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J Genest

Publications and source records attributed to J Genest.

537 records · Page 30Linked to original sources
PubMedDate not supplied

Effects of tonin, an angiotensin II-forming enzyme, on vascular smooth muscle in the normal rabbit.

Tonin is an enzyme of the serine protease family present in different rat tissues which releases angiotensin II (AII) directly from angiotensinogen and the tetradecapeptide renin substrate and from angiotensin I (AI). Tonin potentiates the effect of norepinephrine (NE) in the rat mesenteric artery preparation and in the aortic strips from normal and hypertensive rats. In rabbit aortic and mesenteric artery strips tonin potentiates the effect of NE, almost doubling its response. A similar effect was observed on the KCl and AII-induced contraction. This tonin-induced potentiation is reversible and long-lasting, persisting for 1 to 2 hours after being added into the tissue bath. In 75% of the vascular strips assayed, tonin elicited a contraction with a short latency period and with a maximum tension ranging from a few milligrams to over 1 g. To clarify the mechanisms of tonin effect on vascular smooth muscle, a variety of agents have been used. Neither indomethacin, saralasin, nor alpha- or beta-adrenergic blockers changed the direct contraction or the potentiation induced to NE. Db-cAMP and theophylline blocked the potentiation to the response to NE. A Ca2+-free medium, La3+, and verapamil produced a 75% inhibition of the direct tonin-induced contraction. Papaverine, isoproterenol, and theophylline relaxed the same contraction. Enzymatic inactivation of tonin blocked completely the direct contraction but not the potentiation to NE. These experiments suggest that the vasoactive effect of tonin may be mediated by the release of intracellular-bound calcium, an effect dependent on a proteolytic effect of tonin, and by increasing the cellular permeability to calcium, which is not of a proteolytic effect. It is suggested that tonin remains attached to the vascular strips by mechanisms as yet not clarified.

Angiotensin II↗
PubMedDate not supplied

Unconjugated hyperepinephrinemia: a hallmark of hypertension imitating pheochromocytoma?

Hypertensive patients with elevated and hyperresponsive plasma norepinephrine and epinephrine (NE + E) associated with low conjugated NE + E were previously identified by determination of the sum of NE + E. Because of their excessive E but not NE responses to glucagon and also hypertension corresponding to E excess, we explored whether an elevated unconjugated E resulting from a selective E conjugation defect could be obscured by the sum of NE + E. We found that nine patients with elevated E (reflected by the normal 4:1 ratio of plasma NE to E reversed in favor of E), had, when compared to 31 patients with plasma NE exceeding E:1) lower plasma conjugated E (mean 0.03 vs 0.27 ng/ml, p less than 0.01), lower degree of E conjugation (8 vs 51%, p less than 0.01), and a higher maximum systolic (p less than 0.05), pulse pressure (p less than 0.02) and higher pulse rates (p less than 0.04), but no differences in the unconjugated and conjugated proportions of plasma NE; and 2) an absence of conjugated E throughout the circulation and relative preponderance of E over NE at sampling points close to the peripheral venous blood (p less than 0.05). The absolutely and relatively decreased plasma conjugated E in patients with E exceeding NE (without difference in conjugated NE) is a preliminary indication that a selective sulfoconjugating defect of E results in plasma E higher than NE in accordance with the hyper-beta-adrenergic features of their hypertension. Epinephrine, a circulating hormone, is more dependent on conjugated E reflect better this defect than those measuring the sum of NE and E.

Adolescent↗
PubMedDate not supplied

Effects of tonin on the adrenal secretion in the rat.

Tonin infused intravenously at a rate of 12 micron g/kg/min for 2 hours stimulated aldosterone and corticosterone secretion in conscious rats. In pentobarbital-anesthetized rats treated with dexamethasone and morphine, tonin stimulated aldosterone secretion, but corticosterone was unaffected. Tonin did not stimulate steroidogenesis in isolated rat adrenal glomerulosa cells unless substrate, in the form of "stripped" rat plasma, was added, in which case large amounts of immunoreactive angiotensin II were generated. These results suggest that tonin may generate an angiotensin peptide in vivo, which in turn stimulates aldosterone secretion. ACTH is secreted in response to tonin infusion, and contributes to the adrenal response.

Adrenal Glands↗
PubMedDate not supplied

Dopamine surges in hyperadrenergic essential hypertension.

From a total of 61 referred hypertensive patients, 21 were clinically suspected of pheochromocytoma but in none was this diagnosis confirmed. Instead we found nine of the 21 patients had surges of conjugated dopamine during hyperadrenergic periods unaccounted for by rise in norepinephrine (NE) or epinephrine (E). Overall, essential hypertensive (EH) patients had in plasma (ng/ml) higher conjugated dopamine (DA) (2.3 +/- 0.2 vs 1.0 +/- 0.1, p less than 0.01), increasing with age (p less than 0.01), lower conjugated NE + E (0.6 +/- 0.1 vs 1.2 +/- 0.2, p less than 0.01), and higher free E (p less than 0.007), lower urinary free DA and total DA but higher free NE + E excretions (each p less than 0.05) than 24 control subjects. Following the DA surges, a short-lived urinary overflow of total DA occurred. The patients with DA surges were older, had a higher incidence of low conjugated NE + E (less than 0.23 ng/ml), a higher proportion of arterial free DA, and higher venous baseline conjugated plasma DA than the rest of the patients. Patients with low conjugated NE + E had in turn higher plasma DA concentrations at several regional sampling sites than patients with normal conjugated NE + E. High conjugated DA in EH probably results from pulsatile DA surges leading to a rise of baseline plasma conjugated DA. In the short run DA pulses can result in temporary alpha- and beta-adrenergic actions of huge arterial free DA concentrations prior to DA conjugation; in the long run the excessive high affinity DA conjugation may take preference to the lower affinity NE and lowest affinity E conjugation and free E increases. Both result in an acute or chronic increase of sympathetic tone.

Adolescent↗
PubMedDate not supplied

Atrial natriuretic factor. Characterization and partial purification.

One of the main differences between atrial and ventricular cardiocytes is the presence in former of specific granules with morphological characteristics very similar to secretory granules found in peptide-secreting endocrine cells. It has been suggested that these granules are the storage place for the atrial natriuretic factor. In the rat, water deprivation produces an increase in atrial granularity but a significant decrease in acid-extractable diuretic and natriuretic activity, suggesting that the number of atrial specific granules does not necessarily represent natriuretic activity. The atrial natriuretic factor activity is destroyed by incubation with several proteases and does not inhibit the sodium-potassium ATPase, suggesting that the active substance is a small peptide that is probably different from the so-called natriuretic hormone. After a series of chromatographic steps in Sep-Pak cartridges, Bio-Gel P-10, CM Bio-Gel, and Mono S columns, the specific activity of the atrial natriuretic factor was increased from 193, corresponding to atrial homogenates, to 242,000, which corresponds to the last chromatographic step representing a 1250-fold purification. This material showed a potent natriuretic activity, as 10 picomoles increased natriuresis by 100%.

Animals↗
PubMedDate not supplied

Vascular angiotensin II receptors in renal and DOCA-salt hypertensive rats.

To determine the contribution of receptor number and affinity to changes in vascular reactivity to angiotensin II (AII) in hypertensive rats, we have investigated the binding of 125I-AII to a particulate fraction of the rat mesenteric artery of hypertensive rats. In two-kidney, one clip hypertensive rats, receptor concentration (Bmax) was 83 +/- 13 fmol/mg and the dissociation constant (Kd) 0.6 +/- 0.1 nM vs 75 +/- 5.3 fmol/mg and 0.6 +/- 0.1 nM in normotensive controls, although PRA was much higher in the former. Bmax was reduced in these hypertensive rats after sodium depletion, as in normal rats. One-kidney, one clip hypertensive rats (Bmax 88 +/- 17 fmol/mg, Kd 0.6 +/- 0.1 nM) did not differ from uninephrectomized control rats (96 +/- 9 fmol/mg, Kd 0.5 +/- 0.1 nM). In DOCA-salt hypertensive rats, binding capacity was increased (125 +/- 2 fmol/mg, Kd 0.7 +/- 0.0 nM) vs uninephrectomized salt-loaded rats (Bmax 95 +/- 6 fmol/mg, Kd 0.6 +/- 0.1 nM), although PRA was suppressed comparably in both groups. The salt-loaded rats did not differ from uninephrectomized controls drinking water. We conclude that changes in the circulating renin-angiotensin system do not explain all the variations in receptor number in hypertensive rats. Our results suggest a role of mineralocorticoids in the regulation of vascular AII receptors.

Aldosterone↗
PubMedDate not supplied

Regional sources of free and sulfoconjugated catecholamines in hypertension.

To elucidate the sources of free catecholamines (CA) and their sulfates in hyperadrenergic essential hypertensives (EH), their arteriovenous differences were determined radioenzymatically and by sulfatase hydrolysis (with correction for cross-contamination) across several organs and regions in 16 hyperadrenergic essential hypertensive patients. Comparison with arterial concentrations showed that: the adrenal venous outflow contains 240 times more free epinephrine (E), 55 times more free norepinephrine (NE), and 7 times more free dopamine (DA) concentrations, but E, NE, and DA sulfates are not different; free E concentrations are lower in the peripheral venous blood; NE sulfate concentrations are higher in the superior vena cava (p less than 0.05 for all differences noted). The data suggest the following conclusions for hyperadrenergic EH patients: with the exception of NE sulfate added into the superior vena cava region, no other organ or region can be associated with a net DA or NE sulfate release. The proportional adrenal vein concentrations of DA:NE:E are approximately 1:10:50, which are very close to those seen in other studies performed under different degrees of stress. Free E is extracted in peripheral tissues. The DA surges in hyperadrenergic EH patients probably result from the pulsatile, predominantly adrenal, release of free DA.

Arteries↗
PubMedDate not supplied

Vascular angiotensin II receptors in SHR.

We investigated the density (Bmax) of angiotensin II (ANG II) receptors in the mesenteric vascular bed of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats. In 12-week-old SHR, the Bmax and the dissociation constant (Kd) of ANG II binding sites were not different from those of WKY rats in the sodium replete state or after sodium depletion. In prehypertensive (4- and 6-week-old) SHR, the Bmax of the vascular ANG II receptors was significantly higher (p less than 0.05) than in age-matched WKY rats. This result could not be attributed entirely to differences in the circulating renin-angiotensin-aldosterone system in 4-week-old-rats. In 6-week-old WKY rats, the plasma renin activity was significantly higher (p less than 0.05), which may account in part for the higher density of ANG II binding sites in SHR. There was an age-related decrease in the number of ANG II receptors in SHR. The increased density of vascular ANG II receptors in young SHR may play a role in the development of high blood pressure in this model of spontaneous hypertension. The higher number of ANG II binding sites in young SHR is not selective for ANG II receptors, since an increased density of alpha 1-adrenergic receptors was also found in the mesenteric arteries of 4-week-old SHR.

Aldosterone↗
PubMedDate not supplied

Relative roles of sodium and calcium ions in the steroidogenic response of isolated rate adrenal glomerulosa cells.

To study the relative roles of sodium (Na+) and calcium ions (Ca2+) in the response of adrenal glomerulosa cells, we investigated the effects of different Na+ concentrations in the incubation media and the actions of substances that interfere with Ca2+ fluxes. Basal aldosterone secretion and response to angiotensin II (AII), adrenocorticotropic hormone (ACTH), or potassium (K+) were dependent on extracellular Na+ concentration. Veratridine, a Na+ channel opener that dissipates Na+ gradients, blocked the stimulated steroidogenic response. Mersalyl acid and tetracaine, which are potent Ca2+ antagonists, blocked the effects of aldosterone secretagogues. Divalent cations with Ca2+ antagonistic action such as manganese M(n2+), nickel (Ni2+), and cobalt (Co2+) blocked the aldosterone secretory response to AII, ACTH, and K+. Barium (Ba2+) and strontium (Sr2+), known to mimick Ca2+ effects, increased or did not affect responses of the glomerulosa cells. Sodium vanadate, an inhibitor of ATP-dependent Ca2+ translocation, did not alter the stimulated aldosterone responses. Trifluoperazine (10(-6) M), an inhibitor of calmodulin, blocked AII and K+-induced aldosterone secretion, but was partially effective on ACTH-stimulated aldosterone output only at a concentration of 10(-5) M. The actions of ouabain on aldosterone biosynthesis were similarly affected by all these drugs. Thus, both extracellular Na+ and Ca2+ appear to play a role in the steroidogenic response of isolated glomerulosa cells. The intracellular action of Ca2+ may involve a calmodulin-like protein. The effects of ACTH are only partially dependent on Ca2+ as a second intracellular messenger.

Adrenal Cortex↗