Alterations of the vascular and the myocardial guanylate cyclase/cGMP-system induced by long-term hypertension in rats
Introduction
Activation of soluble guanylate cyclase is a major vasorelaxant principle in the body. Recent investigations have shown that activation of soluble guanylate cyclase also has an effect on myocardial contractility (Brady et al., 1993; Kojda et al., 1996; Mohan et al., 1996). Physiologically, soluble guanylate cyclase is activated by endogenous NO, which is produced by specific NO-synthases (Nathan and Xie, 1994). Pharmacologically, activation of soluble guanylate cyclase occurs through the release of NO from nitrovasodilators such as glyceryl trinitrate (GTN) (Ahlner et al., 1991). Previous data from animal and clinical studies suggest that hypertension is associated with a reduced endothelium dependent vasorelaxation, which itself is mediated by endogenous NO-production (Mayhan et al., 1987; Moncada and Higgs, 1993, Moncada and Higgs, 1995; Panza et al., 1993). By contrast, it is not known whether the production and/or the effects of endogenous NO in the myocardium are altered by hypertension. Furthermore, the mechanism of the impairment of endothelium-dependent vasorelaxation in hypertension is not fully understood. Previous studies provided evidence for a reduced endogenous NO-production, an inactivation of endogenous NO initiated by superoxide radicals and the existence of a counteracting vasocontractile factor (Konishi and Su, 1983; Lüscher et al., 1987; Mayhan et al., 1987, Mayhan et al., 1988; Linder et al., 1990; Panza et al., 1990; Nakazono et al., 1991; Malinski et al., 1993; Taddei et al., 1993; Grunfeld et al., 1995; Küng and Lüscher, 1995; Tschudi et al., 1996; Crabos et al., 1997; Forte et al., 1997). By contrast, it is not known if hypertension alters the sensitivity of the soluble guanylate cyclase/cGMP-system, which is extremely important for the initiation of the effects of NO in both, blood vessels and heart muscle. The aim of the present study was to investigate if long-term hypertension is associated with alterations of the sensitivity of the myocardial and the vascular soluble guanylate cyclase/cGMP-system. To accomplish this we investigated the responses of the heart and the aorta isolated from 15 months old spontaneously hypertensive rats (SHR15). These animals have substantial vascular and myocardial hypertrophic changes due to long-term hypertension with systolic blood pressure >220 mm Hg (Stasch et al., 1987).
Section snippets
Preparation of isolated hearts, experimental protocols
We investigated isolated hearts, lungs and thoracic aortic rings of 11 normal male Wistar rats (WIS) at an age of 3–4 months and of 9 `stroke-prone' spontaneously hypertensive rats at an age of 15 months (SHR15). The average body weight of WIS and SHR15 was similar, while the average wet weight of the WIS-hearts was 1.11±0.05 g and that of SHR15-hearts was 2.1±0.11 g indicating substantial myocardial hypertrophy in SHR15. The hearts were rapidly excised and perfusion was done according to the
Effects of hypertension on myocardial contractility
Changes of the contractile activity of the myocardial muscle were investigated after infusion of NA to stimulate adrenergic receptors, l-NA to inhibit endogenous NO-production, l-arginine to stimulate endogenous NO-production and NO-donors such as DEA/NO and GTN. Infusion of NA increased dP/dtmax significantly stronger (P=0.0007) in WIS as compared to SHR15 indicating an impairment of the myocardial adrenergic response in SHR15 (Fig. 2A).
Activation of soluble guanylate cyclase by infusion of
Discussion
In this investigation the effects of long-term hypertension on the positive inotropic and the vasorelaxing actions of endogenous and exogenous NO were studied. The new finding is that long-term hypertension decreases the activity of the soluble guanylate cyclase/cGMP-system in the vasculature but not in the myocardial muscle. In hypertensive rats stimulation of endogenous NO-production and the response to exogenous NO was impaired only in the vasculature. In parallel, vascular production of
Acknowledgements
This study was supported by the Deutsche Forschungsgemeinschaft SFB 242; Projekt A11.
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