Comparison of the Cardiovascular Effects of Intracellular Cyclic Adenosine 3’,5’- Monophosphate (Camp)-Modulating Agents in Isoflurane-Anesthetized Cats

FULL PAPER Surgery

Comparison of the Cardiovascular Effects of Intracellular Cyclic Adenosine 3’,5’- Monophosphate (cAMP)-Modulating Agents in Isoflurane-Anesthetized Cats

Yoshitaka ARAMAKI1), Masami UECHI2)* and Katsuaki TAKASE1)

1)Departments of Surgery and 2)Veterinary Teaching Hospital, School of Veterinary Medicine & Animal Science, Kitasato University, 23– 35–1 Higashi, Towada, Aomori 034–8628, Japan

(Received 25 February 2002/Accepted 12 July 2002)

ABSTRACT. The inotropic, chronotropic, and vasodilatory effects of five commonly used cyclic adenosine 3’,5’-monophosphate (cAMP)- modulating agents were evaluated. Hemodynamic functions were measured continuously in isoflurane-anesthetized cats during infusion of the following: dobutamine (DOB; 2.5, 5 and 10 µg/kg/min; n=8), dopamine (DOP; 1.25, 2.5, 5 and 10 µg/kg/min; n=5), milrinone (MIL; 2.5, 5 and 10 µg/kg/min; n=8), 6-(3-dimethyl-aminopropionyl) forskolin hydrochloride (COL; 0.2, 0.4, 0.8, and 1.6 µg/kg/min; n=7), and bucladesine sodium (BUC; 10, 20, and 40 µg/kg/min; n=9). At the highest infusion rate, DOB and DOP produced the greatest positive inotropic (increase in left ventricular (LV) dP/dt = 89 ± 4% and 75 ± 6%, respectively) and chronotropic (increase in heart rate (HR) = 42 ± 4% and 22 ± 6%, respectively) effects. MIL and COL produced similar albeit less pronounced positive inotropic (increase in LV dP/dt = 18 ± 3% and 22 ± 6%, respectively) and chronotropic (increase in HR = 13 ± 4% and 21 ± 4%, respectively) effects. Both also had significant vasodilatory effects (decrease in peripheral resistance (PR) = –30 ± 2% and –35 ± 7%, respectively). In con- trast, BUC produced only vasodilatation (decrease in PR = –33 ± 6%). Hence, MIL, COL, and BUC had significant vasodilatory effects and less-pronounced inotropic effects than the catecholamines DOB and DOP. The vasodilatory effects of non-catecholamine drugs for treatment of congestive heart failure should translate into beneficial decreases in both pre-load and after-load. In contrast, the strong inotropic effects of DOB and DOP should be beneficial in the treatment of acute heart failure and anesthetic crisis. KEY WORDS: cardiotonic drug, feline, hemodynamic function, isoflurane. J. Vet. Med. Sci. 64(11): 981–986, 2002

Sympathomimetic agents such as dobutamine (DOB), vasodilatory effects of five agents that are commonly used dopamine (DOP) and epinephrine, enhance myocardial con- in clinical settings were investigated. This study was aimed traction via β-adrenergic stimulation. The management of to observe the changes in cardiac and hemodynamic func- acute or chronic heart failure requires the support of hemo- tions in normal isoflurane-anesthetized cats. Our findings dynamic and cardiac functions with catecholamines. Unfor- apply to situations involving anesthetic-induced hemody- tunately, β-adrenergic receptor down-regulation is namic perturbations, as well as to instances of declining car- frequently observed during heart failure [17]. On the other diac function in the conscious state. hand, other cardiotonic agents enhance cyclic adenosine 3’,5’-monophosphate (cAMP) levels without β-adrenergic MATERIALS AND METHODS receptor stimulation: the phosphodiesterase (PDE) III inhib- itor milrinone (MIL) inhibits cAMP degradation and, thus, This study was conducted followed the Guidelines for increases its intracellular concentration [15]; 6-(3-dimethyl- Institutional Laboratory Animal Care and Use at the School aminopropionyl) forskolin hydrochloride (COL), which is a of Veterinary Medicine and Animal Science at Kitasato potent water-soluble forskolin derivative, increases intracel- University, Japan. lular cAMP by stimulating adenylate cyclase activity [11, Nineteen adult mongrel cats of either sexes, weighing 2.5 29]; bucladesine sodium (BUC) is membrane permeable to 4.0 kg and fed commercial dry food (Hill’s Japan, Tokyo, cAMP [12, 22]. These agents produce inotropic and chro- Japan) were used in the study. Following induction of anes- notropic effects on the heart and induce vascular relaxation thesia with isoflurane (1.5 to 2.0% vol) and ventilation by by modulating intracellular cAMP levels. spontaneous respiration, a fluid-filled Tygon catheter The use of inotropic agents is also necessary during sur- (Norton Elastic and Synthetic Division, OH, U.S.A.) was gery, when anesthetic side effects, hemorrhage, bradycardia implanted via the femoral artery into the descending tho- and precipitous decreases in blood pressure are encountered. racic aorta. A 1.8F Millar catheter tip pressure transducer Since it is often difficult to choose the most appropriate (Millar Industrial, U.S.A.) was passed through the left medication in a particular situation, a better understanding carotid artery and aortic valve, implanted in the left ventric- of the characteristics of these agents is required. However, ular (LV), and used to continuously monitor LV pressure there is no report available for these agents in cats. and maximum rate of pressure development (dP/dt). A Thus, in this study, the chronotropic, inotropic, and median laparotomy (about 10 cm in long) was made to per- mit placement of a blood-flow probe (Transonic Systems, *CORRESPONDENCE TO: UECHI, M., Veterinary Teaching Hospital, School of Veterinary Medicine & Animal Science, Kitasato Uni- NY, U.S.A.) around the abdominal aorta just above the renal versity, 23–35–1 Higashi, Towada, Aomori 034–8628, Japan. artery, for continuous monitoring of blood-flow. The cathe- 982 Y. ARAMAKI, M. UECHI AND K. TAKASE ters and leads were externalized and the laparotomy was were administered at rates of 2.5, 5 and 10 µg/kg/min, while closed. The catheter in the descending thoracic aorta was DOP (n=5) was administered at 1.25, 2.5, 5 and 10 µg/kg/ connected to strain-gauge manometers (Nihon Kohden, min. COL (n=7) was administered at 0.2, 0.4, 0.8, and 1.6 Tokyo, Japan) for arterial blood pressure measurements. µg/kg/min; for BUC (n=9), the rates were 10, 20, and 40 µg/ Heart rate (HR) was determined from electrocardiogram kg/min, respectively. The dosage of each agent was decided (ECG) recordings. by preliminary experiments in cats which referred to litera- Hemodynamic measurements were recorded with cats in tures in dogs [14, 26]. Hemodynamic measurements were right lateral recumbency. After completion of pre-surgical recorded continuously during drug infusion. procedures, a 15- to 20-min stabilization period was pro- In the case of DOB and DOP, which undergo rapid clear- vided to establish stable baseline conditions for HR, blood ance [20, 21], their infusion was followed by a 30- to 60-min pressure, LV dP/dt, and blood flow. washout phase prior to infusion of the next drug. Because of Aortic and LV pressures, LV dP/dt, 1/2tau (indicated iso- their long duration of action [11, 21], MIL and COL were volumetric relaxation phase of left ventricular as index of infused different cats. Baseline hemodynamic measurement diastolic function), HR, and ejection time (ET: duration of was recorded before infusion of each agent. aortic blood flow) were digitized at 500 Hz and analyzed on Data were expressed as mean ± SE. The effects of each a computer-based system (Notocord, Croissy, France). LV drug at the different dose levels were analyzed by repeated- end-diastole was defined as the point of onset of positive LV measures with Super ANOVA, followed by post-hoc test- dP/dt, whereas LV end-systole was defined as the point of ing. The effects of the five agents were analyzed by one- peak-negative LV dP/dt. Peripheral resistance (PR) was way ANOVA, followed by post-hoc testing. A value of calculated as the mean arterial pressure divided by the p<0.05 was considered to be statistically significant. abdominal aortic blood flow. Five cardiotonic drugs dobutamine (DOB) (Shionogi & RESULTS Co., Osaka, Japan), dopamine (DOP) (Nikken Chemicals, Tokyo, Japan), milrinone (MIL) (Yamanouchi Pharmaceuti- Dobutamine: In cats infused with DOB, LV systolic pres- cal, Tokyo, Japan), 6-(3-dimethyl-aminopropionyl) forsko- sure, LV dP/dt, and HR increased significantly with increas- lin hydrochloride (COL) (Nippon Kayaku, Tokyo, Japan) ing dose of DOB (Fig. 1, Table 1). Mean arterial pressure and bucladesine sodium (BUC) (Daiichi Pharmaceutical, (MAP) increased with 2.5 and 5 µg/kg/min infusions but Tokyo, Japan) were tested, using drug solutions that were returned to baseline values at 10 µg/kg/min. Preload, as prepared in normal saline immediately before each experi- assessed by changes in LV end-diastolic pressure, fell ment. The experimental drug was infused for 5–10 min slightly or was unchanged. At 10 µg/kg/min, abdominal through the saphenous vein. DOB (n=8) and MIL (n=8) aortic flow increased by 56 ± 17%, PR decreased by 27 ±

Fig. 1. Representative hemodynamic tracings illustraring dose-response effects of dobutamine (2.5, 5.0, and 10µ g/kg/ min) on arterial pressure (AP) and mean arterial pressure (MAP), left ventricular (LV) pressure, first derivative of LV pressure (dP/dt), and electrocardiogram (ECG) in isoflurane aneasthetized cats. CARDIOACTIVE AGENTS ON ANESTHETIZED CATS 983

Table 1. Effects of dobutamine on hemodynamics Dobutamine (µg/kg/min) % change from baseline nBaseline2.5 5 10 Heart rate (beats/min) 8 113 ±4 +9 ±2∗ +23 ±3∗ +42 ±4∗ Mean arterial pressure (mmHg) 8 85 ± 6+10 ±3∗ +11 ±4∗ +5 ±6 LV peak systolic pressure (mmHg) 8 104 ± 5+11 ± 2* +15 ± 2* +18 ± 3* LV end-diastolic pressure (mmHg) 8 10 ± 2-4 ± 5-14 ± 11 -8 ± 16 LV dP/dt (mmHg/sec) 8 2,368 ± 218 +33 ± 3* +61 ± 3* +89 ± 4* 1/2tau 823 ± 1-10 ± 1* -20 ± 3* -32 ± 2* Abdominal aortic blood flow (ml/min) 8 59 ± 10 +28 ± 10* +48 ± 15* +56 ± 17* Peripheral resistance (mmHg/ml·min) 8 1.9 ± 0.6 -12 ± 7-20 ± 8-27 ± 8 Values are means ± SE. LV: left ventricular. dP/dt: first derivative of LV pressure. * p<0.05, significant changes from baseline values.

Table 2. Effects of dopamine on hemodynamics Dopamine (µg/kg/min) % change from baseline n Baseline 1.25 2.5 5 10 Heart rate (beats/min) 5 121 ± 7+1 ± 2+4 ± 2+10 ± 3+22 ± 6* Mean arterial pressure (mmHg) 5 96 ± 6-4 ± 30 ± 3+7 ± 6+18 ± 8* LV peak systolic pressure (mmHg) 5 103 ± 9-2 ± 2+8 ± 4+28 ± 9* +55 ± 18* LV end-diastolic pressure (mmHg) 5 9 ± 2-1 ± 60 ± 9-3 ± 9-10 ± 12 LV dP/dt (mmHg/sec) 5 2,908 ± 266 0 ± 2+11 ± 3* +36 ± 4* +75 ± 6* 1/2tau 5 18 ± 1 -8 ±9 -7 ±10 -9 ±10 -16 ±10* Abdominal aortic blood flow (ml/min) 5 38 ± 5+18 ± 9+18 ± 22 +10 ± 33 +10 ± 40 Peripheral resistance (mmHg/ml·min) 5 2.8 ± 0.4 -18 ± 8-8 ± 16 +30 ± 45 +72 ± 62 Values are means ± SE. LV: left ventricular dP/dt: first derivative of LV pressure. * p<0.05, significant changes from baseline values.

8%, and LV diastolic function as 1/2tau improved. effects. Neither LV systolic nor diastolic function were Dopamine: DOP produced dose-dependent increases in affected by BUC (Table 5). LV systolic pressure, LV dP/dt and HR. MAP did not change at low infusion rates (1.25 and 2.5 µg/kg/min), but DISCUSSION increased significantly (18 ± 8%; p<0.05) at the highest infusion rate (10 µg/kg/min). LV end-diastolic pressure was Long-term use of inotropic agents leads to increased mor- unchanged, but LV diastolic function as 1/2tau improved tality among patients with severe chronic heart failure [23] (Table 2). Blood flow in the abdominal aorta tended to due to the effects of catecholamines in increasing cardiac increase, as did PR. output and myocardial oxygen consumption [27]. Nonethe- Milrinone: MIL produced dose-dependent increases in less, although chronic catecholamine stimulation is deleteri- LV dP/dt and HR, but MAP decreased. LV end-diastolic ous for patients with heart failure, it is beneficial in the pressures fell slightly. Abdominal aortic blood flow support of cardiac function in decompensated heart failure. increased by 17 ± 5%, and PR decreased by 30 ± 2% at the However, β-receptor down-regulation is frequently highest dose (10 µg/kg/min). LV diastolic function as 1/ observed in cases of heart failure [4, 5, 7], and severe heart 2tau improved (Table 3). failure occasionally does not respond to catecholamine 6-(3-dimethyl-aminopropionyl) forskolin hydrochloride: treatment. Several types of novel cardiac agents, such as COL produced dose-dependent increases in LV dP/dt and MIL, COL, and BUC, have been developed but their effects HR decreases in MAP; LV end-diastolic pressures fell in cats have yet to be reported. slightly. Abdominal aortic blood flow increased by 30 ± 7% The present study compared the cardiovascular effects of at the highest dose (1.6 µg/kg/min). PR decreased by 35 ± DOB, DOP, MIL, COL and BUC in cats that were anesthe- 4% and LV diastolic function as 1/2tau improved (Table 4). tized with isoflurane. Isoflurane has been shown to produce Bucladesine sodium: MAP and LV systolic pressure dose-dependent decreases in systemic arterial pressure, car- decreased significantly at each dose in cats given BUC. diac output, LV dP/dt, vascular resistance and oxygen con- Reduced after-load was demonstrated by increases in sumption [10, 28, 31]. Merin et al. reported that compared abdominal aortic blood flow and decreases in PR. LV dP/dt to the values measured during consciousness, HR and coro- and HR showed no positive inotropic or chronotropic nary blood flow are increased under isoflurane anesthesia in 984 Y. ARAMAKI, M. UECHI AND K. TAKASE

Table 3. Effects of milrinone on hemodynamics Milrinone (µg/kg/min) % change from baseline n Baseline 2.5 5 10 Heart rate (beats/min) 8 117 ±7 +2 ±1 +9 ±3∗ +13 ±4∗ Mean arterial pressure (mmHg) 8 60 ± 6-5 ±1∗ +12 ±2∗ +18 ±3∗ LV peak systolic pressure (mmHg) 8 85 ± 5+4 ± 3+2 ± 4 0 ± 4 LV end-diastolic pressure (mmHg) 8 8 ± 1-5 ± 7-8 ± 11 -16 ± 8 LV dP/dt (mmHg/sec) 8 2,282 ± 178 +8 ± 2* +13 ± 2* +18 ± 3* 1/2tau 8 23 ± 3-6 ± 3-10 ± 4-14 ± 4* Abdominal aortic blood flow (ml/min) 8 45 ± 7+4 ± 1* +9 ± 2* +17 ± 5* Peripheral resistance (mmHg/ml·min) 8 1.7 ± 0.4 -9 ± 1* -19 ± 1* -30 ± 2* Values are means ± SE. LV: left ventricular. dP/dt: first derivative of LV pressure. * p<0.05, significant changes from baseline values.

Table 4. Effects of forskolin hydrochloride on hemodynamics Forskolin hydrochloride (µg/kg/min) % change from baseline n Baseline 0.2 0.4 0.8 1.6 Heart rate (beats/min) 7 117 ± 7+3 ± 3+6 ± 3 +10 ± 5 +21 ± 4* Mean arterial pressure (mmHg) 7 77 ± 5-4 ± 2-6 ± 3 -13 ± 4-16 ± 4* LV peak systolic pressure (mmHg) 7 95 ± 6 0 ± 1+2 ± 2-1 ± 31 ± 3 LV end-diastolic pressure (mmHg) 7 10 ± 1-5 ± 3-11 ± 5 -12 ± 8-12 ± 8 LV dP/dt (mmHg/sec) 7 2,385 ± 203 +4 ± 3+9 ± 3* +11 ± 3* +22 ± 6* 1/2tau 720 ± 3 -1 ± 2 -4 ± 2 -7 ± 2 -9 ± 3* Abdominal aortic blood flow (ml/min) 7 42 ± 8 +11 ± 4 +16 ± 4 +21 ± 6* +30 ± 7* Peripheral resistance (mmHg/ml·min) 7 2.3 ± 0.5 -13 ± 3* -18 ± 3* +30 ± 3* -35 ± 4* Values are means ± SE. LV: left ventricular dP/dt: first derivative of LV pressure. * p<0.05, significant changes from baseline values.

Table 5. Effects of bucladesine sodium on hemodynamics Bucladesine sodium (µg/kg/min) % change from baseline nBaseline10 20 40 Heart rate (beats/min) 9 112 ±8 0 ±1 -2 ±2 -2 ±2 Mean arterial pressure (mmHg) 9 82 ± 6-7 ±2∗ -13 ±3∗ -18 ±4∗ LV peak systolic pressure (mmHg) 9 100 ± 7-4 ± 2-7 ± 2* -11 ± 3* LV end-diastolic pressure (mmHg) 9 12 ± 1-7 ± 4-4 ± 7-1 ± 8 LV dP/dt (mmHg/sec) 9 2,434 ± 175 -4 ± 2-7 ± 3* -10 ± 3* 1/2tau 921 ± 3-3 ± 2-2 ± 3-2 ± 3 Abdominal aortic blood flow (ml/min) 9 50 ± 10 +13 ± 7* +17 ± 8* +32 ± 16* Peripheral resistance (mmHg/ml·min) 9 2.3 ± 0.6 -15 ± 5* -23 ± 5* -33 ± 6 Values are means ± SE. LV: left ventricular. dP/dt: first derivative of LV pressure. * p<0.05, significant changes from baseline values. dogs [19]. Further, Hodgson et al. indicated that isoflurane heart failure or shock. causes hypotension and hypercapnia at 2.0 the minimal DOB produced dose-dependent positive chronotropic and alveolar concentration (MAC), whereas at 1.3 MAC, isoflu- inotropic effects, with no apparent effect on MAP. Thus, rane produces minimal cardiopulmonary depression, espe- DOB can be useful for stimulating cardiac contraction under cially in healthy cats that are allowed to breathe various conditions, such as decompensation, and depression spontaneously [10]. Under these present studies, this study of cardiac function due to anesthetics. compared each inotoropic agent at close to 1.3 MAC in isof- Like DOB, DOP produced positive chronotropic and ino- lurane-anesthetized cats, and would be able to evaluate at tropic effects and improvement of diastolic function. It sig- accurate cardiovascular performance. Our findings high- nificantly increased MAP (+18 ± 8%) and PR (+72 ± 62%) light the compounds that are likely to be beneficial for car- at the highest dose (10 µg/kg/min). Therefore, high-dose diac support in anesthetized cats and in cats undergoing DOP appears to be useful in treating significant hemorrhage CARDIOACTIVE AGENTS ON ANESTHETIZED CATS 985 or severe hypotension. On the other hand, since low doses [2]. However, since no arrhythmia was observed in our of DOP promoted renal and mesenteric artery vasodilata- study, the drugs investigated might be useful in cases of tion, causing increased abdominal aortic blood flow and depressed cardiac function or inducing anesthesia without diuresis [3], DOP may be beneficial in the preservation of chronic heart failure. On the other hand, since MIL, COL, organ function and blood flow in states of anesthesia or low and BUC have significant vasodilatory effects, these can be cardiac output. used to decrease pre-load and after-load in congestive heart MIL, COL and BUC have been used as second-line ino- failure. DOB and DOP, with their potent inotropic activi- tropic agents. These drugs produce positive inotropic, chro- ties, can be beneficial in cases of heart failure and anesthetic notropic and vasodilatory effects, together with increased complications in cats. coronary blood flow [11, 12, 32]. Compared with DOB and DOP, MIL and COL have only slight effects on LV myocar- REFERENCES dial contractility. Further, Hirasawa et al. suggested they also have marked vasodilatory effects, which might depress 1. Alousi, A. A., Canter, J. M., Montenaro, M. J., Fort, D. J. and blood pressure and induce tachycardia or arrhythmia [9]. Ferrari, R. A. 1983. 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