PubMed · 10752857
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W M Stahl. 2000. Improving natural selection.. https://doi.org/10.1097/00003246-200003000-00056
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This study was designed to gain additional insight into the mechanism of the slow force response (SFR) to stretch of cardiac muscle. SFR and changes in intracellular Na(+) concentration ([Na(+)](i)) were assessed in cat papillary muscles stretched from 92% to approximately 98% of L(max). The SFR was 120+/-0.6% (n=5) of the rapid initial phase and coincided with an increase in [Na(+)](i). The SFR was markedly depressed by Na(+)-H(+) exchanger inhibition, AT(1) receptor blockade, nonselective endothelin-receptor blockade and selective ET(A)-receptor blockade, extracellular Na(+) removal, and inhibition of the reverse mode of the Na(+)-Ca(2+) exchange by KB-R7943. KB-R7943 prevented the SFR but not the increase in [Na(+)](i). Inhibition of endothelin-converting enzyme activity by phosphoramidon suppressed both the SFR and the increase in [Na(+)](i). The SFR and the increase in [Na(+)](i) after stretch were both present in muscles with their endothelium (vascular and endocardial) made functionally inactive by Triton X-100. In these muscles, phosphoramidon also suppressed the SFR and the increase in [Na(+)](i). The data provide evidence that the last step of the autocrine-paracrine mechanism leading to the SFR to stretch is Ca(2+) entry through the reverse mode of Na(+)-Ca(2+) exchange.
Nicotine may contribute to smoking-induced endothelial dysfunction because of its ability to impair endothelium-dependent vasodilatation. We investigated whether the acute administration of nicotine changes the hypotensive responses to bradykinin in rats. The effects of pre-treatment with losartan or enalapril on the nicotine-induced changes in the responses to bradykinin were also evaluated. In study 1, anesthetized rats were cannulated via carotid artery for the measurement of mean arterial pressure. Dose-response curves to bradykinin (0.1, 0.4, 1.6, 6.4, 25 and 100 microg/kg) were generated before and 10 min after the injection of nicotine (200 microg/kg, i.v.) or saline. The individual dose-response curves were fitted to a four-parameter logistic equation using the ALLFIT program, which provided an estimate of the maximal response (E(max)) and of the dose of bradykinin producing the half-maximal response (ED(50)). In study 2, rats were pre-treated orally with losartan (10 mg/kg/day) or enalapril maleate (25 mg/kg/day) for 2 weeks. Control rats received tap water alone. After pre-treatment, the rats were anesthetized and used as described in study 1. Nicotine decreased the E(max) (from 73.0+/-7.5 to 65.7+/-3.3 mm Hg; P<0.05) but did not affect the ED(50). In study 2, losartan or enalapril did not affect nicotine-induced decrease in responses to bradykinin; E(max) decreased in both groups (from 68.7+/-6.3 to 62.8+/-4.2 mm Hg, and from 53.8+/-13.0 to 43.1+/-7.1 mm Hg, respectively; P<0.05) without significantly changing the ED(50). These results suggest that nicotine impairs the endothelium-dependent hypotensive responses to bradykinin. This effect is not influenced by inhibition of the angiotensin-converting enzyme or by blockade of the angiotensin AT(1) receptors.
BACKGROUND: -Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis. We propose that hypertrophy and fibrosis are secondary to the activation of trophic and mitotic factors and, thus, potentially reversible. We determined whether the blockade of angiotensin II, a known cardiotrophic factor, could reverse or attenuate interstitial fibrosis in a transgenic mouse model of human HCM. METHODS AND RESULTS: We randomized 24 adult cardiac troponin T (cTnT-Q(92)) mice, which exhibit myocyte disarray and interstitial fibrosis, to treatment with losartan or placebo and included 12 nontransgenic mice as controls. The mean dose of losartan and the mean duration of therapy were 14.2+/-5.3 mg. kg(-1). d(-1) and 42+/-9.6 days, respectively. Mean age, number of males and females, and heart/body weight ratio were similar in the groups. Collagen volume fraction and extent of myocyte disarray were increased in the cTnT-Q(92) mice (placebo group) compared with nontransgenic mice (9.9+/-6.8% versus 4.5+/-2.2%, P=0.01, and 27.6+/-10.6% versus 3.9+/-2.3%, P<0.001, respectively). Treatment with losartan reduced collagen volume fraction by 49% to 4.9+/-2.9%. The expression of collagen 1alpha (I) and transforming growth factor-beta1, a mediator of angiotensin II profibrotic effect, were also reduced by 50%. Losartan had no effect on myocyte disarray. CONCLUSIONS: Treatment with losartan reversed interstitial fibrosis and the expression of collagen 1alpha (I) and transforming growth factor-beta1 in the hearts of cTnT-Q(92) mice. These findings suggest that losartan has the potential to reverse or attenuate interstitial fibrosis, a major predictor of sudden cardiac death, in human patients with HCM.