Pathogenesis Of Renal Hypertension Research Articles

Changes in Autoantibodies against β<sub>1</sub>-Adrenoceptor and M<sub>2</sub>-Muscarinic Receptor during Development of Renovascular Hypertension in Rats

In an experimental rat's renovascular hypertension model, we studied the genesis of anti-cardiac beta1-adrenoceptor and M2-muscarinic receptor autoantibodies in relation to the changes in immunological function during the development of renal hypertension. The biological activities of these autoantibodies were also examined. It was shown that after two weeks of operation both the frequency of occurrence and the titre of autoantibodies to cardiac beta1-adrenoceptor and M2-muscarinic receptor were significantly increased as compared with the control of pre-treatment. The increased autoantibodies lasted for several weeks and then automatically decreased gradually to the pre-clipping level at 10 weeks. Meanwhile the ratio of CD4+/CD8+ was also undergone an initial increase followed by gradual recovery and correlated well with the changes in antibody titre. The biological effects of these autoantibodies displayed an "gonistic-like" activities on the beating frequency of cultured neonatal cardiomyocyte. It is suggested that autoimmune mechanisms are involved in the pathogenesis of renal hypertension and the cardiac receptor autoantibodies might be one of the mechanisms leading to cardiac dysfunction.

Impaired neurogenic control of renal vasculature in renal hypertensive rats.

Renal hypertension is accompanied by alterations in the renal sympathetic innervation involving reduced catecholamine content and histofluorescence. Because the renal nerves are a potentially important factor in the pathogenesis of renal hypertension, the functional significance of renal catecholamine depletion was evaluated. In rats with either one-kidney or two-kidney Grollman hypertension, renal vascular responses to renal nerve stimulation and intraarterial administration of vasoactive hormones were assessed in vivo at various times following renal compression. In the wrapped kidney of one-kidney hypertensive rats, vasoconstrictor responses to renal nerve stimulation were consistently reduced, compared to responses in uninephrectomized control rats, whereas responses to intra-arterial norepinephrine were slightly greater in kidneys from hypertensive animals. In the untouched kidney of rats with two-kidney renal hypertension, vasoconstrictor responses to nerve stimulation were also substantially reduced, although those to norepinephrine were only slightly altered. It was concluded that catecholamine depletion in the kidneys of renal hypertensive animals reflects a diminished capacity of renal sympathetic nerve impulses to produce vasoconstriction. Reduced neurogenic renal vascular resistance may serve to attenuate the rise in blood pressure in renal hypertension.

Role of renin in the pathogenesis of renal hypertension.

To test the hypothesis that renin is circulating in pressor amounts in renal hypertension, two-kidney Goldblatt hypertension was produced in rats. After hypertension had been present for a variable period of time (4 to 21 days), the ischemic kidney was removed, and an infusion of rat renin was started immediately to replace the endogenous renin that the ischemic kidney had been releasing. Since the amount of renin released by the clipped kidney was not known, the amount infused was regulated by a feedback mechanism set to keep the mean blood pressure at the same level as before ipsilateral nephrectomy. Hypertension remission was therefore prevented by this procedure. The PRA at the end of the renin infusion was similar to that prior to the ipsilateral nephrectomy. This finding indicates that the levels of the PRA circulating in renal hypertension are within the pressor range, thus supporting the hypothesis that renin plays a role in the pathogenesis of the acute or semiacute phase of renal hypertension. However, the participation of other factors cannot be ruled out since no correlation was found between PRA and blood pressure.

Pathogenesis of hypertension and implications for its therapeutic management.

Excluding elevations in blood pressure secondary to primary hemodynamic changes and the relatively rare disorders in which hypertension is an accompaniment of extrarenal disturbances, hypertensive cardiovascular disease is attributable to dysfunction of the kidney. In a small group of patients, the elevation in blood pressure is mediated or intensified by a circulating pressor agent secreted by the kidney and detectable in the untreated plasma of the renal venous effluent. This unidentified pressor agent differs from renin and angiotensin, neither of which plays a primary role in the pathogenesis of renal hypertension. Most cases of chronic hypertension, including essential hypertension, are attributable to the loss of a normal renal function concerned in the maintenance of the normotensive state. This fuction appears to be humoral in nature, and replacement therapy with this humoral agent affords the prospect of a rational approach to the effective therapy of essential and related forms of hypertensive cardiovascular disease.

Renal hypertension in rabbits immunized with angiotensin.

RENOVASCULAR hypertension in man and in experimental animals has been attributed to increased production of angiotensin. The exact role of the renin-angiotensin system has remained obscure, however, and whether angiotensin is of prime importance in the pathogenesis of renal hypertension has been doubted1. We have attempted to produce hypertension in rabbits immunized with angio-tensin.

HYPERTENSIVE VASCULAR DISEASE PRODUCED BY HOMOLOGOUS RENIN.

Administration of rat renin to uninephrectomized rats reproduced most, if not all, the changes (hypertension, vascular disease, hypertrophy of the zona glomerulosa of the adrenals) found after partial constriction of the renal artery. This is taken as evidence that the renal pressor system plays a major role in the pathogenesis of renal hypertension.

Role of the Heart in the Pathogenesis of Renal Hypertension

Role of the Heart in the Pathogenesis of Renal Hypertension

Release of pressor substances from renal grafts originating from rats with renal hypertension.

A method is described for grafting kidneys on bilaterally nephrectomized rats without interrupting renal blood flow. Under these conditions, normal kidneys caused a pressor response characterized by a gradual rise in pressure suggesting a continuous endocrine secretion. Kidneys from rats made hypertensive by unilateral clipping of the renal artery, renal encapsulation, or partial infarction were tested during the acute and chronic stages of the experimental disease. Wrapped and infarcted kidneys, as well as the untouched contralateral organs, released little or no pressor substances. On the other hand, clipped kidneys released normal or slightly greater amounts of pressor substances; the eontralateral untouched kidney did not elicit any pressor effect. Morphological examination showed a relationship between presence of nephroselerotic lesions and absence of, or decrease of, reninlike pressor substance released. Both changes are believed to be due to high renal vascular pressure against which the partly clipped kidney is protected. These observations suggest that, if renin is a primary factor in the pathogenesis of renal hypertension, hypertension due to renal artery constriction has a mechanism different from that caused by renal manipulation or infarction.

STUDIES ON EXPERIMENTAL HYPERTENSION

Excision of the thoracic portion of the splanchnic nerves and the lower four dorsal sympathetic ganglia on both sides failed to prevent the development of persistent hypertension which, in dogs, follows the production of renal ischemia by partial clamping of the renal arteries (1). In dogs with this type of experimental renal hypertension existent for varying lengths of time (up to about 4 years), excision of the splanchnic nerves and the lower four dorsal sympathetic ganglia failed to effect any degree of permanent lowering of the blood pressure. For the dog, at least, these results tend to minimize the importance of the splanchnic vasomotor mechanism in the pathogenesis of renal hypertension. This is in agreement with the conclusions of Prinzmetal and Wilson (6) and of Pickering (7) about the part played by the vasomotor system in human hypertension. It is also in agreement with the work of Page (8), and of Collins (9), who showed that in dogs excision of the extrinsic renal nerves alone does not prevent experimental hypertension due to renal ischemia. Although the results of this investigation fail to give experimental support for the operation that is being practised on human beings with hypertension, yet they do not necessarily controvert the reports of beneficial effects in some cases of human hypertension. Further study of the effects on man is necessary before the results of this operation can be adequately evaluated.