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Circulation. 1996;94:2235-2240

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(Circulation. 1996;94:2235-2240.)
© 1996 American Heart Association, Inc.

Articles

Cardiovascular Effects of an Ultra–Short-Acting Nitric Oxide–Releasing Compound, Zwitterionic Diamine/NO Adduct, in Dogs

Ping Zhang, MD; Akitoshi Ohara, MD; Takashi Mashimo, MD; Jianhua Sun, MD; Satoshi Shibuta, MD; Koji Takada, MD; Hiroaki Kosaka, MD; Masaru Terada, PhD; Ikuto Yoshiya, MD

the Department of Anesthesiology (P.Z., A.O., T.M., S.S., K.T., I.Y.), the First Department of Surgery (J.S.), the First Department of Physiology (H.K.), and the Department of Legal Medicine (M.T.), Osaka University Medical School, Japan.

Correspondence to Ping Zhang, Department of Anesthesiology, Osaka University Medical School, Yamadaoka 2-2, Suita City, Osaka 565, Japan.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
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Background This study was conducted to clarify the cardiovascular effects of a new NO-releasing compound, NOC-7, and to compare it with other nitrovasodilators, sodium nitroprusside (SNP) and nitroglycerin, in dogs anesthetized with pentobarbital.

Methods and Results A bolus injection of NOC-7 decreased mean aortic blood pressure in a dose-dependent manner. The onset was rapid and the recovery quick. Continuous infusion of NOC-7 decreased mean aortic pressure from 115±3.9 to 84±2.9 mm Hg and infusion of SNP, from 118±3.8 to 87±3.1 mm Hg. The optimum doses of NOC-7 and SNP were determined to be 2.73±0.77 and 11.5±6.1 µg·kg-1·min-1, respectively. During infusion of NOC-7, heart rate and cardiac output were increased (P<.05), pulmonary artery pressure was not changed, and systemic and pulmonary vascular resistances were decreased (P<.05). Electromagnetic flowmetry showed that portal venous and internal carotid arterial blood flow were increased (P<.05) and that hepatic and renal arterial blood flows were not changed. These hemodynamic changes during NOC-7 infusion were similar to those with SNP. The plasma level of NO2-/NO3- did not change, but methemoglobin increased slightly (P<.05). Comparison between hypotensive responses before and after a 3.5-hour infusion of NOC-7 or nitroglycerin showed that acute tolerance developed to nitroglycerin but not to NOC-7.

Conclusions The results indicate that NOC-7 may be useful as an ultra–short-acting nitrovasodilator that has no major adverse effect or tolerance.


Key Words: endothelium-derived factors • vasodilation • nitroglycerin • hemodynamics


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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Nitric oxide was discovered in 1987 to be a major endothelium-derived relaxing factor.1 2 Endogenous NO produced in vascular endothelial cells rapidly diffuses into smooth muscle cells and activates soluble guanylate cyclase, which, in turn, increases the intracellular content of cGMP. Elevation of cGMP levels causes a decrease in intracellular Ca2+ levels in vascular smooth muscle, resulting in vasodilation.1 2 3

Recent studies have shown that the vasodilating effects of nitrovasodilators such as SNP and NTG were mediated by the generation of NO.4 5 Although SNP and NTG are widely used in the treatment of various cardiovascular disorders and in reducing blood pressure during anesthesia, there are limitations to their use; prolonged use of SNP increases the concentration of the metabolite cyanide, which may produce significant clinical toxicity.6 Tolerance to NTG is a clinically important problem that requires periodic discontinuation to restore effectiveness.7

Recently, a new class of NO-releasing compound, zwitterionic NOCs, were synthesized, which need no cofactor to release NO.8 NOCs can release NO constantly through a simple mechanism without any metabolism in acidic or neutral solution. Among NOCs (NOC-5, -7, -12, and -18), NOC-7 [1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene], the structure of which is shown in Fig 1Down, releases NO most rapidly, with a half-life of 1.7 minutes at pH 7.4 and 37°C in PBS. We first used NOC-18, which has the longest half-life (78 minutes), as a source of NO to determine the roles of NO in the central nociceptive mechanism in vivo9 and in apoptosis in macrophages in vitro.10 However, the cardiovascular effects of these agents have not been studied. Thus, this study was conducted to clarify the effects of NOC-7, administered systemically, on the central and splanchnic hemodynamics in dogs anesthetized with pentobarbital and to compare the results with those for SNP. We also found that acute tolerance developed to NTG but not to NOC-7.



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  		Figure 1. Chemical structure of an NO-releasing compound, NOC-7.

The major route of NO decomposition in vivo is the reaction with oxyhemoglobin in red cells to form nitrate and metHb.11 12 Therefore, we also investigated alterations in the plasma levels of nitrite+nitrate, metHb, and HbNO.


*    Methods
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 *Methods
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This study was approved by the Animal Care Committee of Osaka University Medical School.

Experimental Preparation
Thirty-four beagle dogs weighing 10 to 13 kg were used. Anesthesia was induced with sodium pentobarbital (40 mg·kg-1 IV) and was maintained with the same anesthetic at 4 to 6 mg·kg-1·h-1. The dogs were ventilated with a piston-type ventilator (SN 480, Sinano) to maintain PaCO2 in the normal range (38 to 44 mm Hg) with air. Body temperature was monitored with a rectal thermistor and was maintained at 36.5°C-38°C with a thermostatically controlled heating blanket and an infrared heat lamp.

Instantaneous MAP was continuously measured by a transducer system (Abbott Laboratories Products) via a liquid-filled femoral catheter with the tip in the descending aorta. The same catheter was used for arterial blood sampling. The HR was monitored with a cardiotachometer. A 5F Swan-Ganz catheter was inserted through the right external jugular vein into the pulmonary artery to measure mean PAP, CO, and PAWP. CO was measured by the thermodilution method with a cardiac output computer (model 9520A, Edwards Laboratories). SVR and PVR (in mm Hg·L-1·min-1) were calculated as SVR=MAP/CO and PVR=(PAP-PAWP)/CO. The femoral vein was cannulated for drug administration. Regional blood flows were assessed by electromagnetic flow probes (MFV1200, Nihon Kohden) placed on the left renal artery after the left kidney was exposed retroperitoneally, on the hepatic artery, on the portal vein, and on the right internal carotid artery.

Arterial blood pH, PaCO2, and PO2 were measured with the appropriate electrodes of a blood gas analyzer (ABL300, Radiometer).

NOC-7 was a gift from Dojindo Laboratories, SNP from Maruishi Pharmaceutical Co Ltd, and NTG from Japan Chemical Pharmaceutical Co.

Effects of NOC-7 and SNP on Hemodynamics
Six dogs received a bolus injection of NOC-7, 9 received a continuous infusion of NOC-7 for 90 minutes, and 7 received a continuous infusion of SNP for 90 minutes. We prepared NOC-7 and SNP solutions on the day of the experiment: NOC-7 crystal was dissolved in 0.01N NaOH solution for bolus injection and in 0.1N NaOH solution at a concentration of 0.2 mg·mL-1 for the 90-minute infusion. SNP crystal was dissolved in normal saline at a concentration of 0.5 mg·mL-1.

Intravenous bolus injections of 1, 10, and 100 µg·kg-1 of NOC-7 were given at 40-minute intervals. The order of NOC-7 administration was varied randomly between the animals. All hemodynamic parameters returned to baseline within 25 minutes after administration.

The continuous-infusion experiment was designed to compare the effects of NOC-7 and SNP on hemodynamics when these agents are administered continuously for 90 minutes at doses that reduce MAP by 25% to 30% from control levels. NOC-7 and SNP were infused at the rates of 2.73±0.77 and 11.5±6.1 µg·kg-1·min-1, respectively.

During the experiment, intravenous drip infusion of lactated Ringer's solution was maintained at a rate of 180 to 200 mL·h-1 to maintain PAWP at 6 to 8 mm Hg, with the aim of achieving a constant preload state.

Ninety minutes after the start of NOC-7 infusion, plasma levels of stable endproducts of NO, ie, nitrite (NO2-) and nitrate (NO3-) were measured according to the method of Green et al.13 HbNO was detected by electron spin resonance as described by Kosaka et al.14 During the 90-minute infusion of SNP, whole-blood cyanide levels were determined in four dogs by gas chromatography with nitrogen-phosphorus detection as described by Seto et al.15 The arterial blood metHb concentration was measured with a hemoximeter (OSM3, Radiometer).

Acute Tolerance Test
Six dogs received NOC-7 or NTG for the acute tolerance test. NOC-7 and NTG solutions were prepared on the day of the experiment. NOC-7 crystal was dissolved in 0.1N NaOH solution at a concentration of 0.5 mg·mL-1. NTG was supplied as a 5% solution in ethanol, which was diluted with normal saline before injection at doses of 20 and 100 µg·kg-1. The 0.5% NTG solution was infused after dilution with normal saline.

Acute tolerance was produced by the method of Husain et al.16 The systemic hypotensive responses before and after intravenous NTG or NOC-7 administration were investigated. Incremental bolus injections of NTG (20 and 100 µg·kg-1) were administered at 30-minute intervals. After bolus injections, NTG was infused continuously at a dose of 100 µg·kg-1·min-1 for 3.5 hours. Thirty minutes after the NTG infusion was discontinued, bolus injections of NTG were repeated as outlined above. NOC-7 was investigated by the same method. Bolus injections of NOC-7 (10 and 50 µg·kg-1) were administered at 30-minute intervals, and intravenous NOC-7 was infused continuously at a dose of 1.5 µg·kg-1·min-1.

Statistical Analysis
Data are given as mean±SEM. Intergroup differences were analyzed by one-way ANOVA with repeated measures and assessed by Scheffe's F test. Intragroup differences were analyzed by two-way ANOVA with repeated measures and assessed by the paired t test. A value of P<.05 was considered statistically significant.


*    Results
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 *Results
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Intravenous Bolus Injection of NOC-7
Intravenous bolus injection of NOC-7 decreased MAP and PAP and increased HR in a dose-dependent manner (Fig 2Down). The blood pressure began to fall within a few seconds after the start of injection. All of these parameters returned to preinjection levels within 10 minutes at 10 µg·kg-1 and within 25 minutes at 100 µg·kg-1.



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  		Figure 2. Effects of NOC-7 bolus injection on MAP, mean PAP, and HR. n=6. Data are mean±SEM. *P<.05, **P<.01 vs control.

Continuous Infusion of NOC-7 and SNP
Intravenous infusion of NOC-7 produced hypotension by decreasing MAP by 27%, from 115±3.9 to 84±2.9 mm Hg, after 15 minutes, and SNP produced a 28% decrease, from 118±3.8 to 87±3.1 mm Hg, after 15 minutes. The optimum doses of NOC-7 and SNP were determined to be 2.73±0.77 and 11.5±6.1 µg·kg-1·min-1, respectively. A steady-state blood pressure was obtained 7±0.7 minutes after the start of NOC-7 infusion, compared with 5±0.5 minutes (not significantly different). The blood pressure level could be easily maintained for 90 minutes without adjustment of the infusion rate. Upon termination of infusion, recovery of blood pressure to baseline was slower with NOC-7 than with SNP (6±0.3 minutes with NOC-7 versus 3±0.5 minutes with SNP, P<.05). The HR increased significantly 30 minutes after the start of infusion of NOC-7, and this significant increase lasted until discontinuation. With SNP, the HR was initially increased and was followed by a decrease. HRs after discontinuation were significantly higher with NOC-7 than with SNP. CO increased significantly between 30 and 90 minutes after the start of NOC-7 infusion and between 30 and 60 minutes after the start of SNP infusion (Fig 3Down). PAP did not change significantly with either of the two agents. Both SVR and PVR decreased significantly after administration of NOC-7 or SNP. The decrease in PVR lasted longer with NOC-7 than with SNP (Fig 4Down).



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  		Figure 3. Effects of NOC-7 (n=9) and SNP (n=7) infusion on MAP, HR, and CO. Data are mean±SEM. *P<.05 vs baseline; #P<.05 vs SNP at the same time point.



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  		Figure 4. Effects of NOC-7 (n=9) and SNP (n=7) infusion on mean PAP, SVR, and PVR. Data are mean±SEM. *P<.05 vs baseline; #P<.05 vs SNP at the same time point.

Electromagnetic flowmetry showed similar effects of NOC-7 and SNP on regional blood flow (Fig 5Down). Portal blood flow increased gradually after administration of NOC-7 or SNP and slowly returned to baseline. Hepatic artery blood flow did not change significantly during the 90-minute infusion with either NOC-7 or SNP. Left renal artery blood flow did not change significantly. Internal carotid artery blood flow increased significantly with both NOC-7 and SNP.



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  		Figure 5. Effects of NOC-7 (n=9) and SNP (n=7) infusion on portal blood flow (portal v.), hepatic artery blood flow (hepatic a.), renal artery blood flow (renal a.), and internal carotid artery blood flow (int. carotid a.). Data are mean±SEM. *P<.05 vs control.

Thirty minutes after discontinuation of NOC-7, the plasma level of metHb was significantly elevated (P<.05). Plasma NO end products (NO2-/NO3-) did not change significantly. HbNO was not detected by electron spin resonance in the venous blood. During infusion of SNP, the concentration of cyanide in whole blood increased gradually, and the increase became significant at 60 and 90 minutes after the start of SNP (TableDown).


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  		Table 1. Blood-Gas Changes and Metabolic Products After NOC-7 and SNP Infusion

Tolerance to NOC-7 and NTG
As the vehicle of the drugs during 3.5-hour administration, 12 to 17 mL 0.1N NaOH solution was infused for NOC-7 tolerance, and 40 to 55 mL of 9.5% ethanol solution was infused for NTG tolerance. After 3.5-hour infusion of NTG, the percent changes of MAP in response to bolus injections of NTG (20 and 100 µg·kg-1) were significantly smaller than the control values before infusion (P<.01 and P<.05, respectively). In contrast, the percent decreases of MAP with bolus injections of NOC-7 (10 and 50 µg·kg-1) after a 3.5-hour infusion of NOC-7 did not differ from those before infusion (Fig 6)Down.



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  		Figure 6. Percent changes of MAP in response to bolus injections of NTG (n=6) or NOC-7 (n=6) before and after a 3.5-hour NTG or NOC-7 infusion. Data are mean±SEM. *P<.05 vs preinfusion; **P<.01 vs preinfusion.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The present article is the first report on the cardiovascular effects of a new NO-releasing compound, NOC-7, a zwitterionic NOC. The data showed that NOC-7 possesses the properties of an ideal ultra–short-acting vasodilator. Bolus injection of NOC-7 produced dose-dependent decreases in systemic and pulmonary blood pressures, and the effects disappeared rapidly after its discontinuation. Intravenous infusion of NOC-7 produced potent and stable systemic and pulmonary vasodilation. CO and HR increased, but PaO2, PaCO2, and pH remained unchanged. Underperfusion of vital organs was increased in the liver and brain or was maintained in the kidney during hypotension. The effects on central and splanchnic hemodynamics were similar with SNP. There were neither major adverse effects nor dangerously high levels of metHb. In the present study, acute tolerance to NOC-7 did not develop.

The hemodynamic effects of a similar NO-releasing compound, DEA/NO, have been investigated by Vanderford et al17 ; they showed that intravenous infusion of DEA/NO produced dose-dependent decreases in systemic pressure and PAP in the normal and pulmonary hypertensive states. However, they investigated the effects of only 5-minute infusion of the drug, and tolerance was not investigated. Recently, NOCs have been indicated to be more stable than DEA/NO in the solid state, and DEA/NO can degrade to N-nitrosodiethylamine, a carcinogen, during its decomposition.8 18

SNP has been used clinically in treating hypertensive emergencies, producing controlled hypotension for surgery, and providing afterload reduction in critically ill patients.6 SNP is unique among hypotensive agents in that it produces hypotension rapidly, shows little tachyphylaxis, and acts directly on the smooth muscle of blood vessels, and its short-acting quality permits a quick return to normal blood pressure.19 SNP dilates both arterioles and venules, and the hemodynamic response to its administration results from a combination of venous pooling and reduced arterial impedance.6 The vasodilating effect of SNP is mediated by the generation of NO, but the mechanism of release of NO remains obscure.20

In the present study, the fall in arterial blood pressure induced by NOC-7 was associated with a marked reduction in total peripheral resistance, similar to the changes seen with SNP. The hemodynamic data indicate that NOC-7 may have a potent effect on dilation of both arterioles and venules. The data showed that the recovery from hypotension with NOC-7 was slightly slower than with SNP. NOCs, having different half-lives, are capable of releasing NO in predictable ways if the structure of the polyamine portion of NOCs is varied. The development of an NOC with a shorter action than SNP may be possible in the future.

In the present study, in which dogs were anesthetized with pentobarbital, decreases in the systemic blood pressure with NOC-7 were accompanied by tachycardia, which may reflect activation of the baroreflex.21 The reason why tachycardia and the decrease in PVR during NOC-7 lasted longer than with SNP is not well known. It may be related to the longer effect of NOC-7. Although the effects of NOC-7 on myocardial contractility are unknown, SNP has no effect on myocardial contractile performance22 23 ; thus, the increase in heart rate and reduction of left ventricular afterload due to NOC-7–induced vasodilation may have contributed greatly to an increase in CO.

Underperfusion of vital organs is the primary concern of the anesthesiologist during the induction of hypotension. SNP is considered a nonselective vasodilator that has little effect on regional distribution of blood flow19 24 25 ; the vital organs maintain adequate blood flow or even show an increase in some situations. However, it is known that the results vary greatly with the experimental conditions, such as the preload state, in studies of regional blood flow.19 In the present study, during 90-minute infusion of NOC-7 and SNP, PAWP was kept at 6 to 8 mm Hg with infusion of lactated Ringer's solution at a rate of 180 to 200 mL·h-1. We compared the regional blood flow only at a 25% to 30% decrease in MAP induced by NOC-7 and SNP. We found that the changes in regional blood flows with the two drugs were similar during the 90-minute infusion. Both NOC-7 and SNP increased portal venous flow and maintained hepatic arterial flow (which indicates increased blood flow in liver), maintained renal blood flow, and increased internal carotid flow (which indicates increased cerebral blood flow). Dilating the cerebral circulation is not always beneficial. Turner et al26 found that intracranial pressure increases in humans with use of SNP because of an increase in intracranial blood volume.

We also investigated the vasodilating effect of NOC-7 in the conscious state using normal and hypertensive rats (unpublished observations), and the changes in the hemodynamic responses to intravenous administration of NOC-7 were similar to those in dogs anesthetized with pentobarbital.

It has been found that prolonged administration of SNP results in increased concentrations of cyanide. The main toxic action of cyanide is to bind to and inhibit cytochrome oxidase, preventing oxidative phosphorylation and oxygen consumption.27 Although the blood cyanide level at the end of SNP infusion is below the toxic range of 5 to 7 µg·mL-128 29 30 and there were no signs of cyanide toxicity such as metabolic acidosis, the data strongly suggested that we should carefully monitor patients during prolonged use of SNP.

In the present study, we found that acute tolerance did not develop to NOC-7 but did develop to NTG after 3.5 hours of continuous infusion. Long-term treatment with nitrovasodilators sometimes leads to the development of tolerance to the drug.31 32 33 NTG requires specific thiol-reducing agents for enzymatic release of NO; it is this requirement for thiol-reducing agents that is in part responsible for the development of tolerance to NTG.34 35 Since NOC-7 releases NO spontaneously without any cofactor, tolerance may not occur. In fact, no acute tolerance developed to NOC-7 after 3.5 hours of continuous infusion. However, further studies of long-term administration may be necessary to assess the possibility of delayed development of tolerance to NOC-7. Bigatello et al36 reported that long-term NO inhalation (2 to 27 days) at low concentrations decreased the PAP without the occurrence of tachyphylaxis in patients with adult respiratory distress syndrome.

In the present study, as a vehicle for the drugs, 12 to 17 mL of 0.1N NaOH solution was infused during the 90-minute NOC-7 infusion, and 40 to 55 mL of 9.5% ethanol solution was infused during the 3.5-hour administration for NTG tolerance. These factors may not essentially affect the results. Rush et al37 and Munzel et al38 used ethanol as the vehicle for NTG in studying tolerance and did not find a significant influence.

NO easily converts oxyhemoglobin to metHb, and this binds with hemoglobin to form HbNO. NO reacts rapidly with oxygen to form NO2, which dissolves in solution, yielding nitrite and nitrate. Nitrite oxidizes oxyhemoglobin autocatalytically to metHb.39 Methemoglobinemia is a potential hazard in the administration of NO. We measured the metHb concentration during NOC-7 infusion and found a significant increase, but it was not high enough to disturb the oxygen transport by hemoglobin. Our data also showed that infusion of NOC-7 at 2.7±0.77 µg·kg-1·h-1 for 90 minutes did not cause a significant change in the plasma levels of the NO end products nitrite and nitrate or the formation of HbNO. These results suggest that NOC-7 can produce clinically useful hemodynamic effects at concentrations that produce no adverse effects.

In conclusion, NOC-7 is a new ultra–short-acting nitrovasodilator that may have no major adverse effects or development of tolerance during long-term administration. Further research on these compounds may result in the development of safer NO-releasing agents with different half-lives that are suitable for a variety of clinical situations.


*    Selected Abbreviations and Acronyms
 
CO = cardiac output
DEA/NO = diethylamine/NO adduct
HbNO = nitrosyl hemoglobin
HR = heart rate
MAP = mean aortic blood pressure
metHb = methemoglobin
NOC = polyamine/NO
NTG = nitroglycerin
PAP = pulmonary artery pressure
PAWP = pulmonary artery wedge pressure
PVR = pulmonary vascular resistance
SNP = sodium nitroprusside
SVR = systemic vascular resistance

Received September 27, 1995; revision received May 7, 1996; accepted May 8, 1996.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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