The metabolism of phosphoinositides, a class of membrane lipids that appears to be intimately involved in the regulation by the membrane of the intracellular Ca2+ level, has been reported to be modified in the erythrocyte of the spontaneously hypertensive rat (SHR and SHR/SP). In order to elucidate the link between the phosphoinositide alteration and hypertension, the metabolism of phosphoinositides was studied in human essential hypertension and in Sabra rats under various patho-physiological conditions. Experiments were performed in vitro on isolated ghost membranes by measuring the radioactivity incorporated into triphosphoinositides (PI-P2) and diphosphoinositides (PI-P) following the incubation of membranes with [gamma 32P]-ATP. 32P-PI-P2, in moderate untreated essential hypertensive controls (n = 31) was higher than in normotensives (n = 30) (1.18 +/- 0.06 vs 0.92 +/- 0.04, 32P nmol/15 min/mg prot, p less than 0.005); 32P-PI-P2 and 32P-PI-P in hypertensive patients treated with beta-blocking agents (n = 20) did not differ from the values observed in untreated hypertensives. In Sabra rats, 32P-PI-P2 values were 0.79 +/- 0.03 and 1.32 +/- 0.08 for SbN and SbH, respectively (8-11 animals per group); difference was significant. 32P-PI-P values varied similarly. Both 32P-PI-P2 and 32P-PI-P did not change significantly when animals were fed a high sodium diet or were injected with DOCA, though such treatments rose the blood pressure. Our data indicate that the modification of phosphoinositide metabolism that we observed both in rat and human hypertension is not a consequence of the blood pressure elevation, but may be considered as an intrinsic membrane defect. Changes in the phosphoinositide metabolism may therefore be associated with the functional and structural alterations concerning the transmembrane Na+ and Ca2+ fluxes which may be of pathogenic importance.

A heat-stable, low molecular weight, anionic substance(s) capable of inhibiting 3H-ouabain binding and Na+-K+-ATPase activity could be extracted from human urine and plasma. The level of the inhibitor was elevated in 40%-50% of essential hypertensives, compared to controls, and also in some of the offspring of hypertensive parents. Higher levels of the inhibitor were measured in patients treated with beta-blocking agents than in those treated with diuretics. The inhibitor extracted from plasma also appeared capable of (1) inhibiting the uptake of serotonin in human platelets, an Na+-dependent mechanism, and (2) inducing an increase in blood pressure when injected intracerebroventricularly. From these various data, we propose that the increase in the endogenous inhibitor may play a role in essential hypertension and may modulate, at least partially, some of the various cell functions that depend on a transmembrane Na+ gradient, including cellular excitability.

Ten normotensive patients including 5 parkinsonian and 5 dystonic patients received 3 mg piribedil intravenously over a 15 min period. This dopamine receptor agonist rapidly induced a fall in blood pressure together with a simultaneous reduction in heart rate and temperature. No change was observed when patients (four) were pretreated with a dopamine receptor blocking agent, haloperidol. It is concluded that acute dopamine receptor stimulation leads to a decrease in blood pressure. The hypotension could be centrally-mediated since the hypothermia, considered to be central in origin, parallels the blood pressure and heart rate changes.

The presence in plasma extracts of a sodium pump inhibitor with digitalis-like properties was investigated by two complementary tests: decrease in the affinity of ouabain binding to human red blood cells and inhibition of Na+,K+-ATPase. The results of the two methods were correlated (r = 0.76, n = 44, p less than 0.01), suggesting that the same factor may be responsible for both effects. All subjects with elevated values were hypertensive or normotensive and had a family history of hypertension. Forty percent of the subjects in these two groups had high inhibition values. The elevation was significant (p less than 0.01) when compared with values in normotensive subjects with no hypertensive heredity. Increased inhibition was observed in patients taking beta-blocking agents; conversely, diuretics normalized the values. No correlation was found between pump inhibition and age, sex, blood pressure, levels of plasma K+ or Na+, or plasma renin activity. These data show the existence of a sodium pump inhibitor in the plasma of some subjects and point to a possible association with hypertension. They also underline the importance of genetic background and the heterogeneity of essential hypertension.

The presence of circulating Na+ pump inhibitors was investigated in hypertensive subjects using inhibition of ouabain binding to the pump and of Na+, K+-ATPase activity as tests. Plasma extracts from nearly half the normotensive subjects who were offspring of hypertensive parents as well as the essential hypertensive subjects were potent inhibitors. Three fractions, extracted from plasma, exhibited ouabain-like properties concerning competition for binding, inhibition of the Na+, K+-ATPase and of Na+-dependent serotonin uptake by platelets. When injected intracerebroventricularly, one of these fractions also induces a rise in blood pressure, as does ouabain. These results demonstrate the presence in some plasma of digitalis-like substances.

[D-ala2]-met-enkephalinamide injected intracisternally in anaesthetized rats induced a centrally-mediated increase in blood pressure. The pressor response appeared to be due to activation of opiate receptors and mediated through the sympathetic nervous system. The hypotension observed with high doses may be induced by the respiratory depression. The intracisternal injection of an antagonist of opioid compounds (diprenorphine) caused a similar blood pressure decrease in spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto rats (WKY). Our data suggest a central pressor effect of enkephalins in anaesthetized rats. This represents an important argument concerning a role of endogenous opioids in blood pressure control but suggests that brain stem endogenous opioids may not be involved in the mechanism of hypertension.

Opioid compounds injected intracisternally in rats induce a centrally-mediated increase in blood pressure. In the present study, the intracisternal injection of an antagonist of opioid compounds, diprenorphine was examined. Diprenorphine caused a similar blood pressure decrease in spontaneously hypertensive rats and normotensive control Wistar Kyoto rats both in young and adult animals. This represents an important argument concerning a role of endogenous opioids in blood pressure control in anaesthetized rats but suggests that brain stem endogenous opioids may not be involved in the mechanism of hypertension.

The advantages of this technique are rapidity (performed in less than twenty minutes), reproductibilitky, and low cost. Chemical manipulation of plasma is unnecessary to diagnose phaeochromocytoma as shown in two examples. We propose therefore introduction of this technique in clinical investigation of hypertensive patients.

The cardiovascular effects of morphine, fentanyl, [d‐Ala2]‐met‐enkephalinamide were analyzed after intracisternal injection in anaesthetized rats. Pao2 was measured as an index of respiratory function. At low doses in spontaneously breathing rats, morphine, fentanyl and [d‐Ala2]‐met‐enkephalinamide induced a pressor response with slight tachycardia and no significant change in Pao2. The pressor response appeared to be due to activation of opiate receptors and mediated through the sympathetic nervous system. High doses of morphine and [d‐Ala2]‐met‐enkephalinamide induced a biphasic effect with a secondary hypotension associated with bradycardia in spontaneously breathing rats. A marked reduction in Pao2 was found during the depressor phase. High doses of [d‐Ala2]‐met‐enkephalinamide produced only a pressor response in artificially‐ventilated rats with no signs of secondary hypotension. Our data support the idea that morphinomimetic agents are centrally pressor at low doses in the rat. The respiratory depression observed with high doses may be the cause of hypotension.

Publisher Summary This chapter discusses two aspects of angiotensin on the central nervous system—namely, thirst and the neurogenic pressor response, together with a consideration of what is known about involvement of the cerebral renin–angiotensin system in these responses. It has been reported that intracranial injection of the angiotensin antagonist Sar 1 , A1a 1 -AII causes a fall in arterial blood pressure. In the experiments presented in the chapter, neither Sar 1 , Ile 8 -AII nor Sar 1 , Thr 8 -AII injected into the brain caused a drop in femoral arterial pressure in conscious normotensive or spontaneously hypertensive rats of the Okamoto strain. On the other hand, AII was dipsogenic and pressor in these rats. The lack of a hypotensive effect of intracranially applied blockers suggests that cerebral isorenin contributes neither to the maintenance of vascular tone nor to the development of spontaneous hypertension. The regions of the brain most sensitive to the action of blood-borne and intracranial AII are vascularized periventricular structures lying outside the blood-brain barrier. Injection of vasoplegics, such as papaverine, NaNO 2 , sodium nitroprusside or prostaglandin E 2 into the subfornical organ or the organum vasculosum of the lamina terminalis blocked the dipsogenic action of AII injected through the same cannula. The effect of these substances on the AII pressor response is not known. Antagonism of AII by substances known to relax vascular smooth muscle supports the hypothesis that AII acts by altering stretch receptor discharge from these special cavernous structures.

1. Injections of antagonists of angiotensin II into the cerebral ventricles of normotensive and spontaneously hypertensive rats were performed in order to assess the role of the isorenin-angiotensin system in the brain. 2. No hypotensive effect was obtained in either normotensive or hypertensive rats, suggesting that intracranial isoangiotensin has little role in the pathogenesis of spontaneous hypertension in the rat.

This chapter discusses the role of the brain–iso–renin–angiotensin system in the pathogenesis of hypertension in spontaneous hypertensive rats (SHR). It has been found that immunoreactive angiotensin II (AII) concentrations in cerebrospinal fluid (CSF) are higher in SH rats than in normotensive rats. The A II present in the CSF reflects a cerebral synthesis as radioactive A II when injected intravenously is found only as fragments in the CSF. In normotensive rats, a hypertensive effect of A II injected into the lateral ventricle. It is possible then that high A II concentrations in CSF have a pathogenic role in hypertension of SHR. In a study described in the chapter, the role the of cerebral A II was investigated by administration of acute variations in arterial blood pressure resulting from intracerebral administration of competitive antagonists of A II in conscious rats. An angiotensin antagonist injected into the cerebral ventricles of SHR caused a significant drop in blood pressure. However, such an injection had no effect in normotensive animals. The importance of this finding has intimated to repeat a similar investigation on a larger series of animals.