduced total peripheral resistance by 22%, lemakalim reduced celiac (-28 +/- 2%), mesenteric (-24 +/- 3%), renal (-17 +/- 3%) and iliac (-18 +/- 3%) vascular resistances (i.e., by amounts similar to those observed with the other vasodilators, except for adenosine, which increased renal resistance). At these doses, lemakalim induced a greater decrease (-52 +/- 3%) (P < .05) in coronary resistance, as compared with nifedipine (-35 +/- 3%), adenosine (-38 +/- 3%), nitroglycerin (-25 +/- 2%) and acetylcholine (-32 +/- 3%). However, when near maximal vasodilation was elicited, adenosine elicited the greatest (P < .05) decrease in coronary resistance (-81 +/- 1%), as compared with lemakalim (-74 +/- 2%), nifedipine (-67 +/- 2%), nitroglycerin (-63 +/- 2%) and acetylcholine (-72 +/- 1%). Both the time to maximal increases in regional blood flow and the time for recovery in all vascular beds were significantly prolonged for lemakalim compared with the other vasodilators. Thus, the K+ATP channel opener lemakalim dilates the coronary bed out of proportion to other vascular beds, is relatively more potent at lower doses than other vasodilators and exhibits a delayed and more prolonged action in all regional vascular beds.     

Vascular and cardiac effects of amlodipine in acute heart failure in dogs

BACKGROUND: Amlodipine improves exercise capacity in patients with chronic congestive heart failure (HF), but the mechanisms of this effect are unknown. OBJECTIVE: To test the hypothesis, in a canine model of acute, ischemic HF, that amlodipine increases vascular capacitance and reduces cardiac filling pressures. METHODS: Amlodipine was given to 13 anesthetized, splenectomized dogs (six controls and seven with HF). Aortic, left ventricular end-diastolic (LVEDP) and portal venous (Pportal) pressures, cardiac output, portal flow (ultrasonic probe) and intestinal blood volume (IBV, 99mTc blood-pool scintigraphy) were measured. Intestinal vascular conductance (= 1/resistance) and vascular capacitance (CAP) were measured before and 15 mins after repetitive 150 micrograms/kg dosages of amlodipine (maximum cumulative dosage, 1000 micrograms/kg). Pportal-IBV curves were obtained by impeding portal flow (pneumatic cuff), and change in CAP was defined by the change in IBV at Pportal = 7.5 mmHg. HF was induced by microsphere embolization of the left coronary artery. RESULTS: CAP increased in the control group (+ 28%, P < 0.01) but decreased (-9%, P < 0.05) in the HF group. Left ventricular stroke work increased in the control group (P < 0.05), while it decreased (P < 0.05) in the HF group, suggesting a negative inotropic effect. In the control group, LVEDP increased after amlodipine was given (P < 0.05) but did not change significantly in the HF group. CONCLUSIONS: In the acute experimental HF model, amlodipine failed to increase intestinal vascular CAP or decrease filling pressures, and may have had a negative inotropic effect. The experiment failed to demonstrate a beneficial hemodynamic effect of amlodipine in acute HF, and the mechanism of benefit of this agent in chronic HF remains unclear.     

Effect of diaspirin cross-linked hemoglobin and norepinephrine on systemic hemodynamics and regional circulation in rats

Diaspirin cross-linked hemoglobin (DCLHb) (400 mg/kg, i.v.) produced a pressor effect that was equal to that produced by norepinephrine (NE) (25 micrograms/kg/min i.v. infusion). Total peripheral resistance was increased by DCLHb and more significantly by NE. Heart rate was not affected by DCLHb but was significantly increased by NE. The cardiac output and stroke volume were insignificantly increased by DCLHb but were significantly decreased by NE. DCLHb and NE produced a significant increase in blood flow to the heart. The vascular resistance in the heart was not affected by DCLHb but was decreased by NE. DCLHb did not affect the renal and brain circulation, but NE in kidneys decreased the blood flow and increased the vascular resistance, whereas in the brain it increased the blood flow and decreased the vascular resistance. DCLHb increased the blood flow to the stomach and small intestine. The vascular resistance was not affected by DCLHb in the gastrointestinal tract. NE did not affect the blood circulation in the gastrointestinal tract. Blood flow to the spleen was increased by DCLHb, and there was no change in the vascular resistance. NE insignificantly decreased the blood flow to the spleen and significantly increased the vascular resistance. The blood circulation to the mesentery and pancreas was not affected by DCLHb, whereas NE increased the blood flow without affecting the vascular resistance. DCLHb produced a significant increase in the blood flow to the skin without affecting the vascular resistance, whereas NE did not affect the blood flow but increased the vascular resistance. DCLHb did not affect the blood flow to the musculo-skeletal system but increased the vascular resistance, whereas NE decreased the blood flow and increased the vascular resistance. In summary, although the pressor effect of DCLHb and NE at the doses studied is equal, DCLHb did not decrease the blood flow to any organ, whereas NE produced significant decreases in blood flow to several organs. It is concluded that the blood flow to most of the organs is either increased or not affected by DCLHb.     

Large unidentified open reading frame in plastid DNA (ORF2280) is expressed in chloroplasts

Although many studies investigating the effect of cromakalim on bladder contractility exist, thus far, there are no published studies investigating its effect on micturition function in conscious rats. We measured the effect of cromakalim i.v. on urine output, frequency, volume of each micturition, and blood pressure in saline-diuresed and non-diuresed rats. In saline-diuresed rats cromakalim produced significant decreases in urine output (0.1 mg/kg, 32%; 0.3 mg/kg, 46%; 1.0 mg/kg, 68%) and average frequency (0.1 mg/kg, 36%; 0.3 mg/kg, 51%; 1.0 mg/kg, 70%) in the first 3 hours. At 3-6 hours after administration of cromakalim there were rebound increases in both urine output (0.1 mg/kg, 290%; 0.3 mg/kg, 373%; 1.0 mg/kg, 538%), and frequency (0.1 mg/kg, 147%; 0.3 mg/kg, 181%; 1.0 mg/kg, 314%) and by 6-12 hours the effects of cromakalim on micturition function were gone. Mean arterial pressure dropped to 50% of control immediately after cromakalim administration in saline-diuresed rats and began to return to control levels after 3 hours. Cromakalim produced similar results in non-diuresed rats. The decrease in urine output 0-3 hours after cromakalim administration may have been a consequence of cromakalim's profound decrease in blood pressure that occurred during that time.     

The isolated supported canine heart: a model for the evaluation of drug effects on regional myocardial blood flow

The present investigation was designed to determine the effect of propranolol on regional myocardial blood flow and oxygen consumption (MVO2) in the isolated supported dog heart preparation perfused at a constant coronary blood flow. The transmural distribution of blood flow, determined by the radioactive microsphere technique, was expressed as the epicardial/endocardial blood flow ratio (epi/endo). Propranolol (0.5 mg/kg i.v.) produced a significant decrease in heart rate and myocardial contractile force and an increase in coronary artery perfusion pressure due to an increase in coronary vascular resistance. These hemodynamic changes were accompanied by significant decreases in epi/endo (increased endocardial perfusion) and MVO2. Reduction of perfusion pressure to control by a decrease in total coronary blood flow produced no further change in epi/endo or MVO2. However, increasing heart rate to control increased epi/endo to predrug levels. Contractile force and MVO2 remained reduced below control. Norepinephrine infusion (1 mug/min intracoronary) produced a significant increase in heart rate and contractile force and decrease in perfusion pressure. These changes were accompanied by an increase in epi/endo and MVO2. Propranolol (0.5 mg/kg i.v.) abolished the response to norepinephrine. Propranolol may produce beneficial effects in angina pectoris by a decrease in epi/endo (via a reduction in heart rate) and MVO2 and by beta adrenergic blockade of the deleterious effects of catecholamines.     

Primary anastomosis of the trachea: management and pitfalls

The potentiating activity of SG-86[N-(2-hydroxyethyl)nicotinamide], a denitrated metabolite of nicorandil, on the adenosine-induced vasodepression was compared with that of nicorandil in anesthetized rats. Single bolus i.v. adenosine (3-100 micrograms/kg) produced dose-dependent reductions of blood pressure, accompanied by slight decreases (except for 100 micrograms/kg) in heart rate. The adenosine-induced vasodepression was significantly enhanced during i.v. infusion of either SG-86 (100 micrograms/kg per min) as well as nicorandil (10 micrograms/kg per min). The enhancement of adenosine action by them did not occur in the presence of glibenclamide (20 mg/kg i.v.). Single bolus i.v. injections of SG-86 (0.3-30 mg/kg), except for 30 mg/kg, which caused a glibenclamide-sensitive decrease by about 5-10 mmHg in mean arterial blood pressure, had no effects on blood pressure and heart rate, whereas those of nicorandil (30-300 micrograms/kg) elicited overt reduction of blood pressure, accompanied by decreases in heart rate. The present results revealed that SG-86, like nicorandil, significantly enhanced the vasodepressor response to adenosine, probably in part through KATP channel activation, and that the activity of SG-86 was about 10 times less potent than that of nicorandil.     

Triplet repeat disorders

Bosentan is a nonspecific antagonist for endothelin (ET) receptors, and BQ123 is a specific inhibitor for ET-A receptors. We compared the effects of bosentan (10 mg/kg intravenously, i.v.) and BQ123 (10 mg/kg/h i.v.) on blood pressure and renal function in deoxycorticosterone acetate (DOCA)-salt rats, Dahl salt-sensitive (Dahl-S) rats, and normotensive Wistar rats. In normotensive Wistar rats, bosentan and BQ123 decreased blood pressure. Only BQ123 decreased glomerular filtration rate (GFR) and filtration fraction. These results indicate that ET-A receptors play a role in glomerular function. In DOCA-salt rats, bosentan and BQ123 caused a decrease in blood pressure to normal range and a decrease in renal vascular resistances. Bosentan decreased filtration fraction. Paradoxically, BQ123 caused a decrease in GFR. In Dahl-S rats, bosentan and BQ123 decreased blood pressure, but blood pressure did not reach normal ranges. Bosentan did not modify renal function, but BQ123 caused a decrease in the GFR and filtration fraction. Our results confirm the importance of specific and nonspecific ET antagonists in decreasing blood pressure in models of salt-dependent hypertension. However nonspecific inhibition of ET action did not improve renal function and specific inhibition of ET-A receptors by BQ123 temporarily worsened renal function.     

Reduced epicardial coronary vasodilator capacity in patients with left ventricular hypertrophy

BACKGROUND: Enlargement of the epicardial coronary arteries occurs in left ventricular (LV) hypertrophy as an adaptation to the increased coronary blood flow. METHODS AND RESULTS: Vasodilator capacity of the epicardial coronary arteries was determined in 44 patients. The dose-response relation of intracoronary nitroglycerin was assessed in 14 patients (7 control subjects and 7 patients with aortic stenosis [study A]) using quantitative coronary angiography. In a second study (B), vasodilator capacity of the epicardial coronary arteries was determined in 15 control subjects and 15 patients with valvular heart disease. In study A, a curvilinear dose-response relation with maximal vasodilation after 90 micrograms intracoronary nitroglycerin was found in both control subjects and patients with aortic stenosis. Vasodilator capacity was reduced in those with aortic stenosis, although sensitivity to nitroglycerin was similar in both groups. In study B, coronary circumferential length at baseline was larger in those with LV hypertrophy (12.2 +/- 2.2 mm) than in control subjects (8.6 +/- 1.5 mm; P < .001); after 100 micrograms intracoronary nitroglycerin, it increased to 12.9 +/- 2.2 mm (6 +/- 5%) in those with LV hypertrophy and to 10.3 +/- 1.5 mm (21 +/- 8%; P < .001) in control subjects. An inverse relation between baseline circumferential length and its percent increase after nitroglycerin was found (r = -.71, P < .001). CONCLUSIONS: Vasodilator capacity of the epicardial coronary arteries is reduced in patients with LV hypertrophy, although sensitivity to nitroglycerin is normal. This may be due to a flow-mediated decrease in coronary vasomotor tone and/or the occurrence of vascular remodeling with an enlargement of the coronary arteries.     

Comparison of interstitial fluid and coronary venous adenosine levels in in vivo porcine myocardium

There are numerous reports of interstitial fluid (ISF) and coronary venous adenosine measurements in isolated perfused hearts. This study was designed to simultaneously compare ISF and coronary venous adenosine concentrations during various interventions in in vivo porcine myocardium. In anesthetized, open-chest pigs, ISF adenosine, inosine, and hypoxanthine were sampled with cardiac microdialysis. Coronary sinus or venous purines were sampled with a metabolism-stop solution. During basal conditions, ISF adenosine was greater than coronary venous adenosine, but vascular inosine and hypoxanthine were greater than corresponding ISF levels. Dobutamine (20 micrograms/kg/min, i.v.) and systemic hypoxia produced three- and two-fold increases in ISF adenosine, but had no significant effect on coronary sinus adenosine concentration. Hypoxia, but not dobutamine, increased coronary sinus total purines 50%. In contrast to these interventions, intracoronary adenosine infusion (0.5-50 micrograms/kg/min) was associated with significantly greater coronary venous adenosine concentrations than ISF levels. Only during a coronary artery occlusion/reperfusion protocol were ISF and coronary venous adenosine concentrations comparable. The results of this study thus provide in vivo evidence of the powerful endothelial and red blood cell metabolic barriers to both exogenous and endogenous adenosine. These results also illustrate the differences in adenosine concentrations in the ISF and vascular spaces.     

Altered proton extrusion in cells adapted to growth at low extracellular pH

Coronary vasodilator and hemodynamic profiles of JTV-506, a newly synthesized 2,2-bis-methoxymethyl benzopyran-derivative potassium channel opener, were evaluated in conscious dogs. JTV-506 (2.5-10 microg/kg, i.v.) elicited dose-dependent increases in coronary blood flow (CBF) and heart rate (HR) but only slight changes in mean blood pressure (MBP). Other vasodilators such as levcromakalim, nicorandil, diltiazem, and nitroglycerin, when administered intravenously, elicited increases in CBF and HR and a decrease in MBP. When dosed orally JTV-506 (0.01-0.1 mg/kg), levcromakalim (0.01-0.1 mg/kg), nicorandil (1-10 mg/kg), and nifedipine (3-30 mg/kg) also elicited increases in CBF and HR and a decrease in MBP. JTV-506 caused a marked increase in CBF with slight changes in HR and MBP. In contrast to JTV-506, however, the changes caused by levcromakalim, nicorandil, and nifedipine were accompanied by a marked increase in HR and a marked decrease in MBP. These results suggest that the action of JTV-506 on hemodynamics is different from that of other vasodilators, including reference potassium channel openers, and that the profile of cardiovascular action of JTV-506 may be useful in the treatment of angina pectoris.     

Effect of efonidipine hydrochloride (NZ-105), a dihydropyridine derivative with calcium antagonistic action, on myocardial oxygen tension in anesthetized dogs

Effect of efonidipine hydrochloride (efonidipine) on myocardial oxygen tension (PO2) was investigated in open-chest anesthetized dog and compared with those of nifedipine and nisoldipine. PO2 was measured by a membrane-coated platinum wire, which was inserted into the myocardium. Intravenous administration of efonidipine (10 and 30 micrograms/kg) decreased mean blood pressure to a similar extent to that induced by nifedipine (1 and 3 micrograms/kg) or nisoldipine (1 and 3 micrograms/kg). Efonidipine increased coronary blood flow (CBF) and decreased the double product (DP) dose-dependently. Similar results were observed in nisoldipine-treated animals. Nifedipine produced a transient increase in CBF and a transient decrease in DP. The duration of action of efonidipine on CBF was longer than that of nifedipine or nisoldipine. Efonidipine increased PO2, and the effect was more pronounced in the endocardial region than in the epicardial region. Nifedipine had no significant effect on the PO2, while nisoldipine significantly increased PO2 in the endocardial region. The effect of efonidipine on the PO2 was greater than that of nisoldipine and the duration of action of efonidipine was longer than that of nisoldipine. These results suggest that efonidipine may increase PO2 by mediating, at least in part, a long-lasting increase in oxygen supply and a decrease in oxygen demand in dog heart.