Toshiro Fujita

Effect of Indomethacin on Antihypertensive Action of Captopril in Hypertensive Patients

To evaluate the role of prostaglandin systems in mediating the response of blood pressure (BP) to the converting enzyme inhibitor, single dose of captopril, 100 mg, was administered orally in thirteen patients with essential hypertension, during three experimental periods: on a normal-sodium diet (150 mEq per day), on a low-sodium diet (30 mEq per day), and on a low-sodium diet following with indomethacin 150 mg daily for three days. During the normal-sodium and low-sodium periods, BP was significantly decreased after the administration of captopril, accompanied by a significant increase in urinary PGE2 excretion. With the indomethacin treatment, captopril-induced fall in BP was markedly inhibited, not associated with the apparent increase in urinary PGE2 excretion. The evidence presented suggests that antihypertensive effect of captopril may be due to overproduction of prostaglandin, in addition to a reduction in circulating angiotensin II. Moreover, the indomethacin-inhibiting effect of the fall in BP caused by captopril was more markedly exhibited in the renin-nonresponder subjects than the renin-responder subjects. These results suggest that the prostaglandin systems may play an important role in vasodepressor action of captopril in patients with essential hypertension, especially in a low-renin group.

The role of renal hemodynamics in the antihypertensive effect of captopril

To evaluate the role of regional hemodynamics in mediating the long-term depressor effect of the converting enzyme inhibitor, captopril, at a low dose (37.5 mg/day), for 2 weeks, its systemic, renal, and forearm circulatory actions were determined in 12 patients with mild to moderate essential hypertension. After administration of captopril, there was a significant decline in mean blood pressure (average -12.1 +/- 1.9%) accompanied by a decrease in systemic vascular resistance (-9.1 +/- 3.3%), but cardiac output did not change. Although forearm vascular resistance was not altered, renal vascular resistance decreased considerably (-17.1 +/- 5.0%). Moreover, there was a highly significant (r = 0.891) correlation between the changes in mean blood pressure and renal vascular resistance. Plasma renin activity increased after therapy as plasma aldosterone decreased, while plasma norepinephrine slightly increased. The change in renal vascular resistance significantly (r = -0.617) correlated with the pretreatment level of plasma renin activity. These findings suggest that suppression of the renin-angiotensin system in essential hypertension induces selective vasodilation in the renal vasculature, which may play an important role in the long-term antihypertensive effect of the converting enzyme inhibitor. This renal vasodilator action appears to be the feature that distinguishes the converting enzyme inhibitor from conventional vasodilator drugs.

Peripheral resistance and red cell LiNa countertransport in borderline hypertensives

We have studied ouabain-resistant, external sodium-stimulated, lithium efflux (Li-Na countertransport) in red blood cells from 21 borderline hypertensives with at least one hypertensive first degree relative (BH-F), 19 borderline hypertensives without family history of essential hypertension (BH-NF), and 35 age-matched normotensive subjects. The data indicate the finding of an increased Li-Na countertransport in all BH (F+NF), but with a significant overlap between BH values and control ones: Li-Na countertransport is significantly higher only in BH-F but it is normal in BH-NF. Moreover, there is a significant correlation of Li-Na countertransport to total peripheral resistance but not to mean blood pressure in all hypertensive patients. It is suggested that in BH the increase of erythrocyte Na flux is mediated by the Na-Na exchange diffusion, and its abnormality may be associated to the hereditary trait of essential hypertension rather than the high blood pressure per se, probably resulting in the development of hypertension, through the increased vascular smooth muscle tone.

Norepinephrine Responsiveness in Patients with Borderline Hypertension Under Three Different Sodium Balances

The pressor effects of intravenous norepinephrine (NE) infusion (100 and 200 ng/kg/min for 15 min) were examined in 17 patients with borderline hypertension (BHT) and 15 age-matched normotensive subjects (NT) under three different sodium balances; the regular customary diet, treatment with diuretics, and the high-sodium diet. Treatment with diuretics decreased and high sodium diet increased the pressor response to NE in both groups but there were no significant differences in NE reactivity between the groups. The increments in mean blood pressure after NE infusion (200 ng/kg/min) during the three experimental periods correlated significantly with the preinfusion plasma NE concentration in both BHT and NT: r = -0.58 (p less than 0.01) and r = -0.54 (p less than 0.01), respectively. Neither the slopes nor the intercepts differed between the two groups. Thus, evidence presented indicates that BHT do not have increased pressor responsiveness to NE, and that NE pressor response depends upon basal sympathetic tone.

Effects of angiotensin-converting enzyme inhibition on blood pressure and plasma renin activity in essential hypertension

Oral converting enzyme inhibitor SQ14225 was administered in 11 patients with essential hypertension, in order to investigate the role of the renin-angiotensin system in the regulation of blood pressure in essential hypertension. In the sodium-repleted state (150 mEq sodium intake for 6 days) in 11 patients, converting enzyme inhibitor decreased the average mean blood pressure from 113 +/- 2 to 106 +/- 2 mm Hg (p less than 0.001). Plasma renin activity increased with sodium depletion (30 mEq sodium intake for 3 days after furosemide treatment) from 1.26 +/- 0.07 to 3.26 +/- 0.48 ng/ml/hr (p less than 0.001). In the sodium-depleted state the hypotensive effect of SQ 14225 was more pronounced (mean blood pressure 108 +/- 2 to 93 +/- 3 mm Hg). The decrease in mean blood pressure caused by the inhibitor correlated to the basal plasma renin activity (r = -0.53, p less than 0.02, n = 22 measurements). The results indicate that the renin-angiotensin system participates in the regulation of blood pressure in essential hypertension, even in the sodium-repleted state. This role of the renin-angiotensin system in blood pressure regulation becomes more crucial during sodium depletion.

Increased urinary kallikrein excretion in young borderline hypertensive patients.

Urinary kallikrein excretion was measured in 46 young patients with borderline hypertension and 28 age-matched normotensive subjects. Hypertensives excreted greater amounts of kallikrein than normotensives (2.31 +/- 0.20 units/day vs. 1.56 +/- 0.17 units/day, p less than 0.01). Plasma renin activity (PRA) was also increased in hypertensives. Moreover, urinary kallikrein was increased in hypertensive patients with high PRA (PRA greater than or equal to mean + 1SEM in normotensives; n = 25) as compared to patients with normal PRA (PRA less than mean + 1SEM; n = 21). In hypertensives with normal PRA, urinary aldosterone correlated to urinary kallikrein (r = 0.478, p less than 0.05), as in normotensives (r = 0.451, p less than 0.02). But, no correlation was found in patients with high PRA. Therefore, the results of the present study do not confirm the hypothesis that the deficiency of the kallikrein-kinin system is the primary cause of hypertension. In hypertensives with high PRA, there may be abnormality of the interaction between the renin-angiotensin-aldosterone system and the kallikrein-kinin system, whereas it may be normal in hypertensives with normal PRA as well as normotensives.

Effect of indomethacin on responses to [sar1‐ileu8]‐angiotensin II

The role of prostaglandins in immediate and sustained pressor responses to [sar1‐ileu8]‐angiotensin II was studied, using indomethacin, in 12 patients with essential hypertension. Blood pressure rose within 1 to 2 min, peaked in 4 to 8 min, then fell gradually, but did not return to the baseline level, at the end of 30‐min infusion period of the angiotensin II analogue. After 2 days on indomethacin, both immediate and sustained diastolic pressure responses to the analogue (both, P < 0.01) rose when the basal plasma renin activity (PRA) fell (P < 0.05); this was associated with 56% suppression of urinary prostaglandin E excretion. Both the immediate and late phases of blood pressure response may be affected by indomethacin, probably not only because of greater availability of angiotensin receptors due to decreased endogenous angiotensin, but also because of alteration of end‐organ sensitivity to angiotensin II through inhibition of prostaglandin synthesis. This speculation is supported by the difference in slopes of the regression line relating change in diastolic blood pressure to basal PRA, indicating that there is less effect on controls for a given PRA level than on treated subjects.

Effects of Ketanserin on Systemic and Regional Haemodynamics in Patients with Essential Hypertension

Serotonin (5-hydroxytryptamine) has long been studied as a potent vasoactive agent. Because of its multiple and complex action on the cardiovascular system, however, its role in the pathogenesis and/ or maintenance of human essential hypertension has been controversial (Vanhoutte 1983). Recently, the first relatively specific Srserotonergic antagonist, ketanserin, has been introduced (Vanhoutte et at. 1983); it lowers blood pressure in hypertensive patients (Fagard et at. 1984; Van Nueten et at. 1987; Wenting et at. 1982, 1984; Woittiez et at. 1986). This antihypertensive effect of ketanserin may suggest a close relationship between serotonin and increased vascular resistance in essential hypertension, but its precise mode of action remains unclear (Robertson et at. 1987). Therefore, to clarify the role of serotonin in the pathophysiology of essential hypertension, the effects of ketanserin on systemic and regional circulation were investigated in 10 patients with mild to moderate essential hypertension.

Haemodynamic Changes Associated with Long Term Antihypertensive Therapy with Ketanserin

Ketanserin is a new serotonergic receptor-blocking agent which has specific inhibitory action on the serotonin S2-receptors (Leysen et al. 1981) but is devoid of partial agonistic properties. Experimental and clinical studies ofketanserin have been conducted in patients with pathological conditions in which serotonin is considered to playa role, and the efficacy and safety of the drug have been reported (Janssen 1983). The antihypertensive effect of ketanserin has been clearly demonstrated in both animals and humans (Wenting et al. 1984). The mechanism of action ofketanserin as an antihypertensive agent is complex and remains to be fully clarified, but there is a possibility that ketanserin acts synergistically at S2-serotonergic and (XI-adrenergic receptors to lower blood pressure. Another feature ofketanserin is that it does not have partial agonistic action on serotonin Sl-receptors or cause troublesome central nervous system side effects (Pettersson et al. 1985), which have been observed with conventional antiserotonin agents. Since increases in peripheral vascular resistance are often seen in patients with essential hypertension. the use of a drug with vasodilatory action is a desirable approach to correct some cardiodynamic abnormalities. This study examined the haemodynamic and endocrinological effects of administration of ketanserin for 12 weeks to ambulatory patients with essential hypertension. 1. Subjects and Methods