Chronic regulation of the cardiovascular system by atrial natriuretic factor was investigated by generating transgenic mice with elevated hormone levels in the systemic circulation. A fusion gene comprising the mouse transthyretin promoter and mouse atrial natriuretic factor structural sequences was designed so as to target hormone expression to the liver. Hepatic expression of atrial natriuretic factor was detectable as early as embryonic day 15 in transgenic animals. In adult transgenic mice, plasma immunoreactive atrial natriuretic factor concentration was elevated at least eightfold as compared with nontransgenic littermates. The mean arterial pressure of conscious transgenic mice was 75.5 ±0.9 mm Hg, significantly less than that of nontransgenic siblings (103.9±2.0 mm Hg). This difference in mean arterial pressure was not accompanied by significant changes in several other physiological parameters, including heart rate, plasma and urinary electrolytes, water intake, and urine volume. This study demonstrates that a chronic elevation of plasma atrial natriuretic factor decreases arterial blood pressure without inducing diuresis and natriuresis in transgenic mice and also illustrates the value of the transgenic approach for the study of the cardiovascular system. (Hypertension 1990;16:301-307)
Depressed contractile function plays a primary role in the pathophysiology of acute myocardial ischemia. Intracellular acidification is an important factor underlying the inhibition offorce production in the ischemic myocardium. The effect of acidosis to depress contractiliy is markedly greater in cardiac as compared to skeletal muscle; however, the molecular basis of this difference in sensitivity to acidosis is not clearly understood. In this report, we describe transgenic mice that express the fast skeletal isoform oftroponin C (sTnC) in cardiac muscle. In permeabilized single cardiac myocytes the shift in the midpoint of the tension-pCa relationship (i.e., pCaso, where pCa is -log[Ca2+]) due to lowering pH from 7.00 to 6.20 was 1.27 ± 0.03 (n = 7) pCa units in control cardiac TnC (cTnC) expressing myocytes and 0.96 0.04 (n = 11) pCa unit in transgenic cardiac myocytes (P < 0.001). The effect of pH to alter maximum Ca2+-activated tension was unchanged by TnC isoforms in these cardiac myocytes. In a reciprocal experiment, contractile sensitivity to acidosis was increased in fast skeletal muscle fibers following extraction of endogenous sTnC and reconstitution with purified cTnC in vitro. Our findings demonstrate that TnC plays an important role in determining the profound sensitivity of cardiac muscle to acidosis and identify cTnC as a target for therapeutic interventions designed to modify ischemia-induced myocardial contractile dysfunction.It is well known that force generation diminishes markedly during ischemia in the heart (1-3). In contrast, studies on isolated whole heart or isolated papillary muscles using NMR, fluorescent indicators, or the photoprotein aequorin reveal that the Ca2+ transient of contraction is generally little changed during the time period of ischemia when force is declining markedly (2). Thus, the basis of contractile dysfunction in the ischemic heart appears to involve events in the excitation-contraction coupling scheme distal to Ca2+ release from the sarcoplasmic reticulum. During ischemia in the heart, metabolic byproducts of ATP hydrolysis and the glycolytic energy pathway, including H+, inorganic phosphate, and ADP, accumulate within the myoplasm and these byproducts have been implicated in mediating the observed altered contractile function ofthe failing heart in ischemia (2). For example, it has been shown that intracellular pH declines from about 7.00 to 6.20 during ischemia in the heart (2, 4). Studies using the permeabilized muscle preparation, in which the sarcolemma is chemically or mechanically disrupted to allow access and direct control of the intracellular solution bathing the otherwise intact contractile apparatus, provide evidence that low pH has a direct effect to depress Ca2+-activated contraction in cardiac and skeletal muscle, with the effect being greater in cardiac muscle (refs. 5 and 6; present study). Taken together these results suggest that the basis of pH-induced inhibition of force generation resides in desen-The publication costs of this artic...
Transgenic mice, created from inbred C3HeB/FeJ embryos, were used to overexpress selectively in the liver a fusion gene comprising mouse transthyretin (TTR) regulatory and atrial natriuretic factor (ANF) structural sequences. Animals were anesthetized, and kidney function was studied before and after blood volume expansion. Baseline urine volumes and electrolyte excretions were not significantly different from those of non-transgenic littermates, despite a markedly lower arterial blood pressure in the experimental group. A slightly lower glomerular filtration rate (GFR) in transgenics was not different statistically. Plasma ANF levels measured by radioimmunoassay were approximately 10-fold higher in the transgenic animals, compared with their nontransgenic siblings. After acute blood volume expansion, the diuretic, natriuretic, kaliuretic, and chloruretic responses were markedly enhanced in the transgenic group. Arterial pressure was increased as a result of hypervolemia, although it remained relatively depressed relative to the controls. GFR again was not different. We conclude that transgenic mice overexpressing ANF can maintain normal excretion of salt and water, possibly via ANF-induced reduction of renal perfusion pressure. After acute blood volume expansion, an increase in pressure may allow full renal expression of the chronically elevated ANF levels.
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