Indian Jornal of xperimental Biology Vol. 42, December 24, pp. 1195-1199 ffects of alpha-1 adrenergic receptor antagonist, terazosin, on cardiovasclar fnctions in anaesthetised dogs R Sharma & V M Ahja Department of Physiology, Malana Azad Medical College, New Delhi LLO 3 and M Fahim* Department of Physiology, Vallabhbhai Patel Chest Institte, Delhi University, Delhi 11 7, India Received 31 October 23; revised 24 Agst 24 Initially a dose-response crve of phenylephrine was constrcted at dose strengths of l-16 flg/kg in a cmlative manner. Phenylephrine cased a significant rise in the mean arterial pressre, left ventriclar systolic pressre, left ventriclar contractility, stroke volme and a significant decline in the heart rate. Terazosin was administered in three selected doses of 1, 1 and 3 flglkg. Following each dose of terazosin, dose-response crve of phenylephrine was constrcted. Terazosin, per se, decreased the basal mean arterial pressre, left ventriclar systolic pressre, left ventriclar contractility and stroke volme significantly in a dose dependent manner with an increase in the heart rate with no significant change in the cardiac otpt. The baroreflex sensitivity at all the three doses remained nchanged. In conclsion, the present findings spport the view that terazosin redces the blood pressre in a physiologically more favorable manner by maintaining the neral integrity of the cardiovasclar system. Keywords: Alpha- I adrenergic receptor, Baroreflex, Left ventriclar performance, Terazosin. Hypertension is one of the commonest prevalent disorders in crrent times. It has been sggested that, even in hypertensives, the blood pressre reglatory mechanisms contine to operate althogh at a higher set point. Alpha-1 adrenergic antagonists, eg. terazosin, have been sed as the mainstay of antihypertensive therapy. Stimlation of alpha-1 adrenergic receptors modlates varios steps of the cardiac excitation-contraction copling cascade inclding ionic condctances, cytosolic ionic activities and calcim sensitivity of contractile proteins 1 2 They also reglate the cardiac rhythm, condction and force of contraction 3-5. However, no evidence is available regarding the effect of long term se of alpha-1 adrenergic blockers on the left ventriclar performance and the neral reglation of blood pressre. The fnction of myocardial alpha-1 adrenoceptors can be stdied sing selective alpha-1 adrenergic agonist (phenylephrine) and antagonist (terazosin). Phenylephrine by selectively stimlating alpha-1 *Correspondent athor Phone : 91-11-2766712 Fax: 91-11-2766742 -mail : vpciphysiology@yahoo.com adrenergic receptors, has been shown to prodce a positive inotropic effect 6 7 and an increase in the arterial blood pressre by casing peripheral vasoconstriction 8. Terazosin acts on the same peripheral receptors casing peripheral vasodilation and a fall in the arterial blood pressre 9. It also acts on the myocardial adrenoceptors leading to a decline in the left ventriclar systolic pressre and contractility 1 Althogh effect of different doses of terazosin has been stdied on blood pressre 11, left ventriclar performance has not been assessed. In addition, its effect on the heart rate with the fall in the blood pressre 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 stdy, the effect of three different doses of terazosin, on the phenylephrine indced hemodynamic changes and the sensitivity of the baroreceptor mediated reglation of the arterial blood pressre have been stdied. Materials and Methods All experiments were approved by the V P Chest Institte thical Committee and were performed
1196 INDIAN J XP BIOL, DCMBR 24 nder the gidelines of Care and Use of xperimental Animals. Healthy, male, mongrel dogs (1) weighing between 12-14 kg were anaesthetized with sodim pentobarbitone (35 mg/kg, iv). Trachea was cannlated, polyethylene catheters were placed in the femoral artery to record blood pressre sing (Statham P32 Db) pressre transdcer and in the femoral vein for injecting drgs. Another catheter was placed in the left ventricle throgh the left common carotid artery for recording left ventriclar pressre with a pressre transdcer (Statham P32 Db). The pressre recording system was calibrated with a mercry manometer before each experiment. The left ventriclar plse was electronically differentiated (Differentiator Contractility-Lectromed model-527) to record left ventriclar dp/dt and also to drive a cardiotachometer (Lectromed model-526) to record the heart rate. All these variables were recorded on a polygraph (Lectromed-UK). Room temperatre was mai ntained at 25 ±2 C. The body temperatre 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 measrement of gases (schweiler BGA pls Model Type 331). The blood gases were kept in the normal range throghot the experiment. After srgical procedres, the animal was allowed to stabilize for 3 min before taking observations. Measrement of cardiac otpt and stroke volme--cardiac otpt was measred by the thermodiltion techniqe sing a cardiac otpt compter (COM-1 dward Company USA). Cardiac otpt was measred before terazosin treatment (control) and sbseqently after each dose of terazosin (1, 1 and 3 {tg/kg). Stroke volme was calclated as cardiac otpt/heart rate. Calclation of baroreflex sensitivity-arterial baroreceptor mediated reglation of arterial pressre (Baroreflex) was calclated from the mean arterial pressre (MAP) and heart rate (HR) relationship. Blood pressre was changed by injecting varying doses of phenylephrine and the corresponding changes in heart rate were recorded. Baroreflex sensitivity (HR/ MAP) was calclated from the linear part of the mean arterial pressreheart rate crves. Baroreflex sensitivity after injecting the three doses of terazosin (1, 1 and 3 {tg/kg) was compared with the baroreflex sensitivity vale obtained before injecting terazosin (control). Protocol for drg administration--phenylephrine and terazosin (Sigma Chemicals) were freshly prepared by dissolving in distilled water. Following control recording of all the haemodynamic parameters, a cmlative dose response crve of phenylephrine (1-16 J-t g/kg) was determined for all the parameters. After 2 min, terazosin (1 {tg/kg) was injected and the effects were recorded. The phenylephrine dose response observations were repeated with a maximm strength of 32 {tg/kg. After recovery from the phenylephrine effect, a higher dose of terazosin (1 {tg/kg) was administered and dose response crve of phenylephrine at a maximm dose of 64 {tg/kg was obtained. After a recovery period of 3 min, the highest dose of terazosin (3 {tg/kg) was administered and dose response crve of phenylephrine at a maximm dose of 128 {tg/kg was constrcted. The highest dose of phenylephrine after each dose of terazosin was selected to prodce a 5-7% rise in the arterial pressre. Statistical analysis-the data are expressed as mean±s. One-way ANOV A followed by Newman Kels test was sed for statistical analysis. P<.5 was considered significant. Reslts ffect of terazosin on blood pressre and heart rate--intravenos administration of phenylephrine prodced a dose-dependent rise in systolic blood pressre (SBP), diastolic blood pressre (DBP), plse pressre (PP) and mean arterial pressre (MAP) (Figs 1 and 2) and a corresponding fall in the heart rate (HR) (Fig. 3). Terazosin at all the three doses (1, 1 and 3 {tg/kg) prodced a significant (?<.5) dose-dependent fall in the basal vales of all the parameters of arterial blood pressre (Figs 1 and 2) and a rise in the heart rate which was significant (P<.5) only at higher concentrations (1 and 3 J-tg/kg) (Fig. 3). Terazosin attenated the phenylephrine indced rise in the arterial pressre (Figs 1 and 2) and the fall in the heart rate (Fig. 3) at all the three doses. Thjs effect of terazosin was fond to be dose-dependent. ffect of terazosin on left ventriclar pressre and left ventriclar dp/dt max-on mjection of phenylephrine in progressively increasing doses (1-16 {tg/kg), there was a corresponding rise in both left ventriclar systolic pressre (L VSP) and left ventriclar dp/dt max (Fig. 4).. Terazosin cased a fall in the L VSP which was significant (P<.5) at the dose strengths of 1 and 3 {tglkg (Fig. 4). Control vale of LVSP was
SHARMA et al: ALPHA-1 ADRNOCPTORS AND BARORFLX SNSITIVITY 1197 19 17 15 " c 13.51, 11 (/) 9 15 13.s :: 11.51 9 Dose of Phenylephrine (log gm/kg) Fig.!--ffect of progressively increasing doses of phenylephrine (1-16 j.lg/kg) on Systolic blood pressre (A) and diastolic blood pressre (B) before (o) and after pretreatment with three different doses [1( ), loo(.a.) and 3( ) j.lg/kg] of terazosin. *P<.5 denotes significantly different from respective control vale. All vales are mean±s from 1 dogs. 6 5 " 4 c -; 3 c 2 15 13 " 11 c ii 9 ;:: t: " <( 7 :: " 5 2 4 8 16 32 64 128 Dose of Phenylephrine (log gm/kg) 21±4 mmhg. Terazosin prodced a fall of L VSP to 185±5, 18±7, and 178±5 mmhg at 1, 1 and 3 ttglkg respectively (Fig. 4). Phenylephrine indced rise in L VSP was significantly (P<.5) attenated after terazosin (1 and 3 ttglkg). LV dp/dt max also showed a significant (P<.5) fall at the dose strengths of 1 and 3 tt glkg of 225 215 25 c ;:: c 195 :; 185 > " 175 = J " 165 45 445 44 )( 435, : c > J 43 425 4:2 2 4 16 32 64 128 Dose of Phenylephrine (log IJQmlkg) Fig. 3--Inhibition of phenylephrine indced dose-dependent response in Left ventriclar systolic pressre (L VSP, A) and left ventriclar contractility (LV d P/dl(maxl B) by terazosin in three different doses [1 ( ). 1 (.A.) and 3 ( ) j.lg/kg]. Postterazosin vales for L VSP and LV d P/dt fmaxl were compared with the respective control vale (o). *P<.5 denotes significantly different from respective control vale. All vales are mean±s from 1 dogs. e 19 "2 17 Ui ii 15 Q) e 13 ii t: 11 9 7 2 4 16 32 64 128 Dose of Phenylephrine (log gm/kg) Fig. 2-ffect of progressively increasing doses of phenylephrine (1-16 j.lg/kg) on plse pressre (A) and mean arterial pressre (B) before and after pretreatment with three different doses [1 ( ), 1 (.A.) and 3 ( ) j.lg/kg] of terazosin. * P<.5 denotes significantly different from respective control ( o) vales. All vales are mean±s from 1 dogs. Fig. 4----ffects of terazosin in three different doses [1 ( ). 1 (.A.) and 3 ( ) j.lg/kg] on fall in heart rate prodced by phenylephrine (P). Post-terazosin vales of HR after individal dose of P were compared with the respective control vale (o). *P<.5 denotes significantly different from respective control vale. All vales are mean±s from 1 dogs.
1198 INDIAN J XP BIOL, DCMBR 24 terazosin (Fig. 4 ). From a control vale of LV dp/dt max of 434±115 mmhg, terazosin prodced a fall in LV dp/dt max to 43±116, 427±115, and 424±117 mmhg at 1, 1 and 3 tlglkg respectively (Fig. 4). Terazosin significantly (P<.5) attenated the phenylephrine indced rise in LV dp/dt max at the dose strengths of 1 and 3 tlglkg. ffect of terazosin on stroke volme-stroke volme was calclated as the cardiac otpt divided by the heart rate (CO/HR) after each dose of terazosin. The control vale of stroke volme was 1.45±.5 ml. Following the first dose of terazosin (1 tlg/kg), there was a small fall in the vale to 1.18±.4 mi. (Fig. 4A) After the second (1 tlglkg) and third (3 tlglkg) doses the fall in the stroke volme was significant (P<.5) the vales being 9.4±.3 and 8.87±.2 ml respectively (Fig. 4A). ffect of terazosin on cardiac otpt-the basal vale of the cardiac otpt (CO) was 1.53±.2 L/rnin. After the first dose of terazosin (1 IL glkg), there was no change in the CO (Fig. 5B). With the second ( 1 IL g/kg) and the third (3 IL glkg) dose, the cardiac otpt was 1.53±.4 and 1.54±.3 L/min respectively (Fig. 5B). ffect of terazosin on baroreflex sensitivity-- Baroreflex sensitivity calclated from MAP-HR crves for control was 2.78±.2 beats/min/mrnhg (Fig. 6). Baroreflex sensitivity for 1 tlglkg of terazosin was 2.82±.3 and for 1 tlglkg and 3 tlglkg of terazosin, it was 2.76±.2 and 2.81±.3 (Fig. 6) respectively. There was no significant difference between control and post-terazosin baroreflex sensitivity vales. Discssion Phenylephrine, as expected, indced 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 attenated by terazosin administration which was related to the dose strength. Terazosin is known to block the post-synaptic vasclar alpha-1 receptors leading to a decreased vasclar resistance and the sbseqent vasodilatation prodces a fall in the blood pressre. A corresponding rise in the heart rate with the fall in the blood pressre was observed demonstrating an active baroreflex mechanism compensating for the decline in blood pressre as well as to restore the normal pressre. The baroreflex sensitivity calclated at all the three doses of terazosin did not show any significant change as compared to the control vale. This sggests that terazosin lowers blood pressre in a physiologically favorable manner maintaining the normal baroreceptor reglatory response. Left ventriclar performance was similarly enhanced by phenylephrine as evidenced by a rise in 11.5 11 I 1.5 J 1 -' c > 9.5 J >< 9 V> : " :: :::> Q. :::> a: 8.5 1.6 1.5 1.4 1.3 1.2 1.1 1. @ control T1 T2 T3 Fig. 5--ffect of terazosin in three different doses (T1=1, T2 =1 and T3=3 JJ.g/kg) on stroke volme (A) and cardiac otpt (B). All vales are mean±s from 1 dogs. "2. ; 16 a: 13 t: 1 7 9 11 13 15 17 19 21 Mean Arterial Pressre (mm Hg} Fig. 6---ffects of terazosin in three different doses (1, 1 and 3 flg/kg) on the baroreflex mediated mean arterial pressre (MAP) and heart rate (HR) response to increase in MAP by phenylephrine (P). There was no significant difference between the slopes of the crves of control (o) and post-terazosin [1 ( ), 1 (A) and 3 ( ) flg/kg] observations. All vales are mean±s from 1 dogs.
SHARMA et al: ALPHA-I ADRNOCPTORS AND BARORFLX SNSITIVITY 1199 left ventriclar systolic pressre and left ventriclar dp/dt (max). A significant fall in both left ventriclar systolic pressre and dp/dt (max) by terazosin, sggests an important role of myocardial alpha-1 adrenoceptors in the genesis of the positive inotropic effect. Terazosin did not prodce any significant change in the cardiac otpt which cold be partly de to an increase in the heart rate inspite of the fall in the stroke volme prodced by terazosin. Terazosin was administered in three different doses of 1, 1 and 3 JLg/kg. Thogh the drg demonstrated its alpha-1 blocking properties at all the three doses, the optimal response was prodced at the strength of 1 JLglkg. Hence, the dose strength of 1 JLglkg can be considered as the optimal dose. In conclsion, terazosin acts as a potent antihypertensive by inhibiting peripheral alpha-1 adrenoceptors thereby prodcing a fall in peripheral resistance and sbseqently blood pressre. Inspite of a significant negative inotropic effect along with its antihypertensive action, terazosin did not prodce any fall in the cardiac otpt and the baroreflex reglatory mechanism remained naffected which can be considered as an additional advantage of the drg. References 1 Knowlton R & Michel J, Alpha-one Adrenergic receptor sbtypes mediate biochemical, moleclar and morphological changes of cltred myocardial cells, J Bioi Chem, 268 (1993) 15374. 2 Skomedal P & Osnes R, Competitive blockade of alphaadrenergic receptors in rat heart by prazosin, Acta Pharmacal Toxicol, 47 (198) 217. 3 Pceat M, Myocardi al alpha-one adrenergic receptors mediate a positi ve inotropic effect via calcim sensitization, Trends Pharmacal Sci, 13 (1992) 263. 4 Rolea J, Myocardial alpha-one adrenoceptor- inotropic effect, Life Sci, 6 (6) (1997) 135. 5 Scholz J, Alpha-one receptor mediated positive inotropic effect and inositol triphosphate-3 increase in mammalian heart, J Pharmacal xp Ther, 245 (1998) 327. 6 Drew G M, ffects of alpha adrenergic receptor agoni sts and antagonists on pre and post synaptically located alpha adrenoceptors, r J Pharmacal, 36 (1976) 3 13. 7 Beckner R & Scholz H, ffects of alpha adrenergic receptor stimlation with phenylephrine in the presence of propranolol on force of contraction, slow inward crrent and camp content in the bovi ne heart, Br J Pharmacal, 82 (1984) 223. 8 Stokland, Thorvaldson J, Hebbek F & Kiil F, Factors contribting to blood pressre elevation dring norepinephrine and phenylephrine infsion in dogs, Acta Physiol Scand, 117 ( 1983) 481. 9 Kyncll J J, Pharmacology of terazosin, Am J Med, 8, sppl 58 (1986) 9. 1 Titmarsh S & Monk JP, Terazosin- a review of its pharmacodynamic and pharmacokinetic properties, and therapetic efficacy in ess<';ntial hypertension, Drgs, 33 (1987) 461. 11 Kenny B A, Read A M, Naylor A M, Greengrass PM, Carter A J, Wyllie M G, ffects of alpha-one ad renoceptor antagonists on prostatic pressre and blood pressre in the anaesthetised dog, Urology, 44 (1994) 52. 12 Sasso H & O'Connor D T, Prazosin depression of baroreflex fnction in hypertensive man, r J Clin Phannacol, 22 (1982) 7.