Stimulation of renin by blockade of alpha 2-adrenoceptors in man: role of the beta 1-adrenoceptor.

Previous experiments have shown that blockade of intrarenal alpha 2-adrenoceptors will cause a rise in renin secretion. Therefore, we designed the present study to explore whether this could be due to noradrenaline being released by a prejunctional mechanism and stimulating post-junctional beta 1-adrenoceptors. Two groups of patients in whom diagnostic renal angiography was indicated were studied before administration of contrast material. None of the patients had taken any antihypertensive medication in the 3 weeks preceding this investigation. In group I (n = 8) glucose was infused into the renal artery for 20 min; during the last 10 min yohimbine was also infused at a rate of 3 micrograms/kg per min. In group II (n = 8) the same protocol was carried out with the exception that, instead of glucose, we infused atenolol in a dose of 1 micrograms/kg per min. Blood samples for noradrenaline and renin were taken before infusions started, following 10 min of the glucose (or atenolol) and at the end of the yohimbine infusion. At the same time blood pressure and renal blood flow (133Xe-washout) were measured. The results show that yohimbine increased renin release by 310 +/- 60% in group I, but by only 80 +/- 45% in group II (P less than 0.01). However, noradrenaline 'release' was stimulated to the same degree in both groups (150 +/- 80 versus 138 +/- 75%; NS) During the experiments blood pressure and heart rate did not change. The data are consistent with the hypothesis that the effect of alpha 2-adrenoceptors on renin release is mediated by beta-adrenoceptors. Thus, the relevant alpha 2-receptor may be located prejunctionally.

Role of alpha 1- and alpha 2-adrenergic receptors in the human hypertensive kidney.

Since it is not known for certain which alpha-adrenergic receptors mediate renal vasoconstriction in human essential hypertension, we infused either doxazosin (n = 7) or yohimbine (n = 7) into the renal arteries of hypertensive subjects immediately prior to diagnostic angiography. Both agents caused an increment in renal blood flow as assessed with the xenon-washout technique. Doxazosin increased renal flow from 342 +/- 36 to 360 +/- 55 ml/min per 100 g (0.05 less than p less than 0.10). Yohimbine enhanced flow from 380 +/- 41 to 485 +/- 63 ml/min per 100 g (p less than 0.01). The effect of yohimbine was significantly greater than that of doxazosin. In a control group (n = 7) receiving only saline, no changes in renal blood flow occurred. Doxazosin enhanced renin secretion in the kidney by 10 +/- 4% over levels in controls (0.05 less than p less than 0.10), whereas yohimbine increased renin release by 80 +/- 23% (p less than 0.01). The latter increase was apparently not due to alterations in flow alone, since the arteriovenous gradient for renin also widened. We conclude that in resting conditions, neurogenic vascular tone in the kidney depends mainly upon activation of alpha 2-adrenergic receptors. Moreover, these receptors exert a tonic inhibitory influence on renin release.

Acute renal effects of doxazosin in man.

To evaluate the role of alpha 1-adrenoceptors in the regulation of renal blood flow and renin secretion, we infused doxazosin in incremental doses (group I, n = 5) or at a fixed rate of 1 microgram kg-1 min-1 (group II, n = 6) into the renal artery of hypertensive patients just prior to diagnostic renal angiography. In group I, stepwise increasing doses of doxazosin were associated with increases in renal perfusion and, at doses above 1 microgram kg-1 min-1, also with a fall in blood pressure. Compared with observations in control subjects, doxazosin enhanced renal renin release at rest but did not modify the renin response to isometric exercise in group II. alpha 1-Adrenoceptors are involved in causing renal vasoconstriction and inhibition of renin secretion. However, the latter is only of importance in resting subjects.

Effect of sympathetic stimulation and intrarenal alpha-blockade on the secretion of renin by the human kidney.

This study was initiated to explore the possible involvement of renal alpha-adrenoceptors in the regulation of active and inactive renin. In fifteen hypertensive patients who proved not to have vascular abnormalities on diagnostic renal arteriography, blood samples were collected simultaneously from the renal artery and vein before and during an intrarenal infusion of either saline (n = 5), or the alpha-1 blocker doxazosin (n = 5) or the non-selective alpha-1 blocker doxazosin (n = 5) or the non-selective alpha-blocker phentolamine (n = 5). Subsequently, responses of renal blood flow and renin secretion were assessed following 3 min of handgrip exercise. In none of the experiments secretion of inactive renin could be detected. Release of active renin increased from 580 (SEM 170) to 650 (SEM 220) microU min-1 (100 g)-1 during infusion of doxazosin (P less than 0.05) and from 760 (SEM 100) to 1000 (SEM 340) microU min-1 (100 g)-1 during infusion of phentolamine (P less than 0.01). Saline infusion had no effect on secretion of active renin. While handgrip exercise had no significant effect on active renin secretion in the saline and in the doxazosin group, it enhanced secretion from 1000 (SEM 340) to 1280 (SEM 390) microU min-1 (100 g)-1 in the phentolamine group (P less than 0.01). The results indicate that mainly alpha-2 adrenoceptors exert an inhibitory effect on release of active renin, although alpha-1 receptors participate to some degree. There is no evidence that the kidney secretes inactive renin.

Blood platelets and angiotensin II.

To investigate whether human blood platelets contain angiotensin II, platelets were isolated from platelet-rich plasma and resuspended in buffer solution. No angiotensin was detectable by radio-immunoassay in this suspension. However, after sonification all samples appeared to contain significant amounts of angiotensin II. This amount was not reduced by the addition of angiotensinase inhibitors, thus ruling out an assay artefact due to breakdown of tracer. Subsequent experiments showed that the immunoreactive material behaved similarly to standard angiotensin II in several respects.

Humoral changes during and following coronary bypass surgery: relationship to postoperative blood pressure.

In this study we investigated the role of the renin-angiotensin system and the adrenergic system in the hypertensive response during and following coronary bypass surgery. Arterial blood samples for measurement of active renin, angiotensin II, aldosterone and catecholamines were drawn before, during and in the first period after coronary artery grafting. Both noradrenaline and adrenaline rose significantly during extracorporeal circulation and remained elevated afterwards, the rise in adrenaline preceding that of noradrenaline. During cardiopulmonary bypass renin also increased while angiotensin II increased after an initial fall. Postoperatively, renin tended to return to control levels. However, angiotensin II fell in some patients but remained elevated in others. The latter group had significantly lower blood pressure during cardiopulmonary bypass, but higher pressure thereafter. Aldosterone levels were markedly reduced during cardiopulmonary bypass. The results suggest that low pressure during extracorporeal circulation may trigger enhanced formation of angiotensin II, apparently involving extrapulmonary converting enzyme. This mechanism may, when acting in concert with an activated sympathetic nervous system, produce significant blood pressure elevation postoperatively.

Effect of sympathetic stimulation on inactive renin.

In the present study we investigated the effect of three manoeuvres known to be associated with enhanced sympathetic activity on plasma levels of active and inactive renin. To this end, active and trypsin-activatable renin were measured in blood drawn from 12 untreated essential hypertensive patients before, during and after any of the following tests: isometric exercise (handgrip), noise stimulation and 45 degrees head-up tilt. These studies were repeated after the patients had been treated with either atenolol (n = 6) or SL 77499 (n = 6), an alpha-1 adrenoceptor blocking agent for 10 days. The results indicate that active and inactive renin often change in an unpredictable way in response to sympathetic stimulation. There are, as yet, no conclusive explanations which describe the behaviour of both forms of renin during these manoeuvres.