Effects of enalapril in cats with pressure overload-induced left ventricular hypertrophy

Abstract

In order to evaluate the effect of enalapril on haemodynamics and renal function in a pressure overload model, we prepared eight feline models of left ventricular hypertrophy (LVH) by banding of the aortic arch. The LVH cats were assigned to the placebo group or the enalapril group (0.5 mg/kg, PO, sid) 3 months following surgery, and each received its respective drug for 4 weeks. Each week, blood pressure, angiotensin converting enzyme (ACE) activity in blood, and creatinine clearance were measured, and complete blood count (CBC), biochemical examination of the blood, echocardiography, and chest radiography were carried out. The interventricular septum thickness (IVSd, IVSs), fractional shortening (FS), and ejection fraction (EF) increased significantly in the LVH cats following surgery (P<0.05). There was no significant difference between the placebo group and the enalapril group with respect to general physical parameters, CBC, biochemical parameters and renal function. In the enalapril group, systolic arterial pressure, mean arterial pressure, and ACE activity in blood decreased significantly following administration (P<0.05). In addition, the left ventricular free wall thickness in diastole and IVSd decreased significantly following administration (P<0.05). These results suggest that, in a pressure overload model, enalapril (0.5 mg/kg, sid) inhibits cardiac hypertrophy, reduces blood pressure, and does not adversely affect renal function.

Angiotensin converting enzyme (ACE) inhibitors decrease blood pressure by dilating arteries and veins and inhibit vascular and myocardial remodelling. Because of these effects, ACE inhibitors are well recognised as the first-choice drug for the treatment of heart failure (COVE Study Group 1995, Ettinger et al 1998, Borghi et al 1999). Many studies have reported the effect of ACE inhibitors in treating mitral regurgitation in dogs (COVE Study Group 1995, Atkins et al 2002). An ACE inhibitor was reported to be effective in the treatment of hypertrophic cardiomyopathy in cats (Rush 1998). In humans, an ACE inhibitor has been reported to improve the clinical condition of patients with aortic stenosis or other outflow tract obstruction (Chockalingam et al 2004). There has been some concern that patients with aortic stenosis may be at particular risk of hypotensive reactions with ACE inhibitors (Cox et al 1998), but there are no published reports to substantiate this.

Much remains unknown about the effect of enalapril on remodelling and haemodynamics in cats with left ventricular outflow tract obstruction. In this study, we evaluated the acute effect of enalapril (an ACE inhibitor) in feline models of pressure overload-induced cardiac left ventricular hypertrophy (LVH) and examined the efficacy of enalapril against left ventricular outflow tract obstruction.

Materials and Methods

The Institutional Laboratory Animal Care and Use Committee of The School of Veterinary Medicine and Animal Science of Kitasato University approved this study. We used eight clinically healthy adult cats (body weight: 3–4 kg). The cats were kept individually in cages and fed commercially available cat food (Hill's, Japan). The cats had free access to water.

Butorphanol (0.1 mg/kg) and diazepam (0.5 mg/kg) were intramuscularly administered as pre-anaesthetic agents to prepare the LVH model. Ketamine (5 mg/kg) was intramuscularly administered as an induction agent. A tube was inserted into the trachea to maintain anaesthesia by means of inhalation of halothane. The cat was laid in the left decubitus position. The fur on the right side of the chest was shaved and the area was sterilised using the standard method. The heart was exposed by opening the fourth intercostal space. The root of the ascending aorta was exposed and bound with a nylon thread (0). During these procedures, heart rate was monitored by electrocardiography, and the presence of a thrill at the aorta was confirmed by palpation after banding. A thoracostomy tube was placed after surgery to carry out the standard drainage procedure. An antibiotic (ampicillin, 20 mg/kg) was administered three times a day for 5 days following surgery.

We performed echocardiography every 14 days following surgery. The echocardiography recordings were stable from 42 to 70 days after surgery, and we started the experiment at 70 days after surgery. The cats were divided into two groups, the enalapril group (n=4) and the placebo group (n=4). Enalapril (0.5 mg/kg, QD) was administered for 4 weeks by mixing it with commercially available tinned cat food, and we confirmed that the cats consumed the entire dose. Following completion of administration, the animals had at least a 4-week drug withdrawal period. The groups were then reversed and all the animals received their respective drugs for 4 weeks. The scores for the daily general condition of the animals, appetite, activity, cough, breathing, body temperature, heart rate, cardiac murmur, were recorded for the 4 weeks starting from the commencement of administration (Fig. 1).

Fig 1

Experiment time course.

The indirect blood pressure was measured by placing a cuff on the tail and using Dinamap (Dinamap, USA) at 8:00–9:00 am, before drug administration, at baseline, and at 1, 2, 3, and 4 weeks. The left ventricle pressure and the aortic pressure gradient were measured in the eight LVH cats after all the experiments. Diazepam (0.5 mg/kg) was intravenously administered as a pre-anaesthetic agent, and ketamine (5 mg/kg) was intravenously administered as an induction agent. A tube was inserted into the trachea to maintain anaesthesia by means of inhalation of isoflurane. A catheter was inserted into the carotid artery, and the catheter was connected to a polygraph (Nihon Kohden Corporation, Japan) to measure blood pressure. In one cat, we could not insert the aortic and left ventricular catheter tip via a carotid artery. An antibiotic (ampicillin, 20 mg/kg, bid) was administered for 5 days following surgery, and the cats were observed.

Haematological examination

In order to measure ACE activity, 6 ml of blood was taken from the catheter in the jugular vein, at rest, after measuring blood pressure but before administration. The blood was centrifuged (3000 rpm, 10 min) to obtain serum. The isolated serum was stored at −75°C.

We used an ACE assay kit, ACE Color (Fujirebio, Inc., Japan), and an automated analyser, AU-510 (Olympus Corporation, Japan), to measure ACE activity. The following formula was used for correction (Manual of ACE color).

Serum ACE activity (IU/l) = 2.256 \times measured value + 1.6

For the general haematological examination, 3 ml of blood was taken from the jugular vein and treated with heparin to prevent coagulation. A complete blood count (CBC) was carried out using whole blood. Plasma was isolated and used to measure the biochemical parameters, blood electrolyte level, and plasma osmotic pressure. An automated blood cell counter (PC-607, Erma Inc., Japan) was used for CBC. An automated blood analyser AU-510 (Olympus Corporation, Japan) was used for the biochemical examination. The blood electrolyte level was measured using EA 06T (A&T Corporation, USA). Plasma (P) and urine (U) osmotic pressures (P-Osm and U-Osm) were measured using Osmotron-10 (Orion Science Inc., Japan). Osmotic pressure was measured twice for each sample, and the mean value was calculated.

A urethral catheter was put in place to collect the urine. For male cats, 3 Fr catheters were used; for female cats, 6 Fr all silicon balloon catheters were used. Urine was collected for at least 3 h at baseline and at 1, 2, 3, and 4 weeks before drug administration (Fig. 1). The collected urine was centrifuged (3000 rpm, 10 min) and the supernatant was used to measure urine creatinine, urine electrolyte level, and U-Osm.

Creatinine (Cr, cr) clearance (C) was calculated using the following formula (Uechi et al 1994).

C-cr = (U-cr \times V) / (P-cr \times BW)

Fractional excretion of Na or K in urine was calculated based on Na, K, and Cr values in plasma and urine, using the following formulae (Agras et al 2005).

Fractional excretion of Na in urine (FE-Na) = (U-Na \times P-Cr) / (P-Na \times U-Cr)

Fractional excretion of K in urine (FE-K) = (U-K \times P-Cr) / (P-K \times U-Cr)

Osmotic pressure clearance (C-Osm) was calculated based on P-Osm, U-Osm and U-volume (ml/min), and free-water clearance (C-H₂O) was calculated based on U-volume (ml/min) and C-Osm, using the following formula (Berl and Schrier 1992).

C-Osm = (U-Osm / P-Osm) U-volume

C- H_{2} O = U-volume - C-Osm

We used an ultrasonic diagnostic system, SONOS 5500 (Hewlett Packard, USA), and an S12 ultrasound probe for echocardiography. A left ventricular short-axis view at the level of the papillary muscle was projected, and the interventricular septum thickness (IVSd, IVSs), the left ventricular free wall thickness (LVPWd, LVPWs) and the left ventricular internal dimension (LVIDd, LVIDs) at the peak of the R-wave in the electrocardiogram (at end-diastole) and at the end of T-wave (at end-systole) were measured. The fractional shortening (FS) was calculated by (LVIDd - LVIDs)/LVIDd × 100.

Statistical analysis

Changes in parameters with time were statistically analysed by means of repeated two-way ANOVA. When P<0.05, the change was regarded as significant.

Results

Difference between pre-banding values and 42 days post-banding values

There was no significant difference between the placebo group and the enalapril group with respect to general clinical findings. There was no significant difference between the pre-banding values and post-banding values for heart rate, LVIDd, cardiac output (CO), and stroke volume (SV). LVIDs decreased significantly (P<0.05) following banding. LVPWd, LVPWs, IVSd, IVSs, FS, and EF increased significantly following banding (P<0.05) (Table 1). The blood pressure gradient at the banding site was 64±15 mmHg (37–80 mmHg), as measured by cardiac catheterisation.

Table 1

Echocardiographic values in cats before and 42 days after aortic banding

	n	Pre-banding	Post-banding
HR (beats/min)	8	296±26	205±40
LVIDd (cm)	8	1.45±0.12	1.43±0.18
LVIDs (cm)	8	0.95±0.14	0.72±0.14*
LVPWd (cm)	8	0.39±0.06	0.49±0.08*
LVPWs (cm)	8	0.56±0.11	0.77±0.11*
IVSd (cm)	8	0.38±0.07	0.55±0.12*
IVSs (cm)	8	0.45±0.06	0.68±0.08*
FS (%)	8	34±10	50±10*
CO (l/min)	8	0.44±0.19	0.50±0.12
SV (ml)	8	2.22±0.78	2.63±1.15
EF (Tech)	8	0.66±0.14	0.83±0.14*
EF (cubed)	8	0.70±0.13	0.86±0.09*

HR=heart rate, LVIDd/s=left ventricular internal diameter diastole/systole, LVFWd/s=left ventricular free wall thickness diastole/systole, IVSd/s=intraventricular septal thickness diastole/systole, FS=fractional shortening, CO=cardiac output, SV=stroke volume, EF=ejection fraction.

P<0.05 compared with pre-banding.

Changes caused by administration of enalapril

There was no significant difference between the placebo group and the enalapril group with respect to heart rate. Systolic arterial pressure and mean arterial pressure in the enalapril group were significantly lower than those in the placebo group (P<0.05) (Table 2).

Table 2

Arterial blood pressure in LVH cat with placebo and enalapril

		n	Baseline	1 week	2 weeks	3 weeks	4 weeks
HR (beats/min)	Placebo	8	150±30	163±27	161±28	166±34	162±30
Enalapril	8	173±35	162±36	165±35	158±38	160±31
Systolic AP (mmHg)	Placebo	8	116±14	126±24	121±17	114±18	116±14
Enalapril	8	121±17	114±10	109±13*	125±15	111±9*
Mean AP (mmHg)	Placebo	8	85±16	83±23	81±14	82±17	81±16
Enalapril	8	84±15	80±10	76±10*	92±12	78±8*
Diastolic AP (mmHg)	Placebo	8	72±16	68±22	66±12	64±14	64±14
Enalapril	8	69±15	65±8	61±7*	77±11	63±5*

HR=heart rate; AP=arterial pressure.

P<0.05 compared with baseline.

ACE activity in blood in the enalapril group was significantly lower than that in the placebo group (P<0.05) (Fig. 2).

Fig 2

ACE activity with enalapril in LVH cats.

There was no significant difference between the groups with respect to haematological and biochemical parameters.

There was no significant difference between the groups with respect to creatinine clearance, FE-Na, and FE-K in urine, C-Osm, and C-H₂O (Table 3). LVIDd in the enalapril group was greater than that in the placebo group. LVIDs in the enalapril group was significantly greater than that in the placebo group (P<0.05). At weeks 3 and 4, LVPWd and IVSd in the enalapril group were significantly lower than those in the placebo group (P<0.05). LVPWs and IVSs in the enalapril group tended to decrease with time. At week 4, FS in the enalapril group decreased significantly (P<0.05). There was no significant difference between the groups with respect to the left atrium–aorta ratio (Table 4).

Table 3

Renal function in left ventricular hypertrophy cat with placebo and enalapril

		n	Baseline	1 week	2 weeks	3 weeks	4 weeks
Urine volume (ml)	Placebo	8	7.7±3.5	9.0±3.6	7.7±2.5	7.5±2.3	7.9±1.9
Enalapril	8	7.1±0.9	8.6±2.8	10.0±3.2	7.6±1.7	7.8±2.8
Cr clearance (ml/min/kg)	Placebo	8	2.3±0.5	2.3±0.6	2.3±0.6	2.4±0.5	2.4±0.5
Enalapril	8	2.3±0.3	2.5±0.4	2.4±0.3	2.4±0.4	2.2±0.7
FE-Na	Placebo	8	0.57±0.30	0.70±0.40	0.44±0.35	0.60±0.32	0.64±0.27
Enalapril	8	0.41±0.22	0.67±0.24	0.68±0.62	0.67±0.27	0.54±0.28
FE-K	Placebo	8	21.8±10.5	23.8±6.3	17.5±4.7	22.0±8.2	18.5±3.3
Enalapril	8	22.4±5.4	21.5±6.4	23.7±6.8	19.6±5.2	22.2±4.2
Osm clearance (ml/min/kg)	Placebo	8	0.072±0.026	0.075±0.039	0.068±0.019	0.076±0.015	0.074±0.018
Enalapril	8	0.067±0.09	0.082±0.020	0.083±0.020	0.073±0.012	0.070±0.024
H₂O clearance (ml/min/kg)	Placebo	8	−0.038±0.025	−0.035±0.024	−0.034±0.015	−0.041±0.012	−0.039±0.013
Enalapril	8	−0.036±0.011	−0.043±0.016	−0.037±0.011	−0.039±0.013	−0.035±0.014

Osm=osmolal

Table 4

Echocardiographic values in left ventricular hypertrophy cat with placebo and enalapril

		n	Baseline	1 week	2 weeks	3 weeks	4 weeks
HR (beats/min)	Placebo	7	205±29	207±23	199±41	192±46	184±33
Enalapril	7	194±44	199±45	195±44	196±46	190±37
LVIDd (cm)	Placebo	7	1.39±0.11	1.36±0.09	1.33±0.08	1.33±0.13	1.39±0.12
Enalapril	7	1.39±0.19	1.43±0.14	1.42±0.25	1.53±0.21	1.49±0.17
LVIDs (cm)	Placebo	7	0.72±0.07	0.70±0.14	0.64±0.11*	0.68±0.09	0.61±0.18*
Enalapril	7	0.81±0.22	0.74±0.09	0.74±0.22	0.74±0.11	0.83±0.18
LVPWd (cm)	Placebo	7	0.47±0.07	0.46±0.10	0.54±0.06*	0.50±0.04*	0.51±0.08*
Enalapril	7	0.51±0.06	0.50±0.08	0.46±0.05*	0.46±0.06*	0.47±0.08*
LVPWs (cm)	Placebo	7	0.71±0.07	0.73±0.15	0.79±0.09	0.75±0.06	0.75±0.08
Enalapril	7	0.74±0.12	0.71±0.10	0.72±0.07	0.68±0.05	0.70±0.08
IVSd (cm)	Placebo	7	0.52±0.11	0.57±0.12	0.58±0.08	0.61±0.07*	0.63±0.05*
Enalapril	7	0.63±0.10	0.55±0.11	0.53±0.07	0.52±0.10*	0.57±0.11*
IVSs (cm)	Placebo	7	0.67±0.10	0.69±0.12	0.75±0.06	0.71±0.10	0.76±0.05
Enalapril	7	0.72±0.10	0.71±0.12	0.65±0.08	0.69±0.06	0.68±0.06
FS (%)	Placebo	7	47.4±8.7	48.5±10.0	51.5±8.1	48.4±7.2	53.6±8.1
Enalapril	7	47.0±7.0	48.1±3.2	48.3±8.1	51.7±2.8	44.4±6.3
CO (1/min)	Placebo	7	0.47±0.11	0.45±0.10	0.40±0.06	0.40±0.15	0.44±0.12
Enalapril	7	0.44±0.11	0.50±0.14	0.50±0.22	0.56±0.17	0.53±0.17
SV (ml)	Placebo	7	2.33±0.68	2.17±0.48	2.07±0.38	2.06±0.62	2.42±0.53
Enalapril	7	2.33±0.77	2.55±0.72	2.58±1.32	2.94±0.96	2.73±0.76
EF (Tech)	Placebo	7	0.74±0.20	0.82±0.09	0.85±0.06	0.83±0.06	0.87±0.06
Enalapril	7	0.81±0.08	0.83±0.03	0.82±0.08	0.86±0.02	0.79±0.07
TPR	Placebo	7	277±88	249±46	289±53	288±176	283±81
Enalapril	7	269±98	252±107	271±147	244±115	247±101
LA/Ao	Placebo	7	1.62±0.28	1.68±0.34	1.62±0.27	1.78±0.21	1.70±0.19
Enalapril	7	1.75±0.40	1.65±0.19	1.84±0.43	1.75±0.17	1.79±0.20

HR=heart rate; LVIDd=left ventricular internal diameter in diastole; LVIDs=left ventricular internal diameter in systole; LVPWd=left ventricular posterior wall thickness in diastole; LVPWs=left ventricular posterior wall dimension in systole; IVSd=diastolic interventricular septal thickness in diastole; IVSs=diastolic interventricular septal thickness in systole; FS=fractional shortening; CO=cardiac output; SV=stroke volume; EF=ejection fraction; TPR=total peripheral resistance.

*P<0.05 compared with baseline.

Discussion

There was no significant change in the clinical condition of LVH cats in either the enalapril or placebo groups throughout this study. This suggests that the LVH cats in this study were level I of the New York Heart Association (NYHA) heart failure classification (Nelson et al 1998).

LVPWd, LVPWs, IVSd, IVSs, and FS in the feline models increased significantly after induced cardiac hypertrophy, owing to pressure overload. It has been thought that the renin–angiotensin–aldosterone system (RAAS) is activated as a compensatory response in pressure overload and that this induces cardiac hypertrophy by increasing angiotensin II (Ang II) levels in blood (Dzau 1993, Weir and Dzau 1999). Dzau (1993) reported the association of the tissue renin–angiotensin system with cardiac hypertrophy. It is known that cardiac hypertrophy occurs in patients with systemic hypertension (Fouad-Tarazi and Liebson 1987, Grandi et al 1989). Schunkert et al (1990) reported that ACE activity and the production of Ang II in the myocardium increase following ligation of the aorta in rats. Grimm et al (1998) reported myocardial hypertrophy and accumulations of fibronectin, collagen I, and collagen III in the stroma of rats with ligated aortas. The results of our study and these reports suggest that RAAS in the myocardium of aorta-banded cats was activated as a compensatory response to an increase in afterload, thus leading to cardiac hypertrophy.

ACE activity in blood in the enalapril group was significantly lower than that in the placebo group. LVPWd and IVSd decreased significantly, and LVIDd tended to increase in the enalapril group following administration. In addition, systolic arterial pressure and mean arterial pressure decreased significantly, and peripheral blood vascular resistance tended to decrease following administration. In the enalapril group, SV and CO increased following administration. ACE inhibitors are considered to lower ACE activity in blood and inhibit the production of Ang II (Uechi et al 2002). It has been reported that an ACE inhibitor inhibits myocardial hypertrophy and the accumulations of fibronectin, collagen I, and collagen III in aorta-banded rats (Grimm et al 1998). In hypertensive patients, an ACE inhibitor reduces blood pressure and alleviates cardiac hypertrophy (Fouad-Tarazi and Liebson 1987). The results of our study and these reports suggest that enalapril inhibited the production of Ang II, reduced afterload, decreased blood pressure, and inhibited myocardial remodelling in aorta-banded cats.

With respect to the evaluation of renal function, there was no significant change in creatinine clearance, FE-Na, FE-K, C-Osm, or C-H₂O in LVH cats. The results suggest that renal dysfunction did not occur in our study.

In addition, adverse drug reactions to ACE inhibitors include dry cough, hypotension, exacerbation of renal function, fainting, vasogenic oedema, and hyperkalaemia. Cough is the most frequently observed adverse drug reaction in humans (Morimoto et al 2004, Zee et al 1998). ACE inhibitors are thought to cause cough by inhibiting the decomposition of bradykinin, which then accumulates and induces cough (Morimoto et al 2004). In our study, cough was observed in one case, but its relationship with enalapril is unknown.

In this study, we administered enalapril for only 4 weeks; therefore, further long-term study is necessary. Although its effects are not clear in severe congenital aortic stenosis, enalapril inhibited ACE activity and cardiac hypertrophy, and decreased blood pressure slightly in cats with mild pressure overload-induced hypertrophy. Enalapril did not affect renal function. These results suggest that enalapril (0.5 mg/kg, sid) decreased blood pressure, reversed remodelling, and did not adversely affect renal function in mild pressure overload-induced hypertrophy.

Footnotes

Acknowledgements

This study was supported in part by a Grant-in-Aid for General Scientific Research (C-16580268) from the Japanese Ministry of Education, Science and Culture.

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