Claudia Hirth

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.

The use of a monoclonal antibody to measure plasma atriopeptins in rat

A monoclonal antibody with specificity for atrial natriuretic peptides (ANP) was produced, that can be used for the radioimmunological determination of ANP-immunoreactivity (ANP-IR) in rat plasma. The antibody recognizes atriopeptin I, II, III, as well as alpha-hANP and alpha-hANP fragment (7-28) and does not crossreact with ANP-fragments (13-28) and (18-28). Plasma levels of ANP-IR in conscious Wistar rats were determined before and after volume-loading. Basal plasma levels of ANP-IR were 108 +/- 12 pg/ml, and after volume-loading increased to 800 +/- 59 pg/ml.

The reduction of renin and aldosterone as a response to acute hypervolemia is blocked by a monoclonal antibody directed against atrial natriuretic peptides.

We have previously reported that the strong diuresis, natriuresis and urinary cyclic GMP excretion after acute volume loading in rats are caused by ANP and can be blocked by additionally given monoclonal antibodies directed against ANP. The present report describes that in contrast to the changes in ANP and cyclic GMP, the plasma renin activity and aldosterone concentration are decreased after volume loading. This decrease is completely blocked by simultaneous administration of the monoclonal antibodies. Plasma cyclic AMP levels are not affected. From this study it seems to be clear that the inhibition of the renin-aldosterone system is not a direct effect of volume expansion but is specially mediated by the released ANP.

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.

Protective Effects of Calcium Antagonists on Hypertensive Diseases in Heart, Brain, and Kidney of Hypertensive Rats

The most evident result of calcium antagonist action in hypertension is the lowering of blood pressure. However, the protective effects of this type of agents on tissue structure and function may be largely independent of their vasorelaxant action. The natriuretic effect of dihydropyridine calcium antagonists is found in their antihypertensive dose range and was demonstrated to prevent volume expansion in (1-kidney, 1-clip)-hypertension. The functional recovery of the post-ischemic kidney was improved by treatment with nifedipine. With the help of biopsies of small mesenteric arteries of salt-loaded Dahl-S-rats with preexistent hypertension before arid after 6 weeks of nifedipine, the formation of new arterial endothelium and internal elastic lamina was observed. Morbidity, mortality, and incidence of organ lesions were largely reduced or prevented by the treatment of adult stroke-prone SHR with blood-pressure-neutral doses of nitrendipine or nimodipine. Nimodipine was shown largely to normalize brain and kidney calcium concentrations without altering serum ionized calcium concentration or blood pressure. It is concluded that the direct protective effects of calcium antagonists on cell structure and function might be therapeutically more important than their depressor effect.