Changes in right ventricular relaxation during acute anterior myocardial infarction in pigs.

To determine the effect of an anteroseptal myocardial infarction on right ventricular systolic and diastolic function, we studied 12 pigs before and 1 h after left anterior descending coronary artery occlusion. Total arterial occlusion was achieved by the percutaneous, transcatheter placement of a 1 mm Teflon plug into the mid portion of the artery. The resulting infarction involved 28 (SEM 3)% of the left ventricular wall, in the anterior and septal regions. A small rim of the right ventricular free wall adjacent to the septum and the right ventricular apex were also affected. End diastolic pressures in both ventricles rose significantly: left ventricular from 12(1) to 20(2) mm Hg and right ventricular from 8(1) to 10(1) mm Hg. Right ventricular peak systolic pressure increased from 29(2) to 35(2) mm Hg while left ventricular peak systolic pressure did not change. One hour after infarction the half time of isovolumic relaxation of the right ventricle was prolonged from 6.9(0.5) to 8.7(0.4) ms. Ejection fraction in both ventricles was depressed: from 46(1) to 34(2)% in the right ventricle and from 69(3) to 49(3) in the left ventricle. There was no change in either right or left ventricular dP/dt. These data suggest that right ventricular systolic and diastolic dysfunction occurs as the result of an anteroseptal myocardial infarction in pigs.

Cocaine and cardiovascular function in dogs: effects on heart and peripheral circulation.

The effects of cocaine on the heart and peripheral circulation were examined in seven mongrel dogs. Hemodynamic variables, in addition to data on ventricular relaxation, mean circulatory filling pressure and arterial compliance, were measured during an intravenous infusion (0.5 mg/kg per min) of cocaine. Holter monitor recordings (6 h) and coronary arteriograms were also obtained. Cocaine increased (p less than 0.01) mean aortic pressure from 72 +/- 5 to 92 +/- 5, left ventricular systolic pressure from 102 +/- 3 to 121 +/- 5, left ventricular end-diastolic pressure from 4.9 +/- 1.3 to 8.2 +/- 1.4 and mean circulatory filling pressure from 7.9 +/- 0.4 to 10.9 +/- 0.5 mm Hg. Cardiac index and stroke volume decreased (p less than 0.01) from 166 +/- 17 to 125 +/- 8 ml/min per kg and from 44 +/- 4 to 29 +/- 3 ml, respectively. Ejection fraction decreased (p less than 0.01) from 61 +/- 1 to 49 +/- 3%. Heart rate, first derivative of left ventricular pressure (dP/dt) and right atrial, mean pulmonary artery and pulmonary artery wedge pressures did not change. The result was a 58% increase in systemic vascular resistance and a 32% decrease in arterial compliance. The pressure gradient for venous return did not change, but resistance to venous return increased 42%. Cocaine prolonged (p less than 0.05) the half-time of left ventricular isovolumic relaxation from 13.4 +/- 0.8 to 16.4 +/- 0.8 ms and the time constant of left ventricular isovolumic relaxation from 19.3 +/- 1.2 to 23.6 +/- 1.1 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of tolerance to nitroglycerin in the arterial and venous circulation of dogs.

The purpose of this study was to define the effects of nitroglycerin on venous tone and to investigate the time course of nitroglycerin tolerance in the peripheral circulation. The changes in the arterial and venous circulation resulting from an intravenous infusion of nitroglycerin (5 micrograms/kg per min) after 5 minutes (acute infusion) were compared with those changes that occurred after 2 hours (chronic infusion) of the same infusion in six splenectomized, ganglion-blocked dogs. Hemodynamics, blood volume and venous and arterial compliance were measured during each infusion. Nitroglycerin initially decreased mean arterial pressure from 81.5 +/- 2.0 to 57.6 +/- 2.7 mm Hg (p less than 0.01). Central blood volume decreased from 21.1 +/- 1.4 to 15.9 +/- 1.1 ml/kg (p less than 0.01), while total blood volume and unstressed vascular volume did not change. In the acute study, nitroglycerin increased venous compliance 33% from 1.75 +/- 0.14 to 2.32 +/- 0.16 ml/mm Hg per kg (p less than 0.01) and arterial compliance 33% from 0.049 +/- 0.007 to 0.065 +/- 0.007 ml/mm Hg per kg (p less than 0.01). At the end of the 2 hour infusion, arterial pressure increased and was now unchanged from control. Central blood volume had returned to baseline, 17.8 +/- 0.9 ml/kg. Total blood volume and unstressed vascular volume remained unchanged. With the long-term infusion, both arterial and venous compliance decreased (p less than 0.02) to 0.050 +/- 0.006 and 1.50 +/- 0.06 ml/mm Hg per kg, respectively, such that neither value was different from control. Nitroglycerin levels remained constant throughout.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-2 adrenoceptor control of the venous circulation in intact dogs.

The effects of beta-2 adrenoceptor stimulation on the peripheral circulation in 10 dogs were evaluated. All studies were done during ganglion blockade with hexamethonium. Venous capacitance was assessed by measuring mean circulatory filling pressure, venous compliance and unstressed vascular volume. Beta-2 stimulation was achieved with terbutaline (27 micrograms/min) after beta-1 blockade with metoprolol (0.75 mg/kg). At a dose of terbutaline that decreased mean aortic pressure from 80.4 +/- 3.5 to 58.9 +/- 1.9 mm Hg (P less than .01), there was no change in cardiac index (155.8 +/- 10.5 vs. 161.1 +/- 9.1 ml/kg/min) despite an increase in heart rate from 118.6 +/- 5.2 to 132.6 +/- 5.0 beats/min. Right atrial pressure, left ventricular end-diastolic pressure and dP/dt did not change. Systemic vascular resistance decreased from 0.52 +/- 0.02 to 0.39 +/- 0.03 mm Hg . min . kg . ml (P less than .01). Arterial compliance increased from 0.067 +/- 0.003 to 0.088 +/- 0.007 ml/mm Hg/kg and the volume of blood shifted out of the larger arteries was 1.8 +/- 0.4 ml/kg. Mean circulatory filling pressure did not change but venous compliance decreased from 1.90 +/- 0.04 to 1.47 +/- 0.06 ml/mm Hg/kg and unstressed vascular volume increased from -14.5 +/- 0.5 to -8.4 +/- 0.5 ml/kg. Central blood volume increased from 22.8 +/- 1.1 to 27.4 +/- 2.2 ml/kg. There was an increase in total blood volume from 81.1 +/- 2.7 to 90.5 +/- 3.7 ml/kg. To determine the extent to which changes in the spleen were responsible for these observations, five dogs were studied 2 weeks after splenectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Dog model to study the effects of pharmacologic agents on the peripheral circulation: effects of milrinone.

To study the effects of an inotropic agent, milrinone, on the entire cardiovascular system, we developed an intact dog model to assess the responses of the heart, arterial and venous circulations. At a dose that increased left ventricular dP/dt by 30% (P less than .001) from 2033 +/- 133 to 2688 +/- 140 mm Hg/sec, milrinone caused a decrease (P less than .001) in mean aortic pressure from 88.4 +/- 3.5 to 73.1 +/- 3.0 mm Hg and cardiac output from 148.0 +/- 14.6 to 134.5 +/- 13.9 ml/kg/min. Heart rate increased (P less than .01) from 124 +/- 8 to 135 +/- 8 beats/min. Systemic vascular resistance did not change. Right atrial pressure and left ventricular end-diastolic pressure decreased (P less than .01). Total blood volume did not change but central blood volume decreased (P less than .01) from 26.1 +/- 0.9 to 22.3 +/- 0.5 ml/kg. After milrinone administration, mean circulatory filling pressure decreased (P less than .01) by 30% from 7.4 +/- 0.4 to 5.0 +/- 0.2 mm Hg. Vascular or venous compliance increased (P less than .05) slightly from 1.96 +/- 0.4 to 2.20 +/- 0.1 ml/mm Hg/kg. This was accompanied by an increase (P less than .01) in unstressed vascular blood volume of 3.3 +/- 0.6 ml/kg. Arterial compliance also increased (P less than .05). In summary, milrinone produces an increase in inotropy, arterial vasodilatation and venodilatation as evidenced by the increased venous compliance and unstressed vascular volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of cardiac function and venous return in thyrotoxic calves.

The mechanisms responsible for maintenance of the high-output state associated with thyrotoxicosis have been investigated by measurement of cardiac-function curves and venous compliance during ganglionic blockade with trimethaphan. Thirteen calves were injected daily with L-thyroxine (200 micrograms/kg) for 12-14 days. Thyroxine treatment increased heart rate (70%), left ventricular systolic pressure (22%), cardiac output (120%), left ventricular maximum rate of pressure development (dP/dt) (56%), and total blood volume (18%) and decreased systemic vascular resistance (39%). These hemodynamic changes persisted during ganglionic blockade or autonomic blockade with atropine and propranolol. Cardiac-function curves in conscious thyrotoxic calves were displaced upward and to the left. Mean circulatory filling pressure (MCFP), measured during anesthesia, was increased from 8 +/- 1 to 12 +/- 1 mmHg. During autonomic and ganglionic blockade MCFP remained elevated after treatment with thyroxine. Venous compliance decreased from 2.1 +/- 0.2 to 1.3 +/- 0.1 ml X mmHg-1 X kg-1 after thyroxine. Unstressed vascular volume was increased from 52.3 +/- 1.1 to 67.1 +/- 0.9 ml/kg. Thus the elevated cardiac output and new cardiac-function curve in thyrotoxicosis are associated with a combination of increased inotropic state, increased blood volume, and decreased venous compliance. These effects are not the result of autonomic influences and may represent direct actions of thyroid hormone on the heart and peripheral venous circulation.

Effects of changes in airway pressure on the left ventricle and left atrium of dogs.

The effects of negative and positive airway pressure were examined in eight closed chest, chronically instrumented dogs to determine beat to beat changes in left ventricular pressure, left ventricular dP/dt, left ventricular dimensions, and oesophageal pressure. As an index of afterload, systolic transmural pressure was calculated by subtracting oesophageal pressure from left ventricular pressure. With each change in airway pressure left ventricular end systolic minor axis diameter and left ventricular end diastolic minor axis diameter increased significantly. Left atrial end diastolic dimension increased significantly with negative airway pressure and did not change with positive airway pressure. Left ventricular dP/dt and left ventricular fractional shortening did not change. With the Mueller manoeuvre left ventricular systolic pressure decreased significantly from 106(4.2) mm Hg to 100.9(4.2) mm Hg and systolic transmural pressure increased significantly from 105.1(4.6) mm Hg to 110.4(4.3) mm Hg. With a transient increase in positive airway pressure of 30 mm Hg (4.0 kPa), left ventricular pressure increased significantly from 106.9(4.8) mm Hg to 113.9(5.9) mm Hg and systolic transmural pressure decreased significantly from 106.6(4.9) mm Hg to 99.8(4.6) mm Hg. The addition of positive end expiratory pressure of 10 cm H2O (0.98 kPa) or autonomic blockade with atropine and propranolol did not alter these results. Thus manoeuvres which cause opposite effects on systolic transmural pressure produce similar increases in left heart dimensions, suggesting that increases in pulmonary venous return and not changes in afterload may be the important determinants of left ventricular dimensional changes during changes in airway pressure.

Treatment of verapamil toxicity in intact dogs.

The treatment of verapamil toxicity was examined in lightly sedated dogs. Verapamil, administered as a bolus (0.72 mg/kg) followed by a continuous infusion (0.11 mg/kg per min), decreased cardiac output (CO) from 3.1 +/- 0.1 to 1.7 +/- 0.1 liter/min (P less than 0.001), heart rate (HR) from 85 +/- 4 to 57 +/- 3 beats/min (P less than 0.001), left ventricular derivative of pressure with respect to time (LV dP/dt) from 2,085 +/- 828 to 783 +/- 78 mm Hg/s (P less than 0.001), mean aortic pressure (AO) from 77 +/- 4 to 38 +/- 2 mm Hg (P less than 0.001) and stroke volume from 39 +/- 3 to 28 +/- 2 ml/beat (P less than 0.01). In verapamil-toxic animals isoproterenol increased HR, CO, LV dP/dt, and AO; calcium chloride increased LV dP/dt and AO; norepinephrine, epinephrine, and dopamine increased CO, AO, and LV dP/dt, atropine increased HR, CO, and AO. Phenylephrine (13-55 micrograms/kg per min) produced no changes except a small increase in AO while very high dose phenylephrine (300 micrograms/kg per min) increased AO, CO, and LV dP/dt. 4-Aminopyridine (4-AP) increased HR, CO, LV dP/dt, and AO. When administered prior to verapamil, 4-AP prevented the development of verapamil toxicity as shown by the significantly higher AO (P less than 0.001), CO (P less than 0.01), and LV dP/dt (P less than 0.01) when 4-AP followed by verapamil was compared to verapamil alone. In conclusion, there does not appear to be a single specific therapy for verapamil toxicity, however it can be partially corrected by presently available pharmacologic therapy and 4-AP.

Alpha 1- and alpha 2-adrenoceptor stimulation: changes in venous capacitance in intact dogs.

The peripheral circulatory effects of alpha 1-adrenoceptor stimulation with methoxamine hydrochloride were compared with those of alpha 2-stimulation with UK 14304-18 in 12 intact dogs. Doses of each agent were infused to increase systemic vascular resistance and arterial pressure 50 and then 100% above control. Heart rate was controlled with atropine. At the higher dose, methoxamine increased mean aortic pressure (PAo) from a control of 77.3 +/- 1.6 to 152.9 +/- 3.2 mmHg, mean circulatory filling pressure (MCFP) from 8.0 +/- 0.4 to 13.3 +/- 1.3 mmHg, and central blood volume (CBV) from 21.3 +/- 1.1 to 25.9 +/- 1.5 ml X kg-1, whereas cardiac output did not change. UK 14304-18 increased PAo from 78.1 +/- 2.6 to 148.9 +/- 2.7 mmHg, MCFP from 7.9 +/- 0.4 to 10.6 +/- 0.4 mmHg, and CBV from 21.0 +/- 1.1 to 24.1 +/- 1.5 ml X kg-1, whereas cardiac output decreased from 151.7 +/- 9.4 to 126.3 +/- 5.8 ml X kg-1 X min-1. Mean circulatory filling pressure and CBV were higher with methoxamine than with UK 14304-18. Effective vascular compliance, determined by serial measurements of MCFP during ganglionic blockade after rapid changes in blood volume, decreased from a control value of 1.9 +/- 0.1 to 1.3 +/- 0.3 ml X mmHg-1 X kg-1 with methoxamine, but did not change with UK 14304-18 (1.9 +/- 0.1 ml X mmHg-1 X kg-1). At any given change in blood volume, there was a higher MCFP with alpha 1-stimulation compared with alpha 2-stimulation. Both agents decreased unstressed vascular volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of alpha 2-adrenergic stimulation with UK 14,304-18 on the heart and peripheral circulation of intact dogs.

To determine the extent of alpha 2-adrenoreceptor control of cardiovascular function, we studied the hemodynamic effects of the relatively selective alpha 2-adrenergic agonist UK 14,304-18 on the heart and peripheral circulation of intact dogs. Administration of increasing intravenous doses of UK 14,304-18 to conscious dogs given atropine to maintain heart rate (HR) resulted in a reproducible increase in mean aortic (AO) pressure (77.6 +/- 5.0 to 136.4 +/- 6.5 mm Hg, p less than 0.05) and reductions in stroke volume (31.7 +/- 2.9 to 17.9 +/- 1.9 ml/kg/min, p less than 0.05) and left ventricular (LV) dP/dt (2,120 +/- 280.0 to 1,463 +/- 196.1 mm Hg/s, p less than 0.05). In ganglion-blocked dogs UK 14,304-18 did not alter the slope of the LV end-systolic pressure-volume relationship when compared with angiotensin and nitroprusside (79.9 +/- 11.1 control vs. 73.3 +/- 8.7 mm Hg/ml/kg UK 14,304-18, p greater than 0.05), nor did it change the volume intercept (-0.46 +/- 0.12 control vs. -0.53 +/- 0.16 ml/kg UK 14, 304-18, p greater than 0.05) indicating no direct effect on LV contractile function. Changes in indices of diastolic function, including the time constant of isovolumic relaxation, time to peak filling, and chamber volume elasticity were similar to those of equipressor doses of angiotensin, indicating no direct effect on LV diastolic function. Effects on the peripheral circulation were studied in dogs undergoing transient acetylcholine-induced circulatory arrest. UK 14,304-18 increased mean circulatory filling pressure (7.9 +/- 0.3 to 10.3 +/- 0.2 mm Hg, p less than 0.05) and the pressure gradient for venous return (7.6 +/- 0.4 to 9.0 +/- 0.3 mm Hg, p less than 0.05). Central blood volume increased with UK 14,304-18 (15.6 +/- 1.1 to 18.7 +/- 1.5 ml/kg, p less than 0.05), but this increase was not sufficient to maintain cardiac output (CO) during the UK 14,304-18 infusion, which decreased from 157.4 +/- 11.1 to 131.5 +/- 8.9 ml/kg/min (p less than 0.01) in the presence of increased LV afterload. The time constant of relaxation of the arterial system increased and the arterial compliance decreased with increasing mean arterial pressure. Thus, this relatively selective alpha 2 agonist does not directly alter cardiac function but increased tone in arterial resistance vessels and in systemic veins. The fall in CO appears to be caused by a mismatch between preload and afterload, which is the net result of quantitatively different effects on systemic veins and arteries.

Alpha-1 adrenergic control of the venous circulation in intact dogs.

To study alpha adrenergic control of the venous circulation, 17 dogs were lightly sedated and instrumented with thermodilution pulmonary flow and aortic catheters. Hemodynamics, cardiac output and central blood volume were measured at rest. Mean circulatory filling pressure, pressure gradient for venous return and resistance to venous return were calculated from pressures obtained during transient acetylcholine-induced circulatory arrest. Phenylephrine was then infused at two steady-state levels to increase mean aortic pressure by 50 and 100% above control values. Heart rate was controlled with atropine. Phenylephrine increased (P less than .025) mean aortic pressure from 80.7 +/- 2.9 to 121.3 +/- 7.6 to 164.7 +/- 6.1 mm Hg and systemic vascular resistance from 23.3 +/- 2.0 to 32.2 +/- 3.5 to 43.5 +/- 4.1 mm Hg/min/ml and did not change cardiac output (161.9 +/- 12.6-175.6 +/- 13.8-169.6 +/- 11.9 ml/min/kg). Mean circulatory filling pressure increased from 7.1 +/- 0.5 to 9.7 +/- 0.6 to 13.2 +/- 1.3 mm Hg (P less than .025). Pressure gradient for venous return increased from 6.4 +/- 0.4 to 7.7 +/- 0.4 to 8.9 +/- 0.4 mm Hg (P less than .025). Central blood volume increased from 16.2 +/- 0.9 to 19.4 +/- 1.4 to 22.0 +/- 1.9 ml/kg (P less than .025). To eliminate reflex changes in vascular tone, eight dogs received ganglionic blockade with trimethaphan. After ganglionic blockade phenylephrine increased cardiac output, systemic vascular resistance, mean circulatory filling pressure, pressure gradient for venous return and central blood volume (P less than .025). Thus, in conscious dogs, phenylephrine reduces peripheral vascular capacitance and shifts blood from the venous circulation to the central and arterial vascular compartments.

Comparison of left atrial and left ventricular performance in conscious dogs.

The velocity of contraction has been reported to be more rapid in left atrium (LA) than left ventricle (LV), but the mechanics of contraction in these two chambers have not been compared under physiological conditions. Accordingly, sonomicrometer crystals and solid state pressure transducers were used to measure LV and LA systolic function simultaneously in seven conscious dogs. Two sets of crystals (LA-1, LA-2) were placed perpendicularly across the LA. Phenylephrine was infused at increasing doses from 0.4 to 1.2 microgram . kg-1 . min-1 to increase LV and LA afterloads. Constant heart rates were maintained by atrial pacing. The results indicated that LA motion was virtually identical in both diameters. LA fractional shortening (0.07 +/- 0.01) and ejection time (0.057 +/- 0.002 s) were much smaller than the ventricular values (0.21 +/- 0.01 and 0.18 +/- 0.01 s, respectively). The velocity of circumferential fibre shortening (Vcf) for the LV (1.16 +/- 0.05 cir . s-1) was not significantly different from LA-1 Vcf (1.19 +/- 0.09 cir . s-1) or LA-2 Vcf (1.22 +/- 0.08 cir . s-1). During phenylephrine infusions, LV systolic pressure increased from 120.0 +/- 3.4 to 190.8 +/- 15.5 mmHg and LV end-diastolic pressure increased from 3.6 +/- 0.3 to 27.7 +/- 2.7 mmHg. When Vcf for each chamber was plotted against the peak systolic pressure in that chamber, the curve of the LA was located upward and to the right of the LV curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of cardiac output in thyrotoxic calves. Evaluation of changes in the systemic circulation.

The contribution of peripheral vascular factors to the high output state in thyrotoxicosis was examined in 11 calves treated with daily intramuscular injections of L-thyroxine (200 micrograms/kg) for 12-14 d. Thyroxine treatment increased cardiac output from 14.1 +/- 1.4 to 24.7 +/- 1.4 liters/min (P less than 0.001) and decreased systemic vascular resistance from 562 +/- 65 to 386 +/- 30 dyn-s/cm5 (P less than 0.01). Blood volume was increased from 65 +/- 4 ml/kg in the euthyroid state to 81 +/- 6 ml/kg when the animals were thyrotoxic (P less than 0.05). The role of low peripheral vascular resistance in maintenance of the high output state was evaluated by infusion of phenylephrine at two dosages (2.5 and 4.0 micrograms/kg per min). In the euthyroid state, no significant decrease in cardiac output was observed at either level of pressor infusion. In the thyrotoxic state, the higher dosage of phenylephrine increased peripheral resistance to the euthyroid control level and caused a small (6%) decrease in cardiac output (P less than 0.05). This small decrease in cardiac output probably could be attributed to the marked increase in left ventricular afterload caused by the pressor infusion as assessed from measurements of intraventricular pressure and dimensions. Changes in the venous circulation were evaluated by measurement of mean circulatory filling pressure and the pressure gradient for venous return in six animals during cardiac arrest induced by injection of acetylcholine into the pulmonary artery. Mean circulatory filling pressure increased from 10 +/- 1 mmHg in the euthyroid state to 16 +/- 2 mmHg (P less than 0.01) during thyrotoxicosis, while pressure gradient for venous return increased from 10 +/- 1 to 14 +/- 2 mmHg (P less than 0.02). These changes in venous return curves were not affected significantly by ganglionic blockade with trimethapan (2.0 mg/kg per min) before cardiac arrest. Thus, the high output state associated with thyrotoxicosis is not dependent upon a low systemic vascular resistance, but is associated with increases in blood volume, mean circulatory filling pressure, and pressure gradient for venous return.

Effect of the ouabain-quinidine interaction on left ventricular and left atrial function in conscious dogs.

The effect of the ouabain-quinidine interaction was examined in 10 conscious dogs. Left ventricular (LV) pressure, LV dP/dt, LV diameter and left atrial (LA) diameter were measured with high-fidelity micromanometers and sonomicrometer crystals. Ouabain, 0.025 mg/kg, significantly (p less than 0.05) increased LV dP/dt, LV and LA fractional shortening and LV and LA velocity of circumferential fiber shortening (Vcf). In a separate experiment, quinidine was administered as a bolus dose, 3.85 mg/kg, followed by an infusion, 0.28 mg/kg/min. This resulted in steady-state quinidine concentrations that produced no change in wall motion or hemodynamics. When ouabain was given 1 hour into the quinidine infusion, only LV dP/dt increased significantly (p less than 0.05). Ouabain alone increased LV dP/dt 26.4 +/- 3.5%, whereas ouabain during the quinidine infusion increased it by 9.5 +/- 2.3%. Similar differences were seen in the responses to ouabain in the absence and presence of quinidine: LV Vcf, 22.4 +/- 4.9% vs 6.0 +/- 2.1%, LV fractional shortening, 23.1 +/- 4.6% vs 5.8 +/- 2.1%, LA Vcf, 22.7 +/- 5.9 vs 4.6 +/- 2.0% and LA fractional shortening, 21.8 +/- 7% vs 7.8 +/- 3.3%. Thus, in the presence of quinidine the increase in intropy usually seen with ouabain was markedly attenuated. These data suggest that the quinidine-induced increase in digoxin serum concentrations is accompanied by a decrease in the contractile response of the heart to digoxin.

Cholinergic-sympathetic interactions in the left atrium and left ventricle of conscious dogs.

The extent of cholinergic-sympathetic interaction in the heart was examined in the resting control state and after isoproterenol stimulation in eight conscious dogs. Sonomicrometer crystals and solid-state pressure transducers were implanted in the left atrium and the left ventricle to evaluate mechanical function while heart rate was held constant by atrial pacing. Edrophonium (0.5 mg/kg i.v.) was given as a single dose at rest and during increased sympathetic tone produced by continuous infusion of isoproterenol (0.08 micrograms/kg/min). In the control state, edrophonium administration caused no change in left ventricular dP/dt, fractional shortening or velocity of contraction, but produced significant (P less than .001) decreases in left atrial fractional shortening and contraction velocity. During isoproterenol infusion there were significant increases in dP/dt, the velocity of contraction and fractional shortening in both left atrium and ventricle (P less than .001). Administration of edrophonium during this increase in inotropic state produced significant (P less than .01) decreases in left ventricular dP/dt, fractional shortening and contraction velocity. Moreover, after edrophonium, left atrial fractional shortening and velocity of contraction were decreased to values that were significantly (P less than .001) less than control. Thus, cholinergic stimulation caused selective depression of left atrial systolic function at rest and depression of both left atrial and ventricular function during sympathetic stimulation.

Effects of verapamil on positive inotropic stimulation in the left atrium and ventricle of conscious dogs.

The interaction of verapamil with three known positive inotropic stimuli, ouabain, dopamine and postextrasystolic potentiation (PESP), was studied in 10 conscious dogs. Implanted sonomicrometer crystals and solid state pressure transducers were used to evaluate left atrial (LA) and left ventricular (LV) function while heart rate was held constant by atrial pacing. Ouabain (0.025 mg/kg) and dopamine (3-5 micrograms/kg/min) were administered in amounts sufficient to increase LV dP/dt by about 20%. PESP was achieved by using a programmed stimulator to introduce atrial premature beats. Each of these inotropic interventions caused significant (P less than .05) increases in LV dp/dt, LV fractional shortening, LA fractional shortening LV-velocity of circumferential fiber shortening (Vcf) and LA-Vcf. Administration of a single i.v. dose of verapamil (0.03 mg/kg) caused no change in base-line mechanical and hemodynamic parameters. However, when verapamil was given during the increased inotropic state resulting from ouabain or dopamine administration, significant (P less than .05) decreases occurred in LV dP/dt, LV fractional shortening, LA fractional shortening, LV-Vcf and LA-VCf. Verapamil did not alter the positive inotropic response to PESP in the LV or LA. Thus, a dose of verapamil that did not change resting indices of myocardial contractility depressed function significantly during positive inotropic responses to ouabain and dopamine. This negative inotropic effect seemed to be selective because verapamil did not alter the response to PESP.

Beta adrenergic blockade with propranolol in conscious euthyroid and thyrotoxic calves: dosage requirements and effects on heart rate and left ventricular performance.

The effects of acute beta adrenergic blockade were studied in nine calves which had been instrumented with sonomicrometer crystals and pressure transducers before and after treatment with thyroxine (200 micrograms/kg) for 14 days. The adequacy of beta adrenergic blockade was determined using graded doses of isoproterenol. The results indicated that beta adrenergic blockade had no significant effect on heart rate, left ventricular dimensions or contractile performance in either thyroid state. However, the average dose of propranolol required to achieve beta adrenergic blockade was increased two to three times by thyroxine treatment. Consequently, the kinetics of propranolol disposition were determined in nine animals after a single i.v. dose of the drug. Also, propranolol was administered to four animals by continuous i.v. infusions at graded dosages to produce a range of serum concentrations in each animal. The amount of isoproterenol required to increase the heart rate by 25 beats/min was determined at each dosage level. It was found that in thyrotoxic animals two to three times higher serum propranolol concentrations were required to block challenge doses of isoproterenol. This could not be explained by changes in the disposition of propranolol. The possibility that there are larger numbers of functionally inactive (uncoupled) beta adrenergic receptors in thyrotoxic myocardium is discussed.