S. Kazda

125I-endothelin-1 and 125I-big endothelin-1 in rat tissues: autoradiographic localization and receptor binding

SummaryThe potent vasoconstrictor peptide, endothelin-1 (ET-1), which exhibits a characteristically long-acting activity in vitro and in vivo, is thought to be generated in endothelial cells from a less active intermediate, big endothelin-1 (big ET-1). In addition to ET-1, big ET-1 is also present in the circulation. The autoradiographic localization of 125I-big ET-1 and 125I-ET-1 has been studied after intravenous administration in rat tissues. Highest enrichment of radioactivity was found in the kidney cortex for both peptides. Compared to blood levels, enrichment of radioactivity is also detected, in the vascular wall of the aorta. Comparing the radioactivity pattern of ET-1 and big ET-1, a nearly identical tissue distribution is observed, with the exception of the relative enrichment in the lung and the zona glomerulosa after administration of ET-1.Both radioligands show a specific and saturable binding to lung and kidney membranes. In the case of lung tissue, Ki values are 10−10M for endothelin-1 and 10−8M for big endothelin-1. This difference in affinities may account for the lack of binding of big endothelin-1 to lung tissue.

Interaction of a neutral endopeptidase inhibitor with an ANP-C receptor ligand in anesthetized dogs

Inhibition of important degradative pathways of atrial natriuretic peptide (ANP) in vivo could be a valuable therapeutic tool for regulating endogenous levels of ANP. The aim was to investigate the in vivo effects of both blockade of atrial natriuretic peptide clearance receptor and inhibition of neutral endopeptidase 24.11, an enzyme shown to be involved in ANP breakdown. Therefore, we infused a specific neutral endopeptidase inhibitor ((S)-thiorphan) and an ANP-C receptor ligand (AP 811) alone or in combination into anaesthetized beagle dogs. Compared with vehicle controls, coadministration of (S)-thiorphan and AP 811 (100 micrograms/kg/min and 10 micrograms/kg/min, resp.) had greater effects on endocrine and renal parameters than administration of either substance alone. Coadministration of both compounds increased urinary excretion of volume and sodium, cGMP and ANP. We found also increased plasma cGMP, plasma ANP and decreased plasma renin activity. No effects were observed with respect to blood pressure, left ventricular pressure or heart rate during the infusion period of 2 h. We conclude from these investigations, that blocking both degrading pathways of ANP with the ANP-C receptor ligand AP 811 and the neutral endopeptidase inhibitor (S)-thiorphan is more effective than inhibition of either system alone. Such a combination might therefore be a useful therapeutic tool in cardiovascular diseases.

Influence of Calcium Antagonists on Renal Function and Secondary Hyperparathyroidism in Acute Renal Failure in Rats

Glycerol-induced acute renal failure (ARF) is characterized by an increase in serum creatinine, urea, and phosphate concentration, and severe impairment of creatinine clearance. Secondary hyperparathyroidism develops rapidly during ARF. The calcium antagonist nisoldipine clearly improves renal function, which becomes evident by an improvement of creatinine clearance and attenuation of the increase of serum creatinine, urea, and phosphate concentrations. Further secondary hyperparathyroidism is ameliorated by nisoldipine treatment. In spite of normalization of the hypocalcemia in ARF by nisoldipine, weak hyperparathyroidism persists, suggesting that hypocalcemia is not exclusively responsible for elevated parathyroid hormone serum levels in ARF.

Protection Against Hypertensive Cardiovascular Damage by Dihydropyridine Calcium Antagonists

It is commonly acknowledged that calcium antagonists inhibit transmembrane calcium influx in arteriolar smooth muscle cells and thus reduce total peripheral resistance. This mechanism of action is supposed to be the prime basis of the antihypertensive action of these agents. However, despite their action as arteriolar vasodilators, therapeutically, calcium antagonists differ from vasodilators with other mechanisms of action (e.g., hydralazine or minoxidil) in having a marked natriuretic and diuretic action [6,8,17] and have been shown to preserve structure and function of heart, kidney, and mesenteric arterioles of hypertensive rats [2–4,10,13,18,24–26]. Therefore, tissue-protective effects of dihydropyridine calcium antagonists which might be unrelated to their hemodynamic actions, might add significantly to their long-term therapeutic efficacy in hypertension. We investigated the antihypertensive and tissue-protective effects of dihydropyridine calcium antagonists in long-term experiments: (1) nisoldipine in salt-loaded Dahl S and R rats in a preventive and therapeutic experiment, (2) nitrendipine in spontaneously hypertensive rats and Wistar-Kyoto rats in comparison to a classical vasodilator, and (3) nimodipine in stroke-prone spontaneously hypertensive rats in comparison to parathyroidectomy.

Calcium Overload and Brain Damage in Stroke-Prone Spontaneously Hypertensive Rats: Prevention by Nimodipine and by Parathyroidectomy

Stroke-prone rats were originally derived from the Okamoto strain of spontaneously hypertensive rats (SHRs). Postpuberty they rapidly increase their blood pressure to extremely high values, and at the age of 8–12 months they spontaneously develop cerebrovascular lesions and brain infarctions [8]. Dietary salt load in young stroke-prone SHRs (SHRSPs) has been shown to intensify hypertension as well as cerebro- and renovascular lesions [6]. However, if dietary salt loading was introduced in adult SHRSPs with already established hypertension, it did not produce any additional increase in blood pressure, though it did drastically increase the mortality and produced severe cerebro- and renovascular lesions at a much earlier age (5–6 months) [4]. Moreover, chronic treatment with the calcium antagonist nimodipine dramatically increased the survival time of salt-loaded SHRSPs, prevented brain damage, and, to a certain extent, reduced renal and heart vascular lesions without affecting the high blood pressure [4] (Fig.1).

Pharmacological Modification of the ANP System

The search for drugs interacting with the ANP system to give favourable therapeutic effects has concentrated on the release and the metabolism of ANP. Regarding the release of ANP direct effects have to be distinguished from indirect ones. Both drug induced increases and decreases of ANP plasma levels may be indirectly mediated: Increased ANP plasma levels are noted after sodium retaining antihypertensives such as reserpine and minoxidil. On the other hand, the pathological high ANP plasma levels of SHR are normalized in parallel to the amelioration of cardiac hypertrophy by the natriuretic calcium antagonist nitrendipine. The mechanism for β-blocker-induced increase in plasma ANP is not clear as yet.