We conducted the present study to determine whether the angiotensin II type I receptor (AT1) gene might be implicated in human essential hypertension by using case-control and linkage studies. The entire coding and 3' untranslated regions of the AT1 receptor gene (2.2 kb) were amplified by polymerase chain reaction and submitted to single-strand conformation polymorphism in 60 hypertensive subjects with a familial susceptibility. We identified five polymorphisms (T573-->C, A1062-->G, A1166-->C, G1517-->T, and A1878-->G). However, no mutations that alter the encoded amino acid sequence were detected. A case-control study performed on white hypertensive (n = 206; blood pressure, 168 +/- 16/103 +/- 9 mm Hg) and normotensive (n = 298; blood pressure, 122 +/- 10/75 +/- 9 mm Hg) subjects using three of five polymorphisms showed a significant increase in allelic frequency of C1166 in hypertensive subjects (0.36 versus 0.28 for normotensive subjects, chi 2 = 6.8, P C, A1878-->G) were similar in both groups. We performed a linkage study using the affected sib pair method and a highly polymorphic marker of the AT1 receptor gene. There was no evidence for linkage in 267 sib pairs analyzed from 138 pedigrees. These findings would be compatible with a common variant of the AT1 receptor imparting a small effect on blood pressure; further studies will be needed to address this possibility.

Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension.

Of 78 comparative studies of plasma catecholamines in patients with essential hypertension and in normotensive controls, most reported higher catecholamine levels in the hypertensives, although only about 40% of the studies were positive (reporting statistically significant hypertensive-normotensive differences). Although there was dramatic variability in catecholamine values within and across studies, virtually all studies of norepinephrine in young, consistently hypertensive patients were positive. The likelihood that a study was positive with respect to norepinephrine was independent of the likelihood with respect to epinephrine, so that total catecholamine values, or else the sum of norepinephrine plus epinephrine, differentiated hypertensives from normotensives to a greater extent than levels of either substance alone. The preponderance of literature on the subject supports the hypothesis that increased plasma catecholamine concentrations occur in some patients with essential hypertension. Elevated plasma norepinephrine in relatively young, established hypertensive patients is consistent with a pathophysiologic role for increased sympathetic neural activity in this subgroup.

Plasma catecholamines and essential hypertension. An analytical review.

https://www.cell.com/cell-host-microbe/pdf/S1931-3128(14)00309-6.pdf

Discovery and Characterization of Gut Microbiota Decarboxylases that Can Produce the Neurotransmitter Tryptamine

The functional and morphologic characteristics of isolated subcutaneous resistance vessels (about 170 micron i.d.) from 15 untreated subjects with essential hypertension and 15 matched controls were examined. The vessels from the hypertensives had a 29% increase in the media-thickness-to-lumen-diameter ratio. The maximal force development to noradrenaline (NA) expressed as active pressure (an estimate of the pressure the vessels could have contracted against in vivo) was 30% higher in vessels from the hypertensives, while active media stress (force per square unit of smooth muscle) and sensitivity to NA was not significantly different. Increased active pressure, as well as unaltered active media stress and sensitivity, was seen for vasopressin, serotonin, angiotensin II, and K+. There was, however, an enhanced leftward shift of the NA sensitivity with cocaine (an inhibitor of the neuronal amine pump) in vessels from the hypertensives [pD2(+cocaine) and pD2(-cocaine) were 0.185 +/- 0.53) and 0.040 +/- 0.044, hypertensives and normotensives, respectively, p less than 0.05] suggesting an abnormality of presynaptic function in essential hypertension. Furthermore, the calcium sensitivity was depressed (pD2 was 4.197 +/- 0.050 and 4.381 +/- 0.068, hypertensives and normotensives, respectively, p less than 0.05), and the rate of relaxation was faster (p less than 0.05) in vessels from hypertensives, suggesting that excitation-contraction coupling might be depressed. The results suggest that the increased pressor response in essential hypertension can, to a large extent, be explained by altered vascular structure, while smooth muscle function is either unchanged or possibly depressed.

Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation--contraction coupling in isolated resistance vessels from essential hypertensives.

A variety of biochemical tests, most notably measurement of the plasma concentration of norepinephrine, have been used to quantify overall sympathetic nervous system activity in humans. Plasma norepinephrine values provide a fallible index of sympathetic activity in that they are dependent in part on the rate of removal of norepinephrine from plasma. Measurement of the rate of release of norepinephrine to plasma is a better guide to overall sympathetic nervous tone because it avoids this confounding influence of norepinephrine plasma clearance. The overall norepinephrine spillover measurement, however, suffers from one major limitation: the sources of the released norepinephrine are not identified. Recently developed radiotracer techniques allow the estimation of regional sympathetic nervous activity from measurements of the organ-specific norepinephrine spillover rate. We find that the lungs are the main source of norepinephrine release to plasma, with mean pulmonary norepinephrine spillover of 159 ng/min constituting 40% of total norepinephrine release. Pulmonary norepinephrine release exceeded the combined norepinephrine spillover from the heart (3%), kidneys (17%), and hepatomesenteric circulation (8%).

Measurement of total and organ-specific norepinephrine kinetics in humans

The role of various pressor factors and cardiovascular responsiveness to norepinephrine or angiotensin II in the pathogenesis of borderline hypertension was evaluated. Exchangeable body sodium, blood volume, plasma renin activity, norepinephrine or dopamine levels, and norepinephrine or epinephrine excretion rates were similar between 24 patients with borderline hypertension (mean age 34 +/- 4 (SEM) years and 22 normal subjects matched for age; the patients had a slight increase in supine plasma epinephrine. Pressor doses of norepinephrine or angiotensin II were significantly lower (p less than 0.01 and 0.001, respectively) in the borderline hypertensive group. These findings suggest that borderline hypertension may be maintained by inappropriately increased cardiovascular response to norepinephrine and angiotensin II in the presence of normal sympathetic and renin activity and a normal body sodium-volume state.

Pressor factors and cardiovascular pressor responsiveness in borderline hypertension.

The role of the adrenergic effector-response axis in the pathogenesis of essential hypertension and in the hypotensive mechanism of diuretic treatment was evaluated by combined analysis of plasma catecholamine levels and pressor sensitivity to norepinephrine (NE).Under placebo conditions, plasma NE, epinephrine and dopamine concentrations did not differ significantly between normal subjects and patients with borderline or established essential hypertension. The pressor dose (δ mean blood pressure + 20 mm Hg) of infused NE correlated positively (P < 0.05) with endogenous plasma NE; however, this relationship was shifted in hypertensive patients so that NE pressor dose at any basal plasma NE level tended to be decreased. Compared to normal subjects, NE pressor dose was decreased slightly (P <0.01) in borderline and markedly (P < 0.001) in established hypertension; it correlated inversely (P < 0.01) with basal blood pressure.Adrenergic neuronal blockage with debrisoquine decreased plasma NE by 50% in all thr...

Pathogenic and Therapeutic Significance of Cardiovascular Pressor Reactivity as Related to Plasma Catecholamines in Borderline and Established Essential Hypertension

Responses of blood pressure and plasma catecholamines to intravenous injection of tyramine at increasing dosage (30, 45, and 60 µg/kg, respectively) were evaluated in 25 normal subjects and 20 patients with mild essential hypertension. Basal plasma norepinephrine and epinephrine concentrations before tyramine injections were similar in the two groups. Following tyramine injection, plasma epinephrine was unchanged. Responses of plasma catecholamines and blood pressure to tyramine were similar in the two groups. Plasma norepinephrine increased significantly 2 min after a dose of 30 µg/kg, but higher tyramine doses failed to produce a further increase in plasma norepinephrine. In contrast, pressor responses to tyramine were dose-dependent. Maximal pressor responses were observed within 2 min after injection. These findings reveal a dissociation between changes in blood pressure and plasma norepinephrine following injection of tyramine. Lack of steady state may limit the value of tyramine bolus injections as a tool for the quantitation of pressor responsiveness to variations in endogenous sympathetic output. Alternatively, it is possible that the pressor effects of tyramine may be mediated at least in part by a norepinephrine independent mechanism.

Effects of tyramine on blood pressure and plasma catecholamines in normal and hypertensive subjects

The interrelationships among age, cardiovascular pressor reactivity to intravenously infused norepinephrine (NE) or angiotensin II, and endogenous plasma NE or renin (PRA) levels were evaluated in 31 normal subjects and 37 patients with essential hypertension. In normal subjects both angiotensin II pressor dose and PRA decreased progressively with aging. Angiotensin pressor dose correlated positively with PRA (r=0.41,P<0.025) and inversely with age (r=−0.46,P<0.02). NE pressor dose and basal plasma NE were also positively correlated (r=0.53,P<0.005), but the two factors remained largely unchanged with aging. Findings in essential hypertension differed in certain aspects. Angiotensin II pressor dose did not correlate with either basal PRA or age; and pressor doses of NE and angiotensin II tended to be lower in some patients than in normal subjects. These findings indicate that aging is accompanied by a physiologic increase in cardiovascular reactivity to angiotensin II, probably due to a concomitant decrease in circulating renin. The dissociation between angiotensin pressor dose and PRA in essential hypertension suggests an interference from an other factor.

Age-related profile of cardiovascular reactivity to norepinephrine and angiotensin II in normal and hypertensive man

Bei 11 Patienten mit therapierefraktarer Hypertonie wurden die blutdrucksenkende Wirksamkeit und unerwunschte Nebenwirkungen einer peroralen Behandlung mit den beiden starken Vasodilatatoren Diazoxid und Minoxidil verglichen. Alle Patienten hatten vorausgehend mit ihrem Blutdruck ungenugend auf eine Kombinationstherapie mit Diuretika, Betablockern und/oder Sympatholytika, sowie Dihydralazin oder Prazosin angesprochen. Die beiden letzteren Substanzen wurden deshalb abgesetzt und durch Diazoxid oder Minoxidil ersetzt. Bei neun Patienten ging die Diazoxidbehandlung der Minoxidiltherapie voraus, wahrend bei 2 Patienten Minoxidil zuerst verabreicht wurde. Vor dem Einsatz der potenten Vasodilatatoren betrug der Blutdruck im Mittel 181/107 mm Hg liegend und 161/103 mm Hg stehend. Orales Diazoxid (mediane Dosis 400 mg/Tag) und Minoxidil (mediane Dosis 17,5 mg/Tag) senkten (P<0,02) den mittleren Blutdruck im Liegen (−15% fur beide Medikamente) und im Stehen (−11% gegenuber −12%) vergleichbar. Sie bewirkten eine Tendenz zu Natrium-Wasser-Retention und Gewichtszunahme, welche jedoch, auser bei einem Patienten, durch Intensivierung der Diuretikatherapie korrigiert werden konnte. Eine Hypertrichose kam unter beiden Medikamenten vor, war jedoch unter Diazoxid eher etwas weniger ausgepragt. Das Elektrokardiogramm blieb meist unverandert. Die Plasmaglukose stieg unter Diazoxid bei 6 Patienten an, bei 2 kam es zu schweren Hyperglykamien. Wegen der hyperglykamischen Wirkung muste die Diazoxidtherapie bei 4 Patienten abgebrochen werden. Diese Untersuchungen zeigen, das die antihypertensive Wirksamkeit und die meisten Nebenwirkungen von oralem Diazoxid und Minoxidil weitgehend vergleichbar sind; der hyperglykamische Effekt von Diazoxid durfte jedoch den Einsatz dieser Substanz einschranken.

I. Minder

Papers

Pressor factors and cardiovascular pressor responsiveness in borderline hypertension.

Pathogenic and Therapeutic Significance of Cardiovascular Pressor Reactivity as Related to Plasma Catecholamines in Borderline and Established Essential Hypertension

Effects of tyramine on blood pressure and plasma catecholamines in normal and hypertensive subjects

Age-related profile of cardiovascular reactivity to norepinephrine and angiotensin II in normal and hypertensive man

Comparison of oral diazoxide and minoxidil in refractory hypertension