Indian Journal of Experimental Biology Vol. 42, December 2004, pp. 1195-1199

Effects of alpha-1 adrenergic receptor antagonist, terazosin, on cardiovascular functions in anaesthetised dogs

R Sharma & V M Ahuja

Department of Physiology, Maulana Azad Medical College, New Delhi LLO 003

and

M Fahim*

Department of Physiology, Vallabhbhai Patel Chest Institute, Delhi University, Delhi 110 007, India

Received 31 October 2003; revised 24 August 2004

Initially a dose-response curve of phenylephrine was constructed at dose strengths of l-16 f.,lg/kg in a cumulative manner. Phenylephrine caused a significant rise in the mean arterial pressure, left ventricular systolic pressure, left ventricular contractility, stroke volume and a significant decline in the heart rate. Terazosin was administered in three selected doses of 10, 100 and 300 f.,lglkg. Following each dose of terazosin, dose-response curve of phenylephrine was constructed. Terazosin, per se, decreased the basal mean arterial pressure, left ventricular systolic pressure, left ventricular contractility and stroke volume significantly in a dose dependent manner with an increase in the heart rate with no significant change in the cardiac output. The baroreflex sensitivity at all the three doses remained unchanged. In conclusion, the present findings support the view that terazosin reduces the blood pressure in a physiologically more favorable manner by maintaining the neural integrity of the cardiovascular system.

Keywords: Alpha- I adrenergic receptor, Baroreflex, Left ventricular performance, Terazosin.

Hypertension is one of the commonest prevalent disorders in current times. It has been suggested that, even in hypertensives, the blood pressure regulatory mechanisms continue to operate although at a higher set point. Alpha-1 adrenergic antagonists, eg. terazosin, have been used as the mainstay of anti­hypertensive therapy. Stimulation of alpha-1 adrenergic receptors modulates various steps of the cardiac excitation-contraction coupling cascade including ionic conductances, cytosolic ionic activities and calcium sensitivity of contractile proteins 1

•2

• They also regulate the cardiac rhythm, conduction and force of contraction3

-5

. However, no evidence is available regarding the effect of long term use of alpha-1 adrenergic blockers on the left ventricular performance and the neural regulation of blood pressure.

The function of myocardial alpha-1 adrenoceptors can be studied using selective alpha-1 adrenergic agonist (phenylephrine) and antagonist (terazosin). Phenylephrine by selectively stimulating alpha-1

*Correspondent author Phone : 91-11-27667102 Fax: 91-11-27667420 E-mail : vpciphysiology@yahoo.com

adrenergic receptors, has been shown to produce a positive inotropic effect6•

7 and an increase in the arterial blood pressure by causing peripheral vasoconstriction8

. Terazosin acts on the same peripheral receptors causing peripheral vasodilation and a fall in the arterial blood pressure9

. It also acts on the myocardial adrenoceptors leading to a decline in the left ventricular systolic pressure and contractility 10

• Although effect of different doses of terazosin has been studied on blood pressure 11

, left ventricular performance has not been assessed. In addition, its effect on the heart rate with the fall in the blood pressure needs to be examined as there are some reports of alpha-1 adrenergic antagonists (prazosin) interfering with the sensitivity of the baroreflex 12

•

Therefore, in the present study, the effect of three different doses of terazosin, on the phenylephrine induced hemodynamic changes and the sensitivity of the baroreceptor mediated regulation of the arterial blood pressure have been studied.

Materials and Methods All experiments were approved by the V P Chest

Institute Ethical Committee and were performed

1196 INDIAN J EXP BIOL, DECEMBER 2004

under the guidelines of Care and Use of Experimental Animals. Healthy, male, mongrel dogs (10) weighing between 12-14 kg were anaesthetized with sodium pentobarbitone (35 mg/kg, iv). Trachea was cannulated, polyethylene catheters were placed in the femoral artery to record blood pressure using (Statham P32 Db) pressure transducer and in the femoral vein for injecting drugs . Another catheter was placed in the left ventricle through the left common carotid artery for recording left ventricular pressure with a pressure transducer (Statham P32 Db). The pressure recording system was calibrated with a mercury manometer before each experiment. The left ventricular pulse was electronically differentiated (Differentiator Contractility-Lectromed model-5270) to record left ventricular dP/dt and also to drive a cardiotachometer (Lectromed model-5260) to record the heart rate. All these variables were recorded on a polygraph (Lectromed-UK). Room temperature was maintained ·at 25°±2°C. The body temperature of the animal was recorded with a rectal thermometer and was maintained between 37°-38°C. Arterial blood samples were withdrawn from the femoral artery for measurement of gases (Eschweiler BGA plus E­Model Type 331). The blood gases were kept in the normal range throughout the experiment. After surgical procedures, the animal was allowed to stabilize for 30 min before taking observations.

Measurement of cardiac output and stroke volume--Cardiac output was measured by the thermodilution technique using a cardiac output computer (COM-1 Edward Company USA). Cardiac output was measured before terazosin treatment (control) and subsequently after each dose of terazosin (10, 100 and 300 {tg/kg). Stroke volume was calculated as cardiac output/heart rate.

Calculation of baroreflex sensitivity-Arterial baroreceptor mediated regulation of arterial pressure (Baroreflex) was calculated from the mean arterial pressure (MAP) and heart rate (HR) relationship. Blood pressure was changed by injecting varying doses of phenylephrine and the corresponding changes in heart rate were recorded.

Baroreflex sensitivity (~HR/ ~MAP) was calculated from the linear part of the mean arterial pressure­heart rate curves. Baroreflex sensitivity after injecting the three doses of terazosin (10, 100 and 300 {tg/kg) was compared with the baroreflex sensitivity value obtained before injecting terazosin (control).

Protocol for drug administration--Phenylephrine

and terazosin (Sigma Chemicals) were freshly prepared by dissolving in distilled water. Following control recording of all the haemodynamic parameters, a cumulative dose response curve of phenylephrine (1-16 J-t g/kg) was determined for all the parameters. After 20 min, terazosin (10 {tg/kg) was injected and the effects were recorded. The phenylephrine dose response observations were repeated with a maximum strength of 32 {tg/kg. After recovery from the phenylephrine effect, a higher dose of terazosin (100 {tg/kg) was administered and dose response curve of phenylephrine at a maximum dose of 64 {tg/kg was obtained. After a recovery period of 30 min, the highest dose of terazosin (300 {tg/kg) was administered and dose response curve of phenylephrine at a maximum dose of 128 {tg/kg was constructed. The highest dose of phenylephrine after each dose of terazosin was selected to produce a 50-70% rise in the arterial pressure.

Statistical analysis-The data are expressed as mean±SE. One-way ANOV A followed by Newman­Keuls test was used for statistical analysis. P<0.05 was considered significant.

Results Effect of terazosin on blood pressure and heart

rate--Intravenous administration of phenylephrine produced a dose-dependent rise in systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and mean arterial pressure (MAP) (Figs 1 and 2) and a corresponding fall in the heart rate (HR) (Fig. 3).

Terazosin at all the three doses (1 0, 100 and 300 {tg/kg) produced a significant (?<0.05) dose-depen­dent fall in the basal values of all the parameters of arterial blood pressure (Figs 1 and 2) and a rise in the heart rate which was significant (P<0.05) only at higher concentrations (100 and 300 J-tg/kg) (Fig. 3).

Terazosin attenuated the phenylephrine induced rise in the arterial pressure (Figs 1 and 2) and the fall in the heart rate (Fig. 3) at all the three doses. Thjs effect of terazosin was found to be dose-dependent.

Effect of terazosin on left ventricular pressure and left ventricular dP/dT max-On mJection of phenylephrine in progressively increasing doses (1-16 {tg/kg), there was a corresponding rise in both left ventricular systolic pressure (L VSP) and left ventricular dP/dt max (Fig. 4) . .

Terazosin caused a fall in the L VSP which was significant (P<0.05) at the dose strengths of 100 and 300 {tglkg (Fig. 4). Control value of LVSP was

SHARMA et al: ALPHA-1 ADRENOCEPTORS AND BAROREFLEX SENSITIVITY 1197

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201±4 mmHg. Terazosin produced a fall of L VSP to 185±5, 180±7, and 178±5 mmHg at 10, 100 and 300 ttglkg respectively (Fig. 4). Phenylephrine induced rise in L VSP was significantly (P<0.05) attenuated after terazosin (100 and 300 ttglkg).

LV dP/dt max also showed a significant (P<0.05) fall at the dose strengths of 100 and 300 tt glkg of

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Fig. 3--Inhibition of phenylephrine induced dose-dependent response in Left ventricular systolic pressure (L VSP, A) and left ventricular contractility (LV d P/dl(maxl• B) by terazosin in three different doses [10 (•). 100 (.A.) and 300 (•) j.lg/kg]. Post­terazosin values for L VSP and LV d P/dt fmaxl were compared with the respective control value (o). *P<0.05 denotes significantly different from respective control value. All values are mean±SE from 10 dogs.

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1198 INDIAN J EXP BIOL, DECEMBER 2004

terazosin (Fig. 4 ). From a control value of LV dP/dt max of 4034±115 mmHg, terazosin produced a fall in LV dP/dt max to 4030±116, 4027±115, and 4024±117 mmHg at 10, 100 and 300 tLglkg respectively (Fig. 4).

Terazosin significantly (P<0.05) attenuated the phenylephrine induced rise in LV dP/dt max at the dose strengths of 100 and 300 tLglkg .

Effect of terazosin on stroke volume-Stroke volume was calculated as the cardiac output divided by the heart rate (CO/HR) after each dose of terazosin . The control value of stroke volume was 10.45±0.5 ml. Following the first dose of terazosin (10 tLg/kg), there was a small fall in the value to 10.18±0.4 mi. (Fig. 4A) After the second (100 tLglkg) and third (300 tLglkg) doses the fall in the stroke volume was significant (P<0.05) the values being 9.04±0.3 and 8.87±0.2 ml respectively (Fig. 4A).

Effect of terazosin on cardiac output-The basal value of the cardiac output (CO) was 1.53±0.2 L/rnin. After the first dose of terazosin (1 0 IL glkg), there was no change in the CO (Fig. 5B). With the second ( 100 IL g/kg) and the third (300 IL glkg) dose, the cardiac output was 1.53±0.4 and 1.54±0.3 L/min respectively (Fig. 5B) .

Effect of terazosin on baroreflex sensitivity--­Baroreflex sensitivity calculated from MAP-HR curves for control was 2.78±0.2 beats/min/mrnHg (Fig. 6). Baroreflex sensitivity for 10 tLglkg of terazosin was 2.82±0.3 and for 100 tLglkg and 300 tLglkg of terazosin, it was 2.76±0.2 and 2.81±0.3 (Fig. 6) respectively. There was no significant difference between control and post-terazosin baroreflex sensitivity values.

Discussion Phenylephrine, as expected, induced a significant

pressor response in a dose-dependent manner and a corresponding decline in the heart rate via the arterial baroreceptor pathway. These effects were significantly attenuated by terazosin administration which was related to the dose strength. Terazosin is known to block the post-synaptic vascular alpha-1 receptors leading to a decreased vascular resistance and the subsequent vasodilatation produces a fall in the blood pressure. A corresponding rise in the heart rate with the fall in the blood pressure was observed demonstrating an active baroreflex mechanism compensating for the decline in blood pressure as well as to restore the normal pressure. The baroreflex sensitivity calculated at all the three doses of terazosin

did not show any significant change as compared to the control value. This suggests that terazosin lowers blood pressure in a physiologically favorable manner maintaining the normal baroreceptor regulatory response.

Left ventricular performance was similarly enhanced by phenylephrine as evidenced by a rise in

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Fig. 6---Effects of terazosin in three different doses (10, 100 and 300 f..lg/kg) on the baroreflex mediated mean arterial pressure (MAP) and heart rate (HR) response to increase in MAP by phenylephrine (PE). There was no significant difference between the slopes of the curves of control (o) and post-terazosin [10 (•), 100 (A) and 300 ( •) f..lg/kg] observations. All values are

mean±SE from 10 dogs.

SHARMA et al: ALPHA-I ADRENOCEPTORS AND BAROREFLEX SENSITIVITY 1199

left ventricular systolic pressure and left ventricular dP/dt (max). A significant fall in both left ventricular systolic pressure and dP/dt (max) by terazosin, suggests an important role of myocardial alpha-1 adrenoceptors in the genesis of the positive inotropic effect. Terazosin did not produce any significant change in the cardiac output which could be partly due to an increase in the heart rate inspite of the fall in the stroke volume produced by terazosin.

Terazosin was administered in three different doses of 10, 100 and 300 JLg/kg. Though the drug demonstrated its alpha-1 blocking properties at all the three doses, the optimal response was produced at the strength of 100 JLglkg. Hence, the dose strength of 100 JLglkg can be considered as the optimal dose.

In conclusion, terazosin acts as a potent antihypertensive by inhibiting peripheral alpha-1 adrenoceptors thereby producing a fall in peripheral resistance and subsequently blood pressure. Inspite of a significant negative inotropic effect along with its antihypertensive action, terazosin did not produce any fall in the cardiac output and the baroreflex regulatory mechanism remained unaffected which can be considered as an additional advantage of the drug.

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