antihypertensive effects of oral nebivolol in the conscious dog with 2-kidney, 1-wrapped...
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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 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.
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150
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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
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as ~ ~e 75 ~ ~ Ql -" en to C Ql 50 ~ Cl. u"O
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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.
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.
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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"
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~~ '" '" U; > 100 c ~ ~ 't3 ;: (j; - x 75 ~~ Ol '" alOl ~ a. 50 ~1J U C
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Day 3 Day 4
137 ± 5* 140 ± 6* 93 ± 4' 89 ± 4"
151 ±5 153 ± 5 96 ± 5" 96 ± 4"
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..: 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
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.