Stanislav Kazda

The renal response to acute hypervolemia is caused by atrial natriuretic peptides.

Summary: In anesthetized rats, synthetic rat atriopeptin II produced an increase in urinary volume and sodium excretion as well as a decrease in arterial blood pressure. Both the natriuretic and hypotensive effects were blocked by monoclonal antibodies directed against atriopeptin II. The diuresis and natriuresis caused by furosemide was not inhibited by these antibodies. Thus, the monoclonal antibodies provide a specific inhibitor for atriopeptin-mediated responses in vivo and can be used to investigate the role of atriopeptin in volume regulation. Volume expansion with 20 ml/kg i.v. homologous blood induced strong diuresis and natriuresis in the anaesthetized rat. This response was also blocked by the described monoclonal antibodies. A radioimmunoassay for the determination of atriopeptin-like immunoreactivity (ANP-IR) is described. The plasma levels of ANP-IR 8 min after blood injection were 3–4 times higher than in control rats. Thus, the strong diuresis observed after volume expansion is due to an increase in circulating atrial natriuretic peptides that obviously exert a regulative function in fluid volume control.

The Calcium Channel: Structure, Function and Implications

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Endothelin stimulates release of atrial natriuretic peptides in vitro and in vivo

The effect of endothelin (END) on the release of atrial natriuretic peptides (ANP) was studied in isolated rat atria and in conscious rats. END stimulates the ANP release in vitro in a dose-dependent manner. An increase in ANP plasma levels and cyclic GMP plasma levels was also observed in conscious rats after injection of END. When a monoclonal antibody directed against ANP was injected together with END the increase in cyclic GMP was completely blocked. From this study it is concluded that END is a potent secretagogue for ANP both in vitro and in vivo.

Variability of intercapillary distance estimated on histological sections of rat heart.

The majority of models of O2 supply to myocardial tissue are based on the classical model of Krogh (1919). This model requires the radius of the tissue cylinder as one of the crucial input data. Usually, only its mean value has been considered, as derived on histological sections from the number of capillaries per mm2. However, for a realistic description, the full distribution of the radii of the tissue cylinders has to be taken into account. Recently this distribution was shown to be approximately log-normal (Renkin et al., 1981; Turek and Rakusan, 1981), and thus to be fully defined by median radius and logarithmic standard deviation (log SD), the latter serving as an index of the variability.

The elevation of cyclic GMP as a response to acute hypervolemia is blocked by a monoclonal antibody directed against atrial natriuretic peptides.

Substantial volume expansion in conscious rats induces a strong diuresis and natriuresis that is caused by the increase in plasma levels of atrial natriuretic peptides (ANP) as measured by a radioimmunoassay. This renal response could be blocked by monoclonal antibodies directed against ANP. Parallel to the change in ANP, the cyclic GMP levels in plasma, urine and kidney tissue were increased after volume loading and reduced after additionally given antibodies. From this study it seems to be clear that the cyclic GMP rise is not a direct effect of volume expansion but is specifically mediated by the released ANP.

Calcium Antagonism and Protection of Tissues from Calcium Damage

Calcium antagonism of nifedipine, nitrendipine or nisoldipine prevented salt-induced hypertension, renovascular damage and mortality in Dahl salt-sensitive (S) rats. The calcium agonist BAY K 8644 accelerated the development of salt-induced hypertension in S rats. In some S rats on a low-salt diet BAY K 8644 induced renovascular damage without sustained hypertension. In stroke-prone spontaneously hypertensive rats (SHRSP) on a normal diet the natural appearance of stroke was correlated with an increased calcium content in brain and kidney tissue. Nimodipine prevented stroke and the increase in brain calcium content without affecting the high blood pressure. A similar protective effect without substantial influence on high blood pressure was achieved by bilateral parathyroidectomy. Hypertension-associated vascular damage does not necessarily depend on the systemic intravascular pressure. In malignant hypertension the deleterious calcium overload in tissues may be activated or inhibited independently of the regulation of arterial blood pressure.

Different effects of ANP and nitroprusside on cyclic GMP extrusion of isolated aorta

Atrial natriuretic peptide (ANP) and sodium nitroprusside have potent vasodilator effects on the noradrenaline-precontracted isolated rabbit aorta. A distinct elevation of cyclic GMP in the aortic tissue was observed after both vasodilators. In contrast to sodium nitroprusside, ANP-(5-28) induced a dose-dependent cyclic GMP extrusion from the tissue into the medium. Thus, release of cyclic GMP appears to be specific for activation of particulate guanylate cyclase and provides a mechanism in addition to synthesis and degradation by which the cells can regulate their internal concentrations of cyclic GMP.

Interference of the calcium antagonist nisoldipine with the abnormal response of vessels from hypertensive rats to alpha-adrenergic stimulation.

The effects of the calcium antagonist nisoldipine on contractions stimulated by phenylephrine and B-HT 920 (agonists of α1- and α2-adrenoceptors) in isolated aortic rings from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto rats (WKY) were investigated in vitro. Phenylephrine and B-HT 920 produced concentration-dependent contractions of vessels from both groups of animals. The absolute force of the contractions was less in the aortae from hypertensive rats after all doses of both agonists. Nisoldipine inhibited the B-HT 920-induced contraction much more in vessels from SHRSP than in those from normotensive WKY rats (IC50 = 1.5 x 10 10 versus 7 x 10-9 g/ml). The phenylephrine contractions were inhibited in SHRSP aortae by higher concentrations (IC50 −8.5 × 10 8 g/ml) of nisoldipine: in WKY, nisoldipine only produced a slight inhibition of phenylephrine-induced contractions. The inhibitory concentrations of nisoldipine on BHT-920-induced contractions are similar to those for the inhibition of the calcium or depolarization-induced contractions in other experiments. The α2-agonist-induced contractions of rat aorta are dependent on trans-membrane calcium supply. The higher efficacy of nisoldipine in aortae from SHRSP suggests an increased trans-membrane availability of calcium ions in hypertension.

Mode of antihypertensive action of nitrendipine.

Summary The antihypertensive effect of nitrendipine cannot be explained only by its reduction of the increased peripheral vascular resistance. In contrast to the antihypertensive vasodilators, nitrendipine improves impaired renal function and prevents generalized vasculopathy in hypertensive animals. Chronic treatment with nitrendipine prevents spontaneous (Okamoto rats) and salt-induced (Dahl rats) hypertension and cardiac hypertrophy. In rats with established hypertension, nitrendipine normalizes blood pressure, reduces cardiac hypertrophy, and improves renal ischaemia. In salt-induced malignant hypertension in stroke-prone spontaneously hypertensive rats, nitrendipine only slightly reduces blood pressure but dramatically improves survival and prevents vascular lesions in the heart, brain, andkidneys. Nitrendipine reduces the intracellular availability of calcium ions in vascular smooth muscle responsible for the increased peripheral and renovascular resistance in hypertension. Moreover, in preventing the deleterious calcium overload, nitrendipine preserves tissue integrity and increases life span in malignant hypertension.

Inhibition by atrial natriuretic peptide of endothelin-1-stimulated proliferation of vascular smooth-muscle cells

The effect of endothelin-1 (ET-1) on proliferation of aortic vascular smooth-muscle cells (VSMCs) from spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) rats was assessed by the measurement of [3H]-thymidine incorporation into DNA. ET-1 stimulated DNA synthesis in a concentration-dependent manner. Half-maximal stimulation occurred at a concentration of 7 x 10(-11) M. Three separate administrations of ET-1 to the cell cultures resulted in a half-maximal stimulation at 3 x 10(-12) M in of VSCMs from SHRs. VSMCs from SHRs responded to a far greater extent compared with WKY rats. The stimulatory effect of ET-1 was significantly attenuated by atrial natriuretic peptide (ANP). Repeated administration of ANP led to exacerbation of the inhibitory effect. Serum-stimulated DNA synthesis was not influenced by ANP. The proliferative action of ET-1 and the inhibition by ANP are discussed with respect to the development of vascular disease in atherosclerosis and hypertension.