Carotid Sinus Baroreceptor Control of Right Coronary Circulation in Normal, Hypertrophied, and Failing Right Ventricles of Conscious Dogs

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1 1339 Carotid Sinus Baroreceptor Control of Right Coronary Circulation in, Hypertrophied, and Failing Right Ventricles of Conscious Dogs AUL A. MURRAY AND STEHEN F. VATNER SUMMARY Tlie right coronary vascular response to bilateral carotid occlusion (BCO) was assessed in normal, conscious dogs and also in dogs with right ventricular (RV) hypertrophy alone or in combination with right heart failure, induced by chronic (5- months) pulmonary artery stenosis. In normal, conscious dogs with intact adrenergic neural activity and with heart rate held constant by electrical pacing, BCO increased ( < 0.01) mean aortic pressure (33 ± %) and induced only minor changes in RV hemodynamics, but no change in right coronary blood flow ( ± 3%), and a significant increase ( < 0.01) in right coronary resistance (32 ± 5%). /J-Adrenergic receptor blockade did not unmask a further right coronary constrictor response to BCO. However, combined a- and /3-adrenergic receptor blockades significantly reduced ( < 0.02) the BCO-lnduced Increase in right coronary resistance. When we raised mmi aortic pressure by an amount similar (3 ± 8%) to that which occurred with BCO, but in this case by hydraulically constricting the ascending thoracic aorta in conscious dogs pretreated with a ganglionlc blocker, right coronary blood flow rose ( < 0.01) 55 ± 8%. The BCOinduced increase in right coronary resistance was greatly attenuated ( < 0.O1) in dogs with RV hypertrophy alone, and further depressed ( < 0.01) in dogs with RV failure. Thus, in the normal, conscious dog with intact adrenergic neural activity, BCO elicits an increase hi right coronary resistance which is: (1) not the result of right coronary autoregulation, (2) not enhanced by /3-adrenergic receptor blockade, and (3) largely due to a-adrenergic vasoconstriction. Furthermore, the BCO-induced right coronary constriction is diminished in dogs with RV hypertrophy alone, and further depressed in dogs with RV hypertrophy and failure. Ore Res 9: , 19S1 CAROTID sinus hypotension initiates a complex sequence of events which can exert multiple and counteracting effects on coronary vascular dynamics. For example, carotid sinus hypotension has been shown previously to elicit net increases in left coronary blood flow in anesthetized preparations with adrenergic neural activity intact (Feigl, 1968; Bond and Green, 1969; DiSalvo et al., 191; Mohrman and Feigl, 198). However, when both changes in myocardial metabolic demand initiated by the hemodynamic response to carotid sinus hypotension and also any direct /8-adrenergically mediated vasodilation were limited by administering a ^-adrenergic antagonist, bilateral carotid occlusion (BCO) elicited an increase in calculated left coronary vascular resistance (Feigl, 1968; DiSalvo et al, 191; owell and Feigl, 199). This increase in left coronary resistance has been attributed to reflex From the Department* of Medicine, Harvard Medical School and eter Bent Brigham Hospital, Boston, Massachusetts, and the New England Regional rimate Research Center, Southboro, Massachusetts. Supported in part by U.S. ublic Health Service Grants HL 232, 1516, and 20552, and grants from the Massachusetts ( ) and the American Heart Associations (80 106). Dr. Murray's current address is Department of Anesthesiology, Johns Hopking Medical School, Baltimore, Maryland Address for reprints: Stephen F. Vatner, MX)., New England Regional rimate Research Center, One ine Hill Drive, Southboro, Massachusetts 012 Received January 26,1981; accepted for publication August 26, a-adrenergic receptor activation (Feigl, 1968; Di- Salvo et al., 191; Mohrman and Feigl, 198; owell and Feigl, 199). However, these conclusions have been criticized (Kirchheim, 196) on the basis that coronary autoregulation could also account for increases in resistance in the face of elevated coronary perfusion pressure and no reduction in coronary blood flow (Berne and Rubio, 199). In contrast to these studies which have assessed the left coronary vascular response to carotid 3inus hypotension in anesthetized dogs, the right coronary vascular response of normal, conscious dogs to this stimulus has not been examined. Moreover, extrapolations from those previous studies which examined the left coronary response to carotid sinus hypotension may not be appropriate, because the right ventricle is not subjected to the reflex increase in afterload, as is the left ventricle during BCO. Because the canine right coronary circulation supplies only the right ventricle (Murray and Vatner, 1980), secondary effects due to changes in myocardial metabolic demand during BCO may play a less pronounced role. The coronary vascular response of the hypertrophied or failing right ventricle to carotid sinus hypotension is even less well understood. revious studies in experimental animals (Higgins et al., 192) and man (Eckberg et al., 191) have demon-

2 130 CIRCULATION RESEARCH VOL. 9, No. 6, DECEMBER 1981 strated a generalized depression in the arterial baroreceptor reflex with cardiac diseases of various etiology. Furthermore, peripheral vascular responses to carotid sinus hypotension are attenuated in conscious dogs with severe RV hypertrophy and failure (Higgins et al., 192). However, concomitant changes in coronary vascular dynamics of the hypertrophied and failing right ventricle are entirely unknown. Consequently, the goals of the present study were: (1) to characterize the vascular response of the right coronary circulation to carotid 3inus hypotension in the normal right ventricle of conscious dogs, (2) to determine whether autoregulatory or adrenergic factors were responsible for the right coronary vascular response to carotid sinus hypotension, and (3) to determine whether the response of the right coronary circulation to carotid sinus hypotension is altered following the development of severe RV hypertrophy, and further modified with a progression to chronic RV failure in conscious dogs. Methods I. Surgical reparation and Induction of Right Ventricular (RV) Hypertrophy Twenty-nine mongrel dogs of either sex (conditioned and testing negative for heart worms) were tranquilized with Tranvet-10 (propiopromazine HC1, 0.1 mg/kg, im) and anesthetized with sodium pentobarbital (30 mgag, iv). After intubation, the dogs were ventilated artificially and prepared for sterile surgery. Through a left thoracotomy in the th intercostal space, heparin-filled Tygon catheters (Norton Co.) were implanted in the aorta and right ventricle in all dogs. In addition, an inflatable hydraulic occluder (20-26 mm i.d., Jones Co.) was placed around the main pulmonary artery in 13 dogs and around the ascending thoracic aorta in five dogs. The distal ends of the catheters and occluder were exteriorized and positioned between the scapulae. All animals were placed on a 1-week post-surgical regimen of antibiotics. At least 3 weeks were allowed for recovery from the effects of surgery. At this time, nine of the dogs were subjected to gradual, chronic pressure overload of the right ventricle induced by progressive inflation of the pulmonary artery occluder as previously described (Murray et al, 199; Murray and Vatner, 1980). The pressure overload was sustained over a 5- to -month period. One month (normal dogs) or months (dogs with RV hypertrophy) after the initial surgery, a second thoracotomy was performed through the th right intercostal space. A segment (approximately 2 cm) of the right main coronary artery was dissected carefully in a retrograde direction from the right marginal artery branch to its aortic origin for placement of an inflatable hydraulic occluder ( mm i.d.) and a proximal Doppler ultrasonic flow transducer. A solid state pressure transducer (Konigsberg Instruments, Inc.) was inserted into the RV cavity via a stab wound in the mid-anterior free wall in seven normal dogs and in five dogs (four RV hypertrophy and one RV hypertrophy and failure) subjected to chronic pulmonary artery stenosis. acing electrodes were sutured to the surface of the right atrium and right ventricle. Inflatable hydraulic occluders (6 mm Ld.) were also positioned around both main carotid arteries proximal to the level of the carotid sinus via a small neck incision. Three to weeks were allowed for recovery of the animals from the effects of surgery. II. Experimental Measurements Right main coronary artery blood flow was measured with a CW Doppler ultrasonic flowmeter (Franklin et al., 1966). The accuracy and reliability of this method of measuring coronary blood flow has been described previously in detail (Vatner et al., 190a). At autopsy, a catheter was inserted into the right main coronary artery via the ostium with its tip proximal to the implanted flow probe. Flow probe calibration was achieved in situ by perfusing blood through the catheter at known flow rates. Aortic pressure was measured from the implanted catheter attached to a Statham 23Db strain gauge manometer. In the aortic constriction protocol, aortic pressure was measured proximal to the site of constriction with a Millar microtip pressure manometer (Millar Instruments, Inc.) introduced into the aorta through a femoral artery under local anesthesia (2% lidocaine) on the day of the experiment. RV pressure was measured from the implanted solid state transducer (atrick et al, 19; Baig et al., 19), which was calibrated both in vitro, and in vivo using the implanted RV catheter. HI. Experimental rotocols (i) BCO Experiments were performed in a quiet, dimly lit room with the unsedated, conscious dog resting comfortably on its right side. For this portion of the study, we used normal dogs instrumented in the manner described above, but without chronically implanted hydraulic occluders around the pulmonary artery, four additional normal dogs with chronically implanted (but uninflated) hydraulic occluders around the pulmonary artery, and nine dogs subjected to chronic pulmonary artery stenosis (five with RV hypertropy alone and four with RV hypertrophy and failure). Heart rate was held constant (ventricular pacing) by electrical stimulation from an external pacemaker (Medtronics, Inc.) in all experiments. Following control measurements of all variables, carotid sinus hypotension was achieved by rapidly inflating the hydraulic occluders previously implanted around both main carotid arteries. BCO was maintained until all the measured variables achieved a new steady state level (approxi-

3 RIGHT CORONARY RESOE TO CAROTID SINUS HYOTEION/Mumry & Vatner 131 mately 0 to 60 seconds). This process was repeated in normal dogs, four dogs with RV hypertrophy alone, and three dogs with RV hypertrophy and failure in the presence of ^-adrenergic receptor blockade (propranolol HC1, 1 mgag, iv) and with the further addition of a-adrenergic receptor blockade (phentolamine HC1, 2 mg/kg loading dose plus 1 mg/ml infused at 1.91 ml/min, iv sustaining dose). Bolus intravenous injections of norepinephrine (1.0 fig/kg) and isoproterenol (1.0 fig/kg) were administered to test the efficacy of a- and /?-adrenergic receptor blockades, respectively. (ii) Aortic Constriction The effects of mechanically induced increases in arterial pressure on right coronary blood flow were assessed in five normal, conscious dogs. Following control measurements of all variables, aortic constriction was achieved by gradually inflating the previously implanted hydraulic occluder around the ascending thoracic aorta. The degree of inflation was adjusted to achieve an increment in arterial pressure similar to that observed during BCO. The dogs were pre-treated with hexamethonium chloride (30 mg/kg, iv) to prevent potentially confounding reflex effects of aortic constriction on metabolic determinants of right coronary blood flow. Absence of reflex tachycardia following intravenous injections of nitroglycerin (0.3 mg) confirmed the efficacy of the ganglionic blockade. Following completion of these experimental protocols, the dogs were killed with a high dose of sodium pentobarbital, the heart was excised, and the atria, great vessels, valves, and epicardial fat were separated from the heart and discarded. The free walls of the right and left ventricles were weighed separately, and the values for ventricular mass-to-body weight ratio were computed using the body weight of the dog at the time of the initial surgery. RV wall thickness was measured at a consistent site in the mid-free wall and included trabecular muscles. Evidence of right heart failure (i.e., abdominal ascites and hepatic congestion) was observed in four of the nine dogs with RV hypertro- phy- IV. Data Analysis The experimental data were recorded (Honeywell model 5600 B) and played back onto a multichannel, direct-writing oscillograph (Gould-Brush). The rate of change of RV pressure (d/dt/ where equals isovolumic minus end-diastolic pressure; Braunwald et al, 196) was derived from the pressure signal with an operational amplifier (National Semiconductor, Inc.) connected as a differentiator. A triangular wave signal with known slope (rate of change) was substituted for the pressure signal for direct calibration of the differentiator. Mean aortic pressure and mean right coronary blood flow were derived using passive electronic filters with a 2- second time constant. Mean right coronary resistance was calculated as the quotient of mean aortic pressure minus RV end-diastolic pressure and mean right coronary blood flow. A cardiotachometer (Beckman type 9856) triggered by the electrical signal from the aortic or RV pressure pulse provided instantaneous and continuous records of heart rate. Steady state values of the measured variables were assessed (1) over at least a 30-second period at control prior to the experimental interventions; (2) after approximately 0 seconds of BCO, both before and after administration of the various adrenergic antagonists; and (3) after 3-5 minutes of aortic constriction. Measurements were made after at least 3 minutes of aortic constriction to avoid the transient increases in right coronary blood flow associated with acute aortic constriction. The data were stored and statistically analyzed with a D /3 computer (Digital Equipment Corp.). Threeway analysis of variance (with the 3-way interaction equal to zero) was utilized (1) to assess differences in the measured variables between normal dogs and dogs with RV hypertrophy at control and in response to BCO with sympathetic adrenergic activity intact, following ^-adrenergic receptor blockade and following combined a- and /3-adrenergic receptor blockades, and (2) to assess differences in the measured variables between normal dogs subjected to either BCO or aortic constriction (Armitage, 19). Values presented represent mean ± 1 SEM. Results I. BCO A. Adrenergic Activity Intact. As illustrated in Figure 1 (left panel), the right coronary vascular response of a normal, conscious dog with sympathetic adrenergic activity intact to BCO is characterized by an early (within 20 seconds), transient increase in right coronary blood flow (3.2 ± 0.6 ml/min; < 0.01), and a nonsignificant increase in right coronary resistance (0.56 ± 0.16 mm Hg/ml per min), followed by a sustained, steady state period in which blood flow returns to control levels and resistance is markedly increased. Because the early, transient increase in right coronary blood flow probably reflects a passive response to the BCO-induced increase in arterial pressure, only the steady state changes in the measured variables occurring 0 to 60 seconds after the initiation of BCO will be considered in detail. The steady state effects of BCO in normal, conscious dogs with intact sympathetic adrenergic activity are summarized in Table 1. With heart rate constant, BCO resulted in a small increase { < 0.05) in RV systolic pressure, but no significant change in RV end-diastolic pressure or RV d/dt/. As illustrated in Figure 1 (left panel) and summarized in Table 1, during the steady state, BCO elicited a marked increase ( < 0.01) in mean aortic pressure but no change in right coronary blood flow, resulting in a substantial increase ( < 0.01) in right

4 CIRCULATION RESEARCH 132 VOL. 9, No. 6, DECEMBER 1981 RV HYERTROHY 200^ f- BCO -j Mean Aortic ressure (mmho) 0 5 hasic Right Coronar; Flow (ml/min) 0 5 Mean Right Coronary Flow (ml/min) Mean Right Coronary Re«>ta nca ^n m Hg An l / n Heart Rate 1 Representative response of a normal dog (left panel) and a dog with right ventricular (RV) hypertrophy (right panel) to bilateral carotid occlusion (BCO). Heart rate was held constant by electrical pacing. Note that following a small, transient increase in right coronary blood flow, BCO elicits a marked, sustained steady state increase m right coronary resistance in the normal, conscious dog with an intact sympathetic nervous system. However, it is apparent that the magnitude of this BCO-induced increase in right coronary resistance is significantly reduced in the dog with RV hypertrophy. coronary resistance even with adrenergic activity intact. The sub-group of four normal dogs with chronically implanted (but uninflated) hydraulic occluders around the pulmonary artery had similar control levels of mean aortic pressure (102 ± 3 mm Hg), right coronary blood flow (18.5 ± 2,2 ml/min) and right coronary resistance (5.61 ± 0.81 mm Hg/ ml per min) compared to the normal dogs without pulmonary artery occluders. Moreover, with heart rate constant (18 ± beata/min), the BCOinduced increases ( < 0.01) in mean aortic pressure (3 ± 3 mm Hg) and right coronary resistance (1.59 ± 0.2 mm Hg/ml per min) were similar in normal dogs with and without pulmonary artery occluders. R V Hypertrophy. Chronic pulmonary artery stenosis resulted in substantial hypertrophy of the right ventricle as evidenced by significant increases ( < 0.01) in RV free wall weight-to-body weight ratio (1.1 ± 0.06 to 2.8 ± 0.2 g/kg), RV free wall thickness (6.5 ± 0. to 10.6 ± 0. mm), and RV free wall weight-to-left ventricular free wall weight ratio (0.2 ± 0.01 to 0.8 ± 0.03). This experimental model was not characterized by a significant change in left ventricular free wall weight-to-body weight ratio (3.8 ± 0.1 to 3.3 ± 0.36 g/kg). Control levels of RV systolic and end-diastolic pressures, RV d/dt/, and right coronary blood flow were significantly elevated (< 0.01), whereas mean aortic pressure and right coronary resistance were reduced ( < 0.01) in dogs with RV hypertrophy compared to normal (Table 1). With heart rate constant, BCO resulted in a similar steady state increase ( < 0.02) in RV systolic pressure compared to normal, and no change in RV end-diastolic pressure or RV d/dt/. As illustrated in Figure 1 (right panel) the magnitude and time course of the early transient increase ( < 0.01) in right coronary blood flow (2.1 ± 0. ml/min), and the early increase ( < 0.01) in right coronary resistance (0.31 ± 0.06 mm Hg/ml per min) were similar to that observed in normal dogs. However, as summarized in Table 1, the normal, steady state increase ( < 0.01) in mean aortic pressure (35 ± 5 mm Hg) with BCO was attenuated ( < 0.01) in dogs with RV hypertrophy (19 ± mm Hg). Furthermore, whereas steady state levels of right coronary blood flow during BCO were unchanged, the steady state increase ( < 0.01) in right coronary resistance during BCO was markedly reduced ( < 0.01) in dogs with RV hypertrophy (0.8 ± 0.10 mm Hg/ml per min) compared to normal (1.93 ± 0.39 mm Hg/ml per min). When the dogs comprising the RV hypertrophy

5 RIGHT CORONARY RESOE TO CAROTID SINUS HYOTEION/Afurra^ & Vatner 133 TABLE 1 Steady State Responses to BCO with Adrenergic Activity Intact and Heart Rate Constant RV systolic pressure RV end-diastolic pressure RV d/dt/ (sec"') Mean aortic pressure n Control 25 ±2 86 ± 2.6 ± ± ± ± ±2 98± A BCO ±1* 6± 1* 0.9 ± ± ± ± ±5f 19±f O.01 Mean right coronary flow (ml/min) Mean right coronary resistance (mm Hg/ml per min) Heart rate (beats/min) ± ± ± ± ± 10 ± ± ± ±0.39f 0.B ± 0.10J 0±0 0±0 SymboU represent statistically significant changes in the measured variables (mean ± 1 SEM) during bilateral carotid occlusion (BCO) (* < 0.05, ^ < 0.01). values represent probability that differences between normal dogs and dogs with right ventricular hypertrophy () occur by chance n refers to number of dogs. Where n = 5, comprised of four dogs with alone and one dog with and failure. Where n 9, comprised of five dogs with alone and four dogs with and failure. group were subdivided into dogs with RV hypertrophy alone (n = 5) and dogs with RV hypertrophy and failure (n = ), control levels of right coronary resistance were significantly reduced ( < 0.01) in the sub-group with RV failure (1.55 ± 0.1 mm Hg/ ml per min) compared to the sub-group with RV hypertrophy alone (2.66 ± 0.22 mm Hg/ml per min). Furthermore, as summarized in Figure 2, the increase in right coronary resistance during BCO, which was attenuated ( < 0.01) in dogs with RV hypertrophy alone (0.66 ± 0.12 mm Hg/ml per min) compared to normal (1.93 ± 0.39 mm Hg/ml per min), was further depressed { < 0.05) in dogs with RV failure (0.25 ± 0.0 mm Hg/ml per min). Differences between these two groups in terms of RV hemodynamic response to BCO could not be discerned because of the small number of animals studied with RV instrumentation. The change in right coronary resistance during BCO was examined in a sub-group of dogs with RV hypertrophy {n 5) in which control mean aortic pressure (10 ± mm Hg) was similar to that measured in normal dogs (108 ± 2 mm Hg). At control, right coronary resistance was significantly lower ( < 0.01) in the sub-group of dogs with RV hypertrophy (2.5 ± 0.30 mm Hg/ml per min) compared to normal (5.1 ± 0.6 mm Hg/ml per min). Moreover, during BCO the increase (0.56 ± i Bilateral Carotid Occlusion I5.1to.6. I p<q0 ii66tq22) 1.55tO1. I 1 ** ' FIGURE 2 Changes (A) in right coronary resistance during BCO with sympathetic neural activity intact in normal dogs (n = ; open bar), dogs with RV hypertrophy (H) alone (n 5; lined bar), and dogs with and failure ( and F) (n ; solid bar). Heart rate was held constant by ventricular pacing. Symbol (*) indicates significant increases ( < 0.01) in right coronary resistance during BCO for the respective groups. Note that both control levels of right coronary resistance (values in parentheses for respective groups) and the changes in right coronary resistance during BCO are progressively and significantly reduced from normal to R VH alone, and from R VH alone to and F.

6 13 CIRCULATION RESEARCH VOL. 9, No. 6, DECEMBER 1981 mm Hg/ml per min) in right coronary resistance in this sub-group of dogs with RV hypertrophy was significantly less ( < 0.01) than that measured in normal dogs (1.93 ± 0.39 mm Hg/ml per min). B. ^-Adrenergic Receptor Blockade. As summarized in Table 2, /?-adrenergic receptor blockade had little effect on control levels of the measured variables, although a decrease ( < 0.01) in RV d/dt/ and an increase ( < 0.05) in right coronary resistance was observed. During ys-adrenergic receptor blockade, BCO was not associated with any significant change in RV hemodynamics or right coronary blood flow. Whereas the increase ( < 0.01) in mean aortic pressure during BCO was reduced ( < 0.05), the magnitude of the concomitant increase ( < 0.01) in right coronary resistance (1.9 ± 0.29 mm Hg/ml per min) was similar to that observed with adrenergic activity intact (1.93 ± 0.39 mm Hg/ml per min). Thus, 0- adrenergic receptor blockade did not have the effect of unmasking a more prominent right coronary constriction during BCO in these normal dogs. RV Hypertrophy. /?-Adrenergic receptor blockade significantly reduced ( < 0.01) control levels of RV systolic pressure, RV d/dt/, and right coronary blood flow, and increased ( < 0.01) right coronary resistance (Table 2). Control levels of RV hemodynamics and right coronary blood flow were significantly higher ( < 0.01), and mean aortic pressure and right coronary resistance were lower { < 0.01), compared to normal dogs during /?- adrenergic receptor blockade. In a manner similar to the response of the normal group, BCO had no significant effect on RV hemodynamics or right coronary blood flow in the presence of ^-adrenergic receptor blockade. Moreover, the increases ( < 0.01) in mean aortic pressure and right coronary resistance during BCO were similar before and after ys-adrenergic receptor blockade in dogs with RV 'hypertrophy, and remained attenuated ( < 0.05) compared to normal. Thus, /S-adrenergic receptor blockade also failed to enhance the magnitude of the increase in right coronary resistance during BCO in dogs with RV hypertrophy. C. Combined a- and ^-Adrenergic Receptor Blockades. Combined a- and y3-adrenergic receptor blockades had no significant effect on control levels of RV hemodynamics or the right coronary circulation, but were associated with a decrease ( < 0.01) in mean aortic pressure compared to /3-adrenergic receptor blockade alone (Table 3). BCO once again failed to elicit significant changes in RV hemodynamics or right coronary blood flow. The increments in mean aortic pressure and right coronary resistance during BCO were attenuated ( < TABLE 2 Steady State Responses to BCO after ft-adrenergic Receptor Blockade RV systolic pressure RV end-diastolic pressure RV d/dt/ (sec"') Mean aortic pressure (nun Hg) Mean right coronary flow (ml/min) Mean right coronary resistance (mm Hg/ml per min) Heart rate (beate/min) RVGH n Control 25±2 ± 1* 2.6 ± ± 0. O ±.9* 56. ±.2* 0 ± 99±8 1.5 ± ± 3.' 6.2 ± 0.6$ 2.3 ± 0.35* 15 ± 150 ± 12 A BCO 3± 1 2 ± ± ± ± ± 3.2 2;t3tt 19± < ± ± ±0.29f 0.3 ±0.12f 0±0 0±0 Symbols signify affect* of /3-adren«rgk blockade on measured variables (mean ± 1 SEM) compared with adrenergic activity inuct (' < 0.01; $ < 0.06). Symbol represents statistically significant changes in measured variables during BCO (f < 0.01). values represent probability that differences between normal dogs and dogs with occur by chance, n refers to number of dogs. Where n -, comprised of three dogs with alone and one dog with and failure. Where n, comprised of four dogs with alone snd three dogs with and failure.

7 RIGHT CORONARY RESOE TO CAROTID SINUS HYOTEION/Murray & Vatner 135 TABLE 3 Steady State Responses to BCO after Combined a- and fi-adrtnergic Receptor Blockades RV systolic pressure RV end-diastolic pressure n Control 25±3 69 ± 12* < ± ± 0.9 <0 01 A BCO -1 ± 1 1 ± ±0-0.5 ± 0. RV d/dt/ (sec" 1 ) 26.0 ± ± ± ± 3. Mean aortic pressure 96 ±3* 81 ± 10' 12 ±2*f ± l'j <0.02 Mean right coronary flow (ml/min) 16. ± ± 3.2* 0.3 ± ± 0.f <0.02 Mean right coronary resistance (mm Hg/ml per min) 6.18 ± ± 0.39* ± 0.20ft 0.08 ± 0.0* Heart rate (beats/min) 150 ±8 12 ± 13 0 ±0 0 ±0 Symbols signify effects of combined a- and /?-adrenergic blockades on measured variables (Mean ± 1 SEH) compared with /3-adrenergic blockade alone (' < 0.01; % <0.02). Symbol represents statistically significant change in measured variables during BCO (f < 0.01). values represent probability that differences between normal dogs and dogs with occur by chance, n refers to number of dogs. Where n =, comprised of three dogs with alone and one dog with and failure. Where n, comprised of four dogs with alone and three dogs with and failure. 0.02), but not abolished, during combined a- and /?-adrenergic receptor blockades. The minor component that remained may have been due to incomplete a-adrenergic blockade. R V Hypertrophy. Combined a- and >8-adrenergic receptor blockades had a more prominent effect on control levels of the measured variables in dogs with RV hypertrophy (Table 3). Combined adrenergic receptor blockades significantly reduced ( < 0.01) RV systolic and mean aortic pressures, right coronary blood flow, and resistance. Whereas BCO did not elicit significant changes in RV hemodynamics, right coronary blood flow increased ( < 0.01) slightly during combined adrenergic receptor blockades. Furthermore, the increase in mean aortic pressure during BCO was attenuated ( < 0.01), and the increase in right coronary resistance was abolished ( < 0.01) by combined adrenergic receptor blockades. II. Aortic Constriction Control levels of mean aortic pressure (91 ± 6 mm Hg) were slightly reduced ( < 0.01), whereas levels of right coronary blood flow (16.6 ±1.9 ml/ min), right coronary resistance (5.89 ± 0.98 mm Hg/ml per min), RV systolic (2 ± 3 mm Hg), and end-diastolic (2.2 ± 0.2 mm Hg) pressures and heart rate (10 ± 5 beate/min) all were similar following ganglionic blockade, compared to values (shown in Table 1) for normal dogs with adrenergic neural activity intact. Aortic constriction had only trivial steady state effects on RV systolic (2 ± 3 mm Hg) and end-diastolic (1.2 ± 0.2 mm Hg; < 0.01) pressures, and caused no change in heart rate. However, as summarized in Figure 3, in contrast to the insignificant effect of BCO on right coronary blood flow ( ± 3%), aortic constriction resulted in a significant increase { < 0.01) of 55 ± 8% in right coronary blood flow for a similar increment (3 ± 8%) in mean aortic pressure as observed during BCO. Discussion In contrast to previous studies which observed significant increases in left coronary blood flow in response to carotid sinus hypotension with sympathetic neural activity intact (Feigl, 1968; Bond and Green, 1969; DiSalvo et al, 191; Mohrman and Feigl, 198), in the present investigation BCO did not alter steady state levels of right coronary blood flow and increased right coronary resistance markedly in normal, conscious dogs with adrenergic neural activity intact. There are several reasons for these differences. Most important is that carotid sinus hypotension results in reflex sympathetic a- and ^-adrenergic receptor activation, which have

8 136 CIRCULATION RESEARCH VOL.9, No. 6, DECEMBER 1981 (A*) 0i T MA Bilateral Carotid Occlusion Aortic Constriction p X RCBF tt6 20t FIGURE 3 ercentage changes (A%) in mean aortic pressure (MA) and right coronary blood flow (RCBF) during BCO in normal, conscious dogs with intact sympathetic neural activity (n = ; open bars) and during aortic constriction in normal, conscious dogs with ganglionic blockade (n = 5; lined bars). Heart rate was held constant at similar levels in both groups. Control values for the measured variables are at the base of the bars. Symbol (*) represents significant increases ( < 0.01) from control levels. Despite a similar percentage increment in MA (the absolute increments were 29 ± 6 mm Hg during aortic constriction and 35 ±5 mm Hg during BCO), RCBF is unchanged during BCO, but significantly increased during aortic constriction. potentially opposing influences on the coronary circulation. The positive inotropic and chronotropic effects of ys-adrenergic receptor activation, as well as the associated increase in left ventricular afterload secondary to elevated systemic peripheral resistance, all act to increase myocardial oxygen consumption. The resulting metabolic vasodilator influences tend to mask a-adrenergic receptor-mediated left coronary vasoconstrictor activity. As a result, increases in left coronary vascular resistance in response to carotid sinus hypotension have been demonstrated reproducibly only after /3-adrenergic receptor blockade (Feigl, 1968; DiSalvo et al., 191; owell and Feigl, 199). In contrast to these previous reports concerned with the left coronary vascular response to carotid sinus hypotension in anesthetized dogs, the present study assessed the right coronary vascular response to carotid sinus hypotension in conscious dogs with heart rate held constant by external pacing. BCO had only minimal effects on RV contractility, as has been observed previously in the left ventricle of conscious dogs (Vatner et al, 192; Vatner and Rutherford, 198). Because RV end-diastolic pressure was not significantly increased during BCO, it is unlikely that RV end-diastolic diameter changed in response to this stimulus. Moreover, unlike the left ventricle, the afterload of the right ventricle was not markedly elevated during BCO. Thus, BCO exerted only modest increases in the measured indices of RV myocardial metabolic demands, which apparently were not sufficiently powerful to augment right coronary blood flow in the face of a concomitant increase in sympathetic a-receptor vasoconstrictor activation of the right coronary circulation during BCO. It must be kept in mind that the right coronary circulation in the dog does not normally supply the left ventricle (Murray and Vatner, 1980) and, therefore, would not be responsive to increases in left ventricular myocardial metabolic demand. Thus, in the right coronary circulation, BCO elicited a net increase in calculated coronary vascular resistance when sympathetic neural activity was intact. Furthermore, as might be expected, the right coronary constriction was not enhanced following /?-adrenergic receptor blockade, because the metabolic vasodilator influences (if any) were already minimal. The possibility that some part of the right coronary response to BCO observed in this study was the result of release of catecholamines from the adrenal medulla cannot be discounted. However, it has been demonstrated previously that the increase in left coronary resistance during carotid sinus hypotension and in the presence of /?-adrenergic receptor blockade is largely a neurally mediated response, because it is markedly reduced by upper thoracic sympathectomy, a surgical procedure which would not alter catecholamine release from the adrenal gland (Feigl, 1968). It could be postulated that some component of the right coronary response to BCO involves activation of the carotid chemoreceptors, as a result of carotid sinus hypotension, and a consequent reduction in blood flow to the carotid body (Heistad et al., 19). However, it is unlikely that the right coronary constriction was due to carotid body chemoreceptor activation, because in the conscious dog BCO primarily results in a damping of pulsatile pressure in the carotid sinus, as opposed to large sustained reductions in mean intra-carotid arterial pressure (Vatner and Manders, 199). Because it has been shown that carotid sinus pressures of less than 60 mm Hg are required to cause firing of the chemoreceptor fibers (Biscoe et al., 190), chemoreceptor activation is not likely to be a major factor in mediating the increase in right coronary resistance during BCO. It has been suggested that the reflex left coronary constriction in response to carotid sinus hypotension could be the result of coronary autoregulation, in that coronary flow remains relatively constant in the face of an increase in coronary perfusion pressure (Kirchheim, 196). In the present investigation we addressed this issue. If the lack of change in steady state right coronary blood flow during BCO simply reflected an autoregulatory response of the right coronary vasculature, then a similar response should have been observed when arterial pressure was increased to the same degree by hydraulically constricting the ascending thoracic aorta. However, under these circumstances right coronary blood flow increased significantly (Fig. 3). It is unlikely that this increase in right coronary blood flow with

9 RIGHT CORONARY RESOE TO CAROTID SINUS HYOTEION/Mu/rav & Vatner 13 aortic constriction was secondary to an increased metabolic demand of the right ventricle because (1) reflex chronotropic and inotropic responses to aortic constriction were prevented by pre-treating the normal, conscious dogs with a ganglionic blocker, and (2) aortic constriction did not increase the afterload of the right ventricle. Thus, the constancy of right coronary blood flow during BCO appears not to be due primarily to an autoregulatory process, but rather reflects active sympathetic a-receptor vasoconstriction. These conclusions are consistent with a recent study by owell and Feigl (199), which examined responses of the left coronary circulation to BCO, and during which the reflex changes both in aortic pressure and myocardial oxygen consumption associated with carotid sinus hypotension were matched carefully before and after the intracoronary administration of an a-adrenergic receptor antagonist. The results of that study also indicate that the left coronary constriction observed with BCO was due to sympathetic a-receptor activation. The fact that coronary a-receptor vasoconstriction can compete with metabolic vasodilator influences during sympathetic activation has been conclusively demonstrated by Mohrman and Feigl (198), who showed that a-receptor vasoconstriction restricts metabolically related increases in left coronary blood flow associated with intracoronary norepinephrine infusions or carotid sinus hypotension by approximately 30%. Moreover, we have recently demonstrated that the left coronary vascular response to free-ranging exercise is attenuated (32%) by a-adrenoceptor activation (Murray and Vatner, 199). In addition, the reflex left coronary dilation (22%) associated with carotid sinus nerve stimulation is primarily the result of withdrawal of sympathetic a-adrenergic tone (Vatner et al., 190b), although an early rapid component to the left coronary dilation was also blocked by atropine or bilateral vagotomy (Hackett et al., 192). It is interesting that in this study, with adrenergic activity intact, a similar percent increase in right coronary resistance during BCO was observed in normal, conscious dogs, i.e., 3%. A separate important finding in this study was that the BCO-induced right coronary constriction was attenuated substantially in dogs with RV hypertrophy. Moreover, the magnitude of the right coronary constriction was even more depressed in a subgroup of dogs with RV hypertrophy and failure. It could be argued that the pressure stimulus during BCO was not comparable in dogs with RV hypertrophy compared to normal, because control levels of arterial pressure were lower in the former group. However, this appears not to be the mechanism responsible for the attenuated right coronary constriction, because in a subgroup of dogs with RV hypertrophy and matched control arterial pressures compared to normal, the increase in right coronary resistance was still markedly and significantly reduced. Dogs with RV hypertrophy and failure have been shown also to have a depressed chronotropic response to both carotid sinus hypertension (Higgins et al., 192) and hypotension (Vatner et al., 19), as well as an attenuated increase in peripheral vascular resistance in response to carotid sinus hypotension (Higgins et al., 192). A variety of factors could be responsible for these abnormal responses, as well as the depressed right coronary response to BCO observed in the present study. The locus of dysfunction could involve changes in the pressure receptors themselves (Abraham, 196) or in the distensibility of the arterial vascular wall in the region of the pressure receptors. For example, the altered hemodynamic state associated with RV hypertrophy and failure could be associated with changes in the ionic composition of the blood, which in turn could result in changes in sensitivity or threshold of the baroreceptor reflex (Kunze, 199). Central nervous system integration of afferent information from the baroreceptors could be altered by activation of higher centers of the brain or via an augmentation in afferent vagal activity from cardiopulmonary receptors in dogs with RV hypertrophy and failure (Koike et al, 195). Abnormalities in the efferent limb of the reflex loop also could potentially explain the depressed response to BCO. The heart failure state has been shown to be characterized by depleted cardiac (Chidsey et al., 19), and peripheral vascular (Hayduk et al., 190; Mark et al, 193) stores of norepinephrine. Furthermore, a reduction in either the number or binding affinity of sympathetic coronary vascular a-receptors, or structural alterations in the coronary arterioles might also limit the coronary vascular response to BCO in dogs with RV hypertrophy and failure. Because baseline right coronary resistance is significantly lower in dogs with RV hypertrophy and failure compared to normal, the smaller increment in right coronary resistance during BCO in these dogs cannot be the result of an altered baseline, i.e., a larger change in right coronary resistance would be predicted from a lower level of initial resistance (Murray and Sparks, 198). Moreover, because a marked differential RV hemodynamic response to BCO was not observed between the two groups, and because the attenuated right coronary constriction was observed even after /8-adrenergic receptor blockade, it appears unlikely that an enhanced metabolically induced vasodilation in response to BCO in dogs with RV hypertrophy and failure could be responsible for the attenuated right coronary constriction. However, it is conceivable that the mechanism(s) responsible for the resting right coronary vasodilation in dogs with RV hypertrophy (Murray et al, 199) may compete with the a-adrenergic coronary vasoconstrictor influence, and thus limit the right coronary vascular response to BCO. The mechanising) responsible for the marked, selective increase in resting levels of blood flow to the hypertrophied right ventricle is not known. We have

10 138 CIRCULATION RESEARCH VOL.9, No. 6, DECEMBER 1981 discerned from previous studies that the resting vasodilation is not the result of an increase in coronary perfusion pressure (Murray et al., 199), a decrease in systolic extravascular compression (Murray and Vatner, 1981b), humoral or neural factors (Murray et al., 199), an increase in the ratio of capillary number to muscle fiber number (Murray et al., 199), an increase in heart rate (Murray and Vatner, 1981a), an increase in perfusion of the right ventricle from the left coronary artery (Murray and Vatner, 1980), or an increase in RV contractility. It appears that the vasodilation is the result of increased work that must be performed by the hypertrophied right ventricle to maintain pump function in the face of an increase in afterload. In summary, the results of the present investigation indicate that, in contrast to the response of the left coronary circulation, carotid sinus hypotension does not result in a steady state increase in right coronary blood flow but is associated with a marked increase in right coronary resistance in normal, conscious dogs with intact sympathetic neural activity. This right coronary constrictor response is not the result of right coronary autoregulation, but rather is mediated by a-adrenergic receptor activation. Moreover, the right coronary vasoconstriction is markedly attenuated in dogs with RV hypertrophy alone and is depressed further in dogs with RV hypertrophy and failure. Acknowledgments We wish to express our thanks to Arnold Sherman for engineering support, to Ayerst Laboratories for their generous supply of propranolol and to Ciba harmaceutical Co. for the supply of phentolamine. References Abraham D (196) The structure of baroreceptors in pathological conditions in man. 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