Chronic hypoxia (CH) causes pulmonary hypertension and right ventricular hypertrophy that can eventually progress to heart failure. However, there have been very few studies examining cardiac function in the right and left sides of the intact heart, particularly following CH. Therefore, we have examined the effects of CH on the isolated rat heart using a model that allows independent monitoring of right and left coronary flow rates and cardiac contractility.
Male Wistar rats (250-270 g) were subjected to 3 weeks of normobaric CH (10 % O2). At the end of this period they were terminally anaesthetised (Sagatal 60 mg kg-1 I.P.) and heparinised (500 i.u.) via the tail vein. Haematocrit values were determined and the hearts perfused in vitro, at a constant pressure of 80 mmHg, using a modified Krebs solution and a Langendorff technique with a dual perfusion cannula that allows independent perfusion of the right and left coronary arteries (Avkiran & Curtis, 1991). Coronary flows were measured using in-line flow probes (Transonic). Intraventricular balloons were placed in the right and left ventricles for measurement of right and left ventricular contractility. Right and left reactive hyperaemia following zero flow global ischaemia (5-60 s), Starling curves in the right and left ventricles (balloon volumes 0.03-0.24 ml), and responses to catecholamines were then recorded. At the end of the experiment right and left ventricular wet weights were measured. Results are presented as means ± S.E.M.; P < 0.05, Student’s unpaired t test. Experiments were approved by the University of Bath Ethics Committee.
CH increased haematocrit (CH 60 ± 2.5 vs. 1 ± 0.8 %), right ventricular/total ventricular weight ratio (CH 0.32 ± 0.01 vs. 0.20 ± 0.004), right (CH 6.4 ± 0.27 vs. 4.5 ± 0.2 ml min-1) and left (CH 6.85 ± 0.24 vs. 5.5 ± 0.24 ml min-1) coronary flows, and right developed pressure (CH 77 ± 2.8 vs. 46 ± 1.8 mmHg) (P < 0.05, n = 24). CH did not affect left coronary reactive hyperaemia, but it did attenuate right reactive hyperaemia when flow was restored following 40 or 60 s of ischaemia (P < 0.05, n = 5). Left Starling curves were not affected by CH. When Starling curves were performed on the right ventricles of CH rats there was no significant difference in diastolic pressure over the range of balloon volumes used; in contrast, systolic pressures were significantly enhanced throughout the Starling curve (P < 0.05, n = 5). The coronary dilator and positive inotropic actions of isoprenaline (1-30 nM), on both sides of the heart, were significantly attenuated in CH hearts compared with controls (P < 0.05, n = 6) while the positive chronotropic effect of isoprenaline was unaltered. In control hearts noradrenaline and phenylephrine both caused a significant decrease in left but not right coronary flow. In CH hearts the decreases in left coronary flow induced by phenylephrine and noradrenaline were reduced when compared with control hearts (P < 0.05, n = 5).
These data show that in control hearts there are regional differences in the response of the coronary circulation to α adrenoceptor-mediated stimulation. The responsiveness of the coronary vasculature to α and β adrenoceptor stimulation is attenuated by CH. CH also downregulates β adrenoceptor-mediated inotropic responses. In contrast, β adrenoceptor-mediated chronotropic responses are not affected by CH. The fact that the Starling curve in the right ventricle was enhanced by CH shows that 3 weeks of CH leads to the development of a compensated hypertrophy.This work was supported by the British Heart Foundation.
- Avkiran, N.M. & Curtis, M.J. (1991). Am. J. Physiol. 261, H2082-2090.