M. Olajos

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)

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.

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.

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)

Effects of α2-adrenergic stimulation with UK 14,304-18 on the heart and peripheral circulation of intact dogs

Summary: To determine the extent of α2-adrenoreceptor control of cardiovascular function, we studied the hemodynamic effects of the relatively selective α2-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 < 0.05) and reductions in stroke volume (31.7 ± 2.9 to 17.9 ± 1.9 ml/kg/min, p < 0.05) and left ventricular (LV) dP/dt (2,120 ± 280.0 to 1,463 ± 196.1 mm Hg/s, p < 0.05). In ganglion-blocked dogs UK 14,304-18 did not alter the slope of the LV endsystolic 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 > 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 > 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 < 0.05) and the pressure gradient for venous return (7.6 ± 0.4 to 9.0 ± 0.3 mm Hg, p < 0.05). Central blood volume increased with UK 14,304-18 (15.6 ± 1.1 to 18.7 ± 1.5 ml/kg, p < 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 < 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 α2 agonist does not directly alter cardiac function but increases 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.