Björn Folkow

Activation of the humoral antihypertensive system of the kidney increases diuresis.

Isolated kidneys taken from normotensive Wistar-Kyoto rats were cross-perfused extracorporeally by normotensive strain-matched donor rats. The extracorporeal perfusion circuit was arranged so that the perfusion pressure to the normotensive recipient kidney could be varied from 90 to 200 mm Hg without any change in total flow through this circuit. This setup avoided hemodynamic or mechanical interferences with reflexogenic circulatory control in the normotensive donor rat when the recipient kidney was manipulated. Diuresis and natriuresis were measured in the normotensive donor rat and the normotensive recipient kidney. A few minutes after normotensive recipient kidney perfusion pressure had been raised, mean arterial pressure (MAP) and heart rate started to decline rapidly in the normotensive donor rat, and circulatory collapse ensued within 15 to 100 minutes. During the control period at 90 mm Hg normotensive recipient kidney perfusion pressure, urinary flow, MAP and heart rate were stable in the normotensive donor rat and the normotensive recipient kidney. When perfusion pressure was raised to 200 mm Hg in the recipient kidney, the urinary flow in the donor rat increased 62% on average in the first 10 minutes over values recorded before the pressure rise (p < 0.05) while MAP simultaneously fell by 16% and HR remained unchanged. During the subsequent period, the urinary flow of the donor rat declined together with MAP and heart rate. In the extracorporeally high-pressure perfused recipient kidneys, an eightfold to ninefold increase in diuresis and natriuresis occurred during the first 45 minutes. In conclusion, the present study lends further support to the theory that the humoral renal antihypertensive system is involved in ordinary blood pressure regulation and in the control of kidney excretory function as a possible counterpart to the renocortical renin-angiotensin system.

The debate on the àmplifier hypothesis' - some comments.

Sir Karl Popper is of course right in his thesis that unending scrutiny of concepts and hypotheses is one of the major prerequisites for progress in science. It is, however, also obvious that criticism should be free from misunderstandings, as this rather causes confusion and stagnation. For such reasons, I wish to join the debate between Korner, Angus and Wright [1,3] and Izzard, Heagerty and Leenen [2,4], although also because I am hardly an outsider, as much of the controversy involves my own work.

The importance of hypophyseal hormones for structural cardiovascular adaptation in hypertension

The effect of renal artery clipping was tested in three groups of male Sprague-Dawley rats: (1) 30 control animals, (2) 30 hypophysectomized animals, and (3) 30 hypophysectomized animals treated with growth hormone and thyroxine. Fifteen rats in each group were clipped and 15 acted as controls. In the first group clipping raised arterial pressure and plasma renin activity. Thirty-five days after clipping, pair-perfused hindquarter preparations at maximal dilation and maximal pressor response were both increased, reflecting, respectively, decreased lumen diameters and increased media thickness in the resistance vessels. Clipping also increased left ventricular weight. Hypophysectomy eliminated the weight gain, and the maximal pressor response and maximal dilation were lower than in the control and treated groups. Hypophysectomy also considerably reduced the rise in blood pressure on clipping and, even more so, the associated structural cardiovascular changes. Replacement therapy with growth hormone and thyroxine almost restored the weight gain and also the structural responses of the heart and vessels to clipping. We conclude that pituitary hormones play an important, probably permissive, part in the development of normal vessel structure and in the adaptation of cardiovascular structure to chronic hypertension.

The Humoral Renal Antihypertensive System: Nervous and Hemodynamic Effects in Normotensive and Undipped Renal Hypertensive Rats

A series of studies of the humoral renal antihypertensive system in normotensive and 2K 1C-renal antihypertensive rats is outlined. The rapid structural upward resetting of the cardiovascular system in renal hypertensive rats was associated with a structural downward resetting in the vasculature of the hypotensive clipped kidney. Unclipping of this kidney caused a pronounced release of renomedullary depressor agents, explaining the rapid normalization of pressure seen after unclipping. This normalization of pressure masks a state of pronounced functional hypotension in a structurally still hypertensive cardiovascular system, characterized by marked splanchnic vasodilatation and a lack of neurogenic counter-regulation. Only when this state has lasted long enough to normalize the structural upward resettings, characteristic of hypertension does the cardiovascular system return to normal. Further, cross-circulation techniques have shown that the humoral antihypertensive agents suppress tonic sympathetic activity, thereby inhibiting normal reflex counter-regulation of their vasodilator effects. Presumably this occurs via both vagal cardiac afferents and central actions. Further, behavior and awareness become depressed during intense and prolonged renomedullary release. Finally, experiments for which a normotensive kidney is cross-circulated from a normotensive rat suggest that the humoral renomedullary antihypertensive system has its threshold of release set so low as to contribute to normal blood pressure regulation, presumably in reciprocal balance with the renocortical renin-angiotensin system. Stepwise pressure elevations increasingly enhance release of the depressor agents from the cross-perfused kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of the renal medulla and early treatment with enalapril upon the development of hypertension in young spontaneously hypertensive rats.

Objective: To investigate the role of the renal medulla in early hypertension in spontaneously hypertensive rats (SHR), and to explore whether the attenuated increase of pressure induced by enalapril treatment is affected by chemical medullectomy Design: Forty-four male SHR were studied from 5 to 18 weeks of age: 22 remained intact; 22 were medullectomized at 5.5 weeks of age with 2-bromoethylamine hydrobromide; 11 of each of these two groups were treated with enalapril from 6 to 12 weeks of age. Blood pressure, heart rate and body weight were recorded intermittently, and at 18 weeks renal function was also analysed Results: The results indicate a protective effect of the renal medulla against severe pressure rises in SHR, although even when enalapril also lowered blood pressure in medullectomized SHR, persistent improvements of glomerular filtration rate and renal flow conductance occurred only in intact SHR. Furthermore, after enalapril treatment ended blood pressure rose to higher levels in medullectomized SHR, despite greater sodium—water losses Conclusion: The renal medulla seems to exert a protective role both during and after enalapril treatment.

Neurogenic responses in resistance vessels: roles of alpha 1- and alpha 2-adrenoceptors, transmitter reuptake, ouabain, and plasma factors.

Experiments on the vasoconstrictor fiber control of isolated spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) resistance vessels, which is throughout more efficient in SHR, suggest that the presynaptic alpha 2-negative feedback mechanism and the reuptake pump are largely complementary in adjusting the effective transmitter concentrations in these narrow junctions, and first when both are blocked a marked leftward displacement of the nervous frequency-response curve ensues. Also, ouabain causes a marked leftward displacement of the frequency response curve in a way which suggests a considerable increase of transmitter release/impulse. Finally, normal rat plasma contains agent(s) which, even in very low concentrations, seems to cause a strong ouabain-like effect on the neurogenic responses. However, these various interferences with the neurogenic vascular effects influence SHR and WKY to largely equal extents, implying that the more efficient nervous control in SHR vessels is not merely due to an altered balance of the ordinary local mechanisms that influence the adrenergic transmitter release.

The Resistance Vasculature

In the same way that the relationships among voltage, current, and resistance in parallel-and series-coupled electric circuits used to be outlined in schematic diagrams according to Ohm’s law, similar principles are useful in visualizing the principal hemo dynamic events in the cardiovascular system, though here the related Poiseuille’s law prevails. When the events in the various ardiovascular compartments are so approached, the capillaries stand out as the obvious key feature, simply because the diffusion and iltration-absorption exchange across their walls fulfill the essential purpose of the circulatory system, i.e., the maintenance of an optimal milieu intmeur for the tissue cells. All other parts of the system, as well as the superimposed neurohormonal ontrol echanisms, finally serve to keep capillary flow, pressure, and perfused surface area well adjusted to the prevailing exchange needs in the various tissues. It is mainly when some of these must ransiently be given priority that centrally governed redistributions are induced between the parallel-coupled systemic circuits.

Physiological Approach to Future Developments in Therapy

Summary: First, the multifactorial background of primary hypertension is outlined in principle, where particular attention is given to the early, sometimes even genetically reinforced structural “upward resetting” of the cardiovascular system, which soon dominates hemodynamics in both human and rat hypertension. On this basis, it is then discussed which modes of action that antihypertensive treatment could best achieve regression of the structural changes in heart and vessels. Since both the luminal and wall changes can be affected in a different manner, and since the growth processes may be reinforced by both genetic and neurohormonal “trophic” influences, there are potentially many ways by which regression could be accomplished via specific interferences, apart from the blood pressure lowering per se. As to the “hemodynamic profile” of drug interferences, reasons are given for an approach where a systemic resistance vessel dilatation is combined with a mild damping of the &bgr;‐adrenergic sympathetic drive on the heart.

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