Endothelin receptors in the human coronary artery, ventricle and atrium - A quantitative autoradiographic analysis

In the present experiments we investigated endothelin (ET) receptors in the human coronary artery, and in ventricular and atrial muscle using quantitative receptor autoradiography. Displacement of [125I]Sf6b (Sarafotoxin S6b) (30 pM)- and [125I]ET-1 (30 pM)-labeled binding sites was studied using ET-1, the ETA receptor selective ligand BQ-123 (cyclo[D-Asp-L-Pro-D Val-L-Leu-D-Trp-]), and the ETB receptor selective ligand [Ala1,3,11,15]ET-1. Specific binding was more dense in atrium and coronary artery (relative optical density (r.o.d.): 0.14±0.01 and 0.16±0.01, respectively) than in ventricular muscle (r.o.d.: 0.10±0.01). In the coronary artery, binding was especially dense in the media. ET-1 displaced [125I]ET-1 and [125I]Sf6b monophasically in atrium, ventricle and coronary artery. [Ala1,3,11,15]ET 1 and BQ-123 displaced [125I]ET-1 and [125I]Sf6b-labeled sites biphasically in the ventricle and in the atrium. In the human coronary artery, [Ala1,3,11,15]ET-1 and BQ-123 displaced [125I]ET-1-labeled sites monophasically (pIC50): ET-1 (9.72±0.12) > BQ-123 (6.84±0.08) > [Ala1,3,11,15]ET-1 (6.40±0.12). In contrast, [Ala1,3,11,15]ET-1 and BQ-123 displaced [125I] Sf6b-labeled coronary artery sites biphasically (high affinity pIC50: BQ-123, 9.03±0.25;[Ala1,3,11,15]ET-1, 8.40±0.14; low affinity pIC50: BQ-123, 7.24±0.14; [Ala1,3,11,15]ET-1, 6.99±0.09). These data indicate that both [125I]ET-1 and [125I] Sf6b-labeled ETA and ETB binding sites in human ventricular and atrial muscle. In the human coronary artery, both radioligands labeled ETA binding sites, but [125I] Sf6b also labeled a non-ETA, non-ETB binding site with relatively high affinity for both BQ-123 and [Ala1,3,11,15] ET-1

AT(2) receptor-mediated vasodilation in the heart: effect of myocardial infarction

To investigate the functional consequences of postinfarct cardiac angiotensin (ANG) type 2 (AT(2)) receptor upregulation, rats underwent coronary artery ligation or sham operation and were infused with ANG II 3-4 wk later, when scar formation is complete. ANG II increased mean arterial pressure (MAP) more modestly in infarcted animals than in sham animals. The AT(1) receptor antagonist ir

Chronic aspirin treatment affects collagen deposition in non-infarcted myocardium during remodeling after coronary artery ligation in the rat

Low-dose aspirin (acetylsalicylic acid; ASA), inhibiting platelet thromboxane production in favor of endothelium formation of prostaglandins, is successfully used as primary or secondary prophylaxis against myocardial infarction. Although prognosis may be improved, effects of long-term ASA treatment on wound healing and cardiac remodeling are not well understood. The aim of the present study was to mimic the clinical situation by inducing myocardial infarction in low-dose ASA (25 mg/kg/day, i.p.) pretreated rats, and to determine effects on plasma eicosanoid levels, cardiac hypertrophy and collagen deposition, and left ventricular function during continued ASA treatment. The effects of this dose were verified to selectively inhibit platelet thromboxane production, and lower plasma levels of thromboxane, but did not affect plasma levels of prostacyclin and prostaglandin E2during the acute inflammatory stage following myocardial infarction. As measured by heart dry weight/body weight, cardiac hypertrophy was not affected by ASA treatment. However, interstitial fibrosis in the spared myocardium as well as perivascular fibrosis, associated with infarction-induced cardiac remodeling, were affected by ASA treatment. Replacement fibrosis in the infarct itself, considered as representing wound healing, was not significantly influenced by ASA treatment. Wall thinning following infarction was not aggravated, nor did treatment influence left ventricular cavity diameter in a relaxed state. Results fromin vitroleft ventricular function measurements showed no effects on left ventricular peak velocity of contraction or relaxation after ASA treatment. In conclusion, although low-dose ASA may not be expected to have anti-inflammatory action, it did influence post-infarct cardiac remodeling by affecting interstitial and perivascular fibrosis. ASA treatment did not have effects onin vitroleft ventricular dysfunction

Cardiac renin and angiotensins: uptake from plasma versus in situ synthesis

The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of renin-angiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n = 11) and Ang I (n = 7) and II (n = 7) in the left and right atria were higher than in the corresponding ventricles (P < .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P < .05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n = 11) in cardiac tissue were 10% to 25% of the levels in plasma, which is compatible with its diffusion from plasma into the interstitium. Like angiotensin-converting enzyme, renin was enriched in a purified cardiac membrane fraction prepared from left ventricular tissue, as compared with crude homogenate, and 12 +/- 3% (mean +/- SD, n = 6) of renin in crude homogenate was found in the cardiac membrane fraction and could be solubilized with 1% Triton X-100. Tissue levels of renin and Ang I and II in the atria and ventricles were directly correlated with plasma levels (P < .05), and in both tissue and plasma the levels were undetectably low after nephrectomy. We conclude that most if not all renin in cardiac tissue originates from the kidney. Results support the contentions that in the healthy heart, angiotensin production depends on plasma-derived renin and that plasma-derived angiotensinogen in the interstitial fluid is a potential source of cardiac angiotensins. Binding of renin to cardiac membranes may be part of a mechanism by which renin is taken up from plasma

Cardiac renin and angiotensins: uptake from plasma versus in situ synthesis

The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of renin-angiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n = 11) and Ang I (n = 7) and II (n = 7) in the left and right atria were higher than in the corresponding ventricles (P < .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P < .05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n = 11) in cardiac tissue were 10% to 25% of the levels in plasma, which is compatible with its diffusion from plasma into the interstitium. Like angiotensin-converting enzyme, renin was enriched in a purified cardiac membrane fraction prepared from left ventricular tissue, as compared with crude homogenate, and 12 +/- 3% (mean +/- SD, n = 6) of renin in crude homogenate was found in the cardiac membrane fraction and could be solubilized with 1% Triton X-100. Tissue levels of renin and Ang I and II in the atria and ventricles were directly correlated with plasma levels (P < .05), and in both tissue and plasma the levels were undetectably low after nephrectomy. We conclude that most if not all renin in cardiac tissue originates from the kidney. Results support the contentions that in the healthy heart, angiotensin production depends on plasma-derived renin and that plasma-derived angiotensinogen in the interstitial fluid is a potential source of cardiac angiotensins. Binding of renin to cardiac membranes may be part of a mechanism by which renin is taken up from plasma