Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.

Abstract

Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. disease, valvular heart disease, and left ventricular failure) and pulmonary diseases (eg, emphysema, lung fibrosis, and obstructive airway disease) are often accompanied by pulmonary hypertension, and the severity of pulmonary hypertension is one determinant of the prognosis of such patients.' Although some researchers believe that pulmonary vasoconstriction plays a role in the pathogenesis of pulmonary hypertension,"2 the mechanism for the progression of pulmonary hypertension is still poorly understood. Received October 26, 1992; accepted July 13, 1993. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, was recently identified.3 This peptide induces proliferation of vascular smooth muscle cells.4 ET-1 has several properties suggestive of a potential pathophysiological role in pulmonary hypertension. First, ET-1 contracts isolated pulmonary vessels5 and increases pulmonary vascular resistance.6'7 Second, ET-1 has a mitogenic effect on vascular smooth muscle cells4'8'9 and fibroblasts,'0"' consistent with a role in vascular remodeling, a prominent finding in pulmonary hypertensive stages. ET-1 has also been reported to be produced by nonvascular tissues such as the heart, kidneys, and central nervous system.'2"3 It has been demonstrated that prepro ET-1 mRNA is expressed in cultured rat cardiomyocytes'4 and that ET-1-like immunoreactivity exists in the renal cortex and medulla of rats.15 In the heart, ET-1 induces myocardial cell hypertrophy'6 and has positive inotropic'7 and chronotropic'8 effects.A single subcutaneous injection of monocrotaline (MCT), a pyrrolizidine alkaloid, causes pulmonary hyby guest on

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

“…The reduced expression of the ET B receptor could modify the ET-1-induced pulmonary vasoconstriction. In fact, it has been previously reported that the main pulmonary artery vascular responsiveness to ET-1 was reduced after 25 days in the MCT model of PAH [2]. Using isolated pulmonary resistance arteries, we established that the relative ET-1 responsiveness is maintained 5 weeks after MCT injury, despite overall reduced smooth muscle contractility.…”

“…Hence, despite lower pulmonary levels of the peptide, there is nevertheless proven benefit in blockade of this system in PAH. The increased plasma levels could therefore come from other tissues such as the kidney and the heart, where an increased expression of preproET-1 mRNA has been observed in this model [2]. Importantly, a reduced pulmonary clearance likely contributes to the observed increase in plasma ET-1, the pulmonary circulation playing a major role in the removal of circulating ET-1, and a reduced pulmonary clearance of this peptide contributes to the hyperendothelinemia observed in both human and animal model of PAH [24][25][26][27].…”

“…Increased plasma levels of ET-1 were detected in patients with various forms of PAH [1] and in various experimental models [2,3]. The chief action of ET-1 is its ability to modulate pulmonary vascular reactivity.…”

Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

“…Endothelin (ET)-1 and several other neurohumoral agents play a central role in the complex pathophysiology of PH (11,28) and are used as therapeutic targets for this entity. For instance, several authors observed that ET-1 antagonism decreases PH, restores endothelial metabolic function, inhibits RV hypertrophy, and improves survival both in experimental (5,19,26) and clinical (27) settings. …”

Molecular Pharmacology and Pathophysiological Significance of Endothelin

“…The overproduced endothelin-1 contributed to the enhanced growth of pulmonary artery smooth muscle cells, particularly in the presence of 0.3% serum (162). In monocrotaline-induced PH in rats, plasma endothelin-1 levels increased progressively and preceded the development of PH (163). Infusion of BQ-123 reduced the progression of PH and right ventricular hypertrophy and prevented the characteristic thickening of the pulmonary arterial media.…”