Genetic, neurohumoral, and hemodynamic influences on spontaneously hypertensive rat heart development in oculo.

Abstract

To distinguish among genetic, neurohumoral, and hemodynamic explanations for structural and functional differences in the hearts of young spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) control rats, embryonic SHR and WKY rat heart tissue was cultured in the anterior eye chamber of adult SHR and WKY rats. In study 1, atria from E-L2 WKY rat embryos grafted into anterior eye chambers of either SHR or WKY host rats achieved a larger size than did SHR grafts by 8 weeks in oculo (2.98 ±0. 75 ; WKY rat hearts, 1.75±0J9 vs. 2 J 9 ± 0 J 2 mm 1 ). Ventricle grafts from SHR embryos into SHR host rats beat more rapidly (165 ±19 beats/min) during weekly measurements than either WKY rat ventricles (92±9 beats/min in SHR hosts and 99±9 beats/min in WKY host rats) or SHR ventricles grafted into WKY host rats (109±7 beats/min, p<0Ml).In study 3, atria from E-13 SHR and WKY rat embryos were grafted into sympathectomized and intact eye chambers of SHR or WKY host rats. Sympathectomy of the eye chamber compromised growth of grafts into WKY host rats (1.54±0.24 vs. 0.90±0.14 mm 2 ) but not SHR hosts (1.54±0.25 vs. 1.73±0.24 mm 2 ). Grafts into sympathectomized eye chambers of WKY host rats beat more slowly than grafts into eye chambers with sympathetic innervatlon intact (282±14 vs. 202±14 beats/min); sympathectomy did not alter beating rate of grafts in SHR hosts (266±14 vs. 255±18 beats/min). These results suggest that the growth and beating rate of SHR atrial grafts may be less sensitive to sympathetic innervation than WKY rat atrial grafts. In these studies, SHR grafts did not grow larger than WKY heart grafts and did not show an increased intrinsic beating rate, suggesting that the cardiac hypertrophy and increased intrinsic beating rate observed in intact SHR are unlikely to result from direct genetic programming. (Hypertension 1990;15:247-256) T he predisposition to development of hypertension is manifested very early in rats of the spontaneously hypertensive rat (SHR) strain. Structural alterations in the heart and vasculature observed in young SHR may contribute to or may result from the increase in blood pressure. Blood pressure in SHR has been measured as early as 20 days of gestation and found to be elevated compared Because of technical difficulties, it is not known how early blood pressure in the SHR fetus becomes elevated relative to WKY rat controls. EcclestonJoyner and Gray 7 found both structural alterations in the vasculature and evidence of increased ventricular mass relative to body weight at 17 days of gestation in SHR compared with WKY rats. Possible explanations of these early structural alterations in the heart and vasculature include: 1) adaptation to the increased blood pressure of SHR, 2) altered development in response to neural or humoral signals, and 3) genetically programmed hypertrophy. 8 In hypertensive animals, hypertrophy of the heart and vascular walls results from increased pressure 9 and from non-pressure-related mechanisms.

Use of Embryonic Heart Grafted In Oculo to Assess Neurohumoral Controls of Cardiac Development*

“…This suggests that growth of grafts into SHR hosts may be less influenced by the neural milieu. Thus, contrary to expectation, no differences in growth attributable to strain of the host or to strain of the tissue were observed when embryonic SHR and WKY hearts were grafted in oculo (35). Since grafts are not working against a hemodynamic load, these data suggest that exposure to hemodynamic load may be necessary for expression of hypertrophy in the SHR model.…”

“…Whole hearts, atria or ventricles can be grafted without disrupting po- when blood pressure is maintained within the normal range by pharmacological treatment (11,39). An increased heart size to body size ratio is first observed during fetal life in SHR (12,35). However, since the blood pressure ofSHR is elevated as early as it can be measured (6,9,14), it is possible that the increased heart size of SHR is a result of early exposure to increased hemodynamic load.…”

“…Our recent study of genetic and neurohumoral controls of cardiac development in the spontaneously hypertensive rat (SHR) used this strategy (35). SHR rats consistently show cardiac hypertrophy, even 8.-Atrial growth: SCG intact or removed.…”

“…In SHR hosts (lower panel), growthdid not differsignificantly betweeninnervatedand denervatedeyechambers. (Reprinted with permission from Tucker: Hypertension 15: 247-256, 1990 (35).) terior eye chamber compromised growth of atrial grafts (Fig.…”

Application of stereological analysis of cell volume to isolated myocytes in culture with and without adrenergic innervation

“…The onset of neuroeffector transmission coincides with the cessation of myocyte mitosis (Claycomb, 1976;Kugler, 1980) and the beginning of cellular hypertrophy (Clubb and Bishop, 1984). Using an in oculo model of embryonic heart culture, in which the explanted hearts become vascularized and innervated, but do not contract against a hemodynamic load, Tucker andcolleagues (1986,1990) reported increased ventricular dimensions and weight of innervated hearts compared to noninnervated. The nature of this growth, increase in cell number or cell size, was not determined.…”