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Drug Investigation 3 (Suppl. I): 131-133, 1991 0114-2402/91/0100-0131/$1.50/0 © Adis International Limited, All rights reserved. DISUP3994. Antihypertensive Effects of Oral Nebivolol in the Conscious Dog with 2-Kidney, I-Wrapped Perinephritic Hypertension Linda Gambone and Siu Po Sit Clinical Research Department, Janssen Research Foundation, Piscataway, New Jersey, USA Nebivolol is a novel and highly selective {31- blocker currently under development as an anti- hypertensive agent. The purpose of this study was to evaluate the long term antihypertensive effects of oral nebivolol in conscious dogs with 2-kidney, I-wrapped perinephritic hypertension and to de- termine whether the antihypertensive effects are associated with functional {3-blockade. 1. Methods U sing a modified method of Page I, perinephri- tic hypertension was induced in mongrel dogs of either sex ranging in weight from 15 to 26kg. Un- der sterile conditions and via a laparotomy, the left kidney was isolated from surrounding fat pads, wrapped first with raw silk and then a silastic sheet to protect the other visceral organs from adhering to the silk. Arterial blood pressure was recorded periodic- ally, beginning 3 to 4 weeks after surgery, by in- serting a catheter into a small side branch of the femoral artery under local anaesthesia. The criteria for established hypertension was a minimum mean I Journal of the American Medical Association 113: 2046-2048, 1939. ° en :I: -25 E §. -50 0- « -75 <] -100 150 125 ,h---_-§ C )?'", * I 100 11 " to &," Ql 75 B a: * :I: 50 <] 25 a 0.03 0.1 0.3 1.0 Intravenous Isoprenaline Fig. 1. Mean arterial pressure (MAP) and heart rate (HR) responses to isoprenaline at baseline (0) and after 4 days of treatment with nebivolol 1.0 mg/kg/day (., n = 6). * = P < 0.05. arterial blood pressure of 120mm Hg for at least 4 weeks. After these criteria were met, the animals were anaesthetised with pentobarbital and a left thoracotomy via the fourth intercostal space was en c 125 !!! 100 en > as 75 Ql -" en to C Ql 50 Cl. u"O -5 e 25 en - .0 C « 8 * HR (beats/min) MAP (mm Hg) Fig. 2. Mean arterial pressure (MAP) and heart rate (HR) responses to treadmill exercise before (0) and after 4 days of treatment with nebivolol 1.0 mg/kg/day (., n = 6). * = p < 0.05.

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Page 1: Antihypertensive Effects of Oral Nebivolol in the Conscious Dog with 2-Kidney, 1-Wrapped Perinephritic Hypertension

Drug Investigation 3 (Suppl. I): 131-133, 1991 0114-2402/91/0100-0131/$1.50/0 © Adis International Limited, All rights reserved.

DISUP3994.

Antihypertensive Effects of Oral Nebivolol in the Conscious Dog with 2-Kidney, I-Wrapped Perinephritic Hypertension

Linda Gambone and Siu Po Sit Clinical Research Department, Janssen Research Foundation, Piscataway, New Jersey, USA

Nebivolol is a novel and highly selective {31-blocker currently under development as an anti­hypertensive agent. The purpose of this study was to evaluate the long term antihypertensive effects of oral nebivolol in conscious dogs with 2-kidney, I-wrapped perinephritic hypertension and to de­termine whether the antihypertensive effects are associated with functional {3-blockade.

1. Methods

U sing a modified method of Page I, perinephri­tic hypertension was induced in mongrel dogs of either sex ranging in weight from 15 to 26kg. Un­der sterile conditions and via a laparotomy, the left kidney was isolated from surrounding fat pads, wrapped first with raw silk and then a silastic sheet to protect the other visceral organs from adhering to the silk.

Arterial blood pressure was recorded periodic­ally, beginning 3 to 4 weeks after surgery, by in­serting a catheter into a small side branch of the femoral artery under local anaesthesia. The criteria for established hypertension was a minimum mean

I Journal of the American Medical Association 113: 2046-2048, 1939.

° en :I: -25 E §. -50 0-« ~ -75 <]

-100

150

125 ,h---_-§ C )?'", * I 100 11 " to &," Ql 75 B a: * :I: 50 <]

25

a 0.03 0.1 0.3 1.0

Intravenous Isoprenaline (~g/kg)

Fig. 1. Mean arterial pressure (MAP) and heart rate (HR) responses to isoprenaline at baseline (0) and after 4 days of treatment with nebivolol 1.0 mg/kg/day (., n = 6). * = P < 0.05.

arterial blood pressure of 120mm Hg for at least 4 weeks. After these criteria were met, the animals were anaesthetised with pentobarbital and a left thoracotomy via the fourth intercostal space was

en c 125

~ ~ !!! ~ 100 en >

as ~ ~e 75 ~ ~ Ql -" en to C Ql 50 ~ Cl. u"O

~ ~ -5 e 25 en -.0 C « 8

*

o~--~--~~------~~--~ HR (beats/min) MAP (mm Hg)

Fig. 2. Mean arterial pressure (MAP) and heart rate (HR) responses to treadmill exercise before (0) and after 4 days of treatment with nebivolol 1.0 mg/kg/day (., n = 6). * = p < 0.05.

Page 2: Antihypertensive Effects of Oral Nebivolol in the Conscious Dog with 2-Kidney, 1-Wrapped Perinephritic Hypertension

132 Drug Invest. 3 (Suppi. 1) 1991

Table I. Systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) responses to nebivolol 1.0 and 0.1 mg/kg/day

Nebivolol dosage Baseline Day 1

1.0 mg/kg SAP (mm Hg) 160 ± 4 148 ± 7 DAP (mm Hg) 110 ± 2 95 ± 6"

0.1 mg/kg SAP (mm Hg) 161 ± 4 150 ± 5" DAP (mm Hg) 109 ± 3 100 ± 5"

" = P < 0.05.

performed under sterile conditions. Heparin-filled Tygon catheters were inserted into the thoracic aorta for the measurement of arterial pressure. The chest was sutured closed in layers, normal pleural pressure was re-established and the animals were allowed to recover for 2 to 3 weeks before exper­iments were performed.

Arterial pressure was measured by connecting the catheters to Statham strain-gauge manometers and calibrating them to atmospheric zero. Heart rate was derived from arterial pressure signals and measured with a Buxco haemodynamic analyser.

o

'= ...... ~---~ .... OJ -25 I

E .s -50 11. ..: -75 ::i' <l

-100

150

C 125

~ 100 '" ~ Ol e. 75 a: :x: <l 50

25

0 0.03 0.1 0.3 1.0

Intravenous isoprenaline (Ilg/kg)

Fig. 3. Mean arterial pressure (MAP) and heart rate (HR) responses to isoprenaline at baseline (0) and after 4 days of treatment with nebivolol 0.1 mg/kg/day (., n = 9).

Day 2

148 ± 3 92 ± 4'

153 ± 6 94 ± 5"

g", 125

~~ '" '" U; > 100 c ~ ~ 't3 ;: (j; - x 75 ~~ Ol '" alOl ~ a. 50 ~1J U C

Ol '" ~ e 25 ~t:

Day 3 Day 4

137 ± 5* 140 ± 6* 93 ± 4' 89 ± 4"

151 ±5 153 ± 5 96 ± 5" 96 ± 4"

.0 0

..: u O.L----'--....... --L----'--.LJ MAP (mm Hg) HR (beats/min)

Fig. 4. Mean arterial pressure (MAP) and heart rate (HR) responses to treadmill exercise before (0) and after 4 days of nebivolol 0.1 mg/kg/day (., n = 9).

Animals were trained to stand quietly in a sling before experimentation. On the first day of the ex­periment, baseline values were recorded, while the animals were calm and fully conscious, for ap­proximately 30 minutes before dosing. The long term, antihypertensive effects of oral nebivolol were assessed in a separate series of experiments: at doses of 1.0 mg/kg/day (n = 7), and 0.1 mg/kg/day (n = 10), each for a period of 4 days. Nebivolol was administered as a solution in a capsule and was dissolved at a concentration of 2 mg/ml in a 2% solution of iJ-cyclodextrin in sterile water. Six dogs received the vehicle alone.

To determine the degree of functional iJ-block­ade, the dose-response of arterial pressure and heart rate to isoprenaline (isoproterenol) [0.03, 0.1, 0.3, and 1.0 /-Lg/kg intravenous bolus] was measured at baseline and 24 hours after the fourth day of dos­ing. In addition, the response of arterial pressure

Page 3: Antihypertensive Effects of Oral Nebivolol in the Conscious Dog with 2-Kidney, 1-Wrapped Perinephritic Hypertension

Nebivolol in Perinephritic Hypertension

and heart rate to treadmill exercise (averaging 5 miles/h on a 10% grade for 5 minutes) was also determined at similar time points.

All data are expressed as mean values ± SEM and are summarised at baseline and on each sub­sequent day. All values were compared to predrug control values in the same animal and analysed by 2-way analysis of variance; the individual means were compared and analysed by Duncan's multiple range test. Intergroup analysis between vehicle and drug was done by I-way analysis of variance. The changes were considered significant at p < 0.05.

2. Results

Nebivolol 1.0 mg/kg/day significantly reduced arterial pressure over the 4-day dosing period (table I) and heart rate decreased from 98 ± 2 to 72 ±.3 beats/min (p < 0.05) over the same period. This was accompanied by a significant attenuation of the isoprenaline- and exercise-induced changes in heart rate (figs I and 2). Nebivolol 0.1 mg/kg/ day caused a significant but smaller reduction in

133

arterial pressure (table I), and heart rate fell from 95 ± 5 to 84 ± 4 beats/min (p < 0.05). However, it did not affect the isoprenaline- and exercise-in­duced changes in either of these variables (figs 3 and 4).

3. Comment

These results indicate that in the conscious dog with 2-kidney I-wrapped perinephritic hyperten­sion, nebivolol 1.0 and 0.1 mg/kg/day admini­stered over 4 days is effective in causing a sus­tained reduction in arterial pressure and heart rate. The fact that the 0.1 mg/kg/dose is not associated with functional iJ-blockade may indicate that the mechanism of action at this dose range is inde­pendent of its antagonistic effects on the iJ­adrenergic receptors.

Correspondence and reprints: Dr Linda Gambone, Johns Hop­kins University School of Hygiene and Public Health, Depart­ment of Environmental Health Sciences, Division of Physiology, Baltimore, MD 21205, USA.