Biomedical subjects
C J Limas
Publications and source records attributed to C J Limas.
Effect of salt on the vascular lesions of spontaneously hypertensive rats.
High salt intake accelerates hypertension in humans and increases cardiovascular morbidity and mortality. The temporal relation between blood pressure (BP) elevation and appearance of vascular lesions during salt-loading was studied in the spontaneously hypertensive rat (SHR). Starting at 5 weeks of age, SHRs and normotensive Wistar-Kyoto rats (WKYs) were given 1% NaCl in their drinking water SHRs and WKYs on tap water served as controls. Animals from each group were sacrificed at 10 and 20 weeks of age, and the aorta and intrarenal vessels were studied by light and electron microscopy. Neither BP nor vascular morphology of WKYs were affected by 1% NaCl. In SHRs, the course of BP was not affected by the addition of salt for at least 11 weeks, but vascular changes were significantly aggravated within 5 weeks. Thus, aortic intimal lesions progressed more rapidly so that, by 20 weeks of age, 50% of the animals had 3+lesions while, in control SHRs, they did not exceed the 2+grade. Salt-loading resulted in significant thickening of the aortic media between the 10th and 20th week of age while control SHRs showed no increment within the same time interval. Also, small intrarenal arterial vessels of salt-treated SHRs had significantly narrower lumina and greater wall thickness at both 10 and 20 weeks of age. In addition, they showed intimal proliferations and necrotizing lesions which were absent from control SHRs at these ages. These results show that, in this experimental model, the aggravation of vascular changes is not merely a sequela of further elevation of BP. Since the adverse effect of salt on the vessels was not seen in WKYs, it is likely that this effect is related to genetic factors or to higher susceptibility of hypertensive vessels.
Effect of salt on prostaglandin metabolism in hypertension-prone and -resistant Dahl rats.
The effect of high salt intake on vascular and renomedullary prostaglandin (PG) synthesis was compared in Sprague-Dawley and salt-sensitive (S) and -resistant (R) Dahl rats. Animals were given a diet containing either 0.6% or 8% NaCl starting at 5 weeks of age, and were sacrificed 6 weeks later. Systolic blood pressure of S rats increased to 220 +/- 7 mm Hg but was unaffected in R and Sprague-Dawley rats. Prostaglandin synthesis was studied in aortic rings and renomedullary microsomes using 14C-arachidonate as substrate. [3H]PGE2 degradation was measured in the renocortical cytosol. In Sprague-Dawley and R rats, aortic PGI2 synthesis was not affected by high salt intake, while a significant increase compared to animals on 0.6% NaCl (from 608 +/- 84 to 992 +/-108 pmoles/60 min, p less than 0.05) was noted in S rats. Enhancement of PGI2 synthesis in S rats may be secondary to the hypertension. Salt-loading consistently stimulated renomedullary PGE2 synthesis in all three animal groups. S rats, however, had the lowest PG synthesis in renal medullas compared to Sprague-Dawley and R rats when placed on either diet. Thus, even after 6 weeks on high salt, S rats did not reach the levels of PGE2 synthesis seen in R or Sprague-Dawley rats on regular diet. The activity of cortical 15-hydroxyprostaglandin dehydrogenase was increased by salt-loading in S and Sprague-Dawley, but not in R rats. R rats had lower dehydrogenase activity than the other two groups when placed on either diet. The observed differences in PG synthesis and catabolism will tend to maintain the net output of renal PGs highest in R and lowest in S rats. These differences correlate with the reported differences in renal papillary flow between these two rat strains and may be relevant to their susceptibility or resistance to hypertension in response to salt.
Decreased isoproterenol-induced "down"-regulation of beta-adrenergic receptors in the myocardium of SHR.
The number of cardiac beta-adrenergic receptors and the activity of isoproterenol-stimulated adenylate cyclase are lower in spontaneously hypertensive rats (SHRs) and may account for diminished inotropic responsiveness to beta-agonists. Differences in isoproterenol-induced desensitization of the cardiac adenylate cyclase system between 14- to 16-week-old SHRs and Wistar-Kyoto (WKY) controls were studied using cardiac membranes, isolated cardiac myocytes, and intact animals. In both animal strains, the isoproterenol-induced "loss" of beta-adrenergic receptors in the cardiac membranes required adenosine triphosphate (ATP), magnesium (Mg2+), and guanosine 5'-triphosphate (GTP). The ATP and Mg2+ requirement may reflect a crucial role for a phosphorylation step, since desensitization was prevented by cordycepin, a nonspecific phosphorylation inhibitor. In both isolated myocytes and intact animals, isoproterenol induced a redistribution of the beta-adrenergic receptors (but not of adenylate cyclase) from the cell membrane to the cytosol. Internalization of the receptors was not secondary to the loss of membrane fragments to the cytosol, since the receptors sequestered in a fraction devoid of cell surface markers. In all three preparations, the extent of isoproterenol-induced "loss" of beta-receptors and isoproterenol-stimulated adenylate cyclase was considerably lower in SHRs than WKYs. This difference appeared to be due to a reduced capacity of isoproterenol to induce translocation of beta-receptors from the membranes to the cytosol of SHRs, because of a change in the physical properties of either the beta-receptors themselves or the membranes into which they were embedded.
Cardiac beta-adrenergic receptors in salt-dependent genetic hypertension.
The pattern of cardiac beta-adrenergic receptor changes in different hypertrophy models varies according to the pathophysiology. In salt-sensitive Dahl rats, high dietary salt intake leads to a moderate degree of cardiac hypertrophy associated with increased numbers of cardiac beta-adrenergic receptors but unchanged affinity for agonists. Isoproterenol-stimulated cardiac adenylate cyclase is also higher in salt-loaded hypertensive rats without any change in basal or NaF-stimulated activities. In contrast, neither beta-adrenergic receptors nor adenylate cyclase activities are affected by variations in dietary salt in salt-resistant Dahl rats. The extent of isoproterenol-induced down regulation of beta-adrenergic receptors on isolated cardiac myocytes as well as the recovery from this down regulation is not significantly different in either strain of Dahl rats and is not influenced by dietary salt. The enhancement of beta-adrenergic pathways in salt-dependent genetic hypertension may be involved both in the initiation of cardiac hypertrophy and the preservation of contractile function.
Altered calcium uptake by the sarcoplasmic reticulum following cardiac transplantation in humans.
Abnormalities in the diastolic properties of the heart have been described following human cardiac transplantation and may reflect, at least in part, decreased Ca2+ uptake by the sarcoplasmic reticulum. This possibility was evaluated by obtaining serial myocardial biopsies in 13 patients who underwent cardiac transplantation for severe heart failure. Oxalate-supported Ca2+ uptake by the sarcoplasmic reticulum was measured in homogenates of 83 ventricular biopsies from transplanted hearts. Biopsies from seven subjects with normal cardiac function and morphology served as controls. In the transplanted hearts, there was a tendency for Ca2+ uptake rate to decline with time so that 4-5 months postoperatively, it was significantly lower (4.5 +/- 0.5 nmoles Ca2+/mg/min) compared to controls (5.6 +/- 0.5 nmoles Ca2+/mg/min, p less than 0.01). Plasma norepinephrine levels fell from the high preoperative values (689 +/- 50 pg/mL) towards normal (215 +/- 7 pg/mL) within 30 days after transplantation. Subsequently, however, there was a tendency for norepinephrine levels to increase (369 +/- 55 pg/mL at 4 months). In four patients for which serial observations were available, there was an inverse relationship between myocardial Ca2+ uptake and plasma norepinephrine levels. These results indicate the feasibility of obtaining reproducible serial measurements of Ca2+ uptake in human cardiac biopsies. The decline in sarcoplasmic reticulum function following cardiac transplantation may be, in part, the biochemical basis for the reported impairment in diastolic relaxation.