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Biomedical subjects

I Gavras

Publications and source records attributed to I Gavras.

At least 109 records · Page 6Linked to original sources
PubMed1986

Enalaprilat in hypertensive emergencies.

Enalaprilat (MK-422), an intravenously administered angiotensin-converting enzyme inhibitor, which is the parent compound of the oral angiotensin-converting enzyme inhibitor enalapril (MK-421), was studied in 11 patients with asymptomatic accelerated hypertension. Each patient received an initial intravenous dose of 1 mg, followed at one-hour intervals by enalaprilat 10 mg, furosemide 40 mg, and enalaprilat 40 mg. Six of 11 patients responded with a drop in mean arterial pressure greater than 15 mm Hg to diastolic levels below 110 mm Hg; there were four partial responders and one nonresponder. Pretreatment renins were not predictive of blood pressure response. No patient had any adverse reaction to the drug; there were no significant changes in posttreatment laboratory values. We conclude that enalaprilat is an effective, well-tolerated agent for the treatment of uncomplicated accelerated hypertension and its use does not imperil nonresponding uncomplicated patients.

Adult↗
PubMed1986

Calcium stimulates vasopressin release.

The association of acute hypercalcaemia with hypertension has long been known. Its mechanism has remained unexplained, however, since no significant pressor contribution from the renin-angiotensin system or the sympathetic nervous system has been detected. To assess the possible contribution of arginine vasopressin (AVP), we investigated the effect of a 2 h infusion of 2 ml isotonic calcium gluconate (0.46 mmol/ml Ca2+) on the mean blood pressure of anephric (n = 8) or intact (n = 7) rats and the blood pressure response to a specific vasopressin inhibitor (V1). In anephric rats, blood pressure rose by 30 +/- 3 mmHg (mean +/- s.e.m.) and plasma AVP levels rose to 34 +/- 9 pg/ml. In response to injection of the AVP inhibitor, blood pressure fell by 26 +/- 3 mmHg. In intact rats, blood pressure rose by 12 +/- 4 mmHg with plasma AVP levels 14.5 +/- 3.2 pg/ml (normal range 2.2 +/- 1.1 pg/ml), but did not respond consistently to AVP inhibition. Serum calcium levels at the end of the infusion were 25.0 +/- 4.3 mg/dl in anephric and 24.9 +/- 1.2 mg/dl in intact rats. In order to confirm that the calcium ion was indeed responsible for the AVP-dependent changes in blood pressure, another group of anephric rats (n = 8) received a 2 h infusion of CaCl2 (0.46 mmol/ml Ca2+) and exhibited a blood pressure rise of 35 +/- 3 mmHg, which responded to the AVP inhibitor with a blood pressure fall of 22 +/- 3 mmHg. Moreover, prior treatment with indomethacin greatly attenuated the pressor effect of calcium infusion and prevented the rise of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Central alpha-adrenoceptors during the development of hypertension in rats on high and low salt intake.

Our purpose was to investigate the binding characteristics of central alpha-adrenoceptors during the early stages of the development of hypertension in rats on high and low salt (NaCl) intake. We measured alpha 1-[( 3H]prazosin) and alpha 2-[( 3H]rauwolscine) binding in membranes of the hypothalamus and medulla oblongata of six groups of young Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and subtotally nephrectomized WKY (SN) rats with mean arterial blood pressure (MAP) ranging from normotensive to hypertensive levels after 1 week of salt restriction or loading. In the hypothalamus the SN-high salt rats and both SHR groups had elevated alpha 1-number but there was no change in alpha 2-number. Moreover, MAP was positively correlated with mean hypothalamic alpha 1-number in the six groups. In the medulla oblongata alpha 1-number was unaffected. However, high salt diet influenced medullary alpha 2-binding in the opposite manner in WKY rats versus SN rats and SHR. In these latter groups the affinity was increased and the number decreased in response to high salt intake. Furthermore, a positive correlation between MAP and mean alpha 1:alpha 2 ratio existed in both the hypothalamus and the medulla of the six groups. The data suggest that hypothalamic alpha 1-binding capacity was increased in SHR due principally to a genetic condition which is mimicked by salt loading in the SN rats. Medullary alpha 2-adrenoceptors of WKY, which remained normotensive despite salt loading, responded differently to high salt intake than those of the SN and SHR, whose blood pressure rose significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Hypertensive effect of a bradykinin antagonist in normotensive rats.

The purpose of these experiments was to study the possible contribution of bradykinin to normal blood pressure maintenance. The bradykinin analogue B4146, a competitive antagonist-partial agonist of bradykinin, was used in three groups of normotensive unanesthetized Wistar rats. Two intra-aortic injections of B4146 (1 mg in 0.2 ml of dextrose) were given 5 minutes apart (i.e., well after return of blood pressure to baseline, which occurred within 68 +/- 19 seconds). One group had been pretreated with the angiotensin converting enzyme inhibitor HOE 498, 1 mg/kg (Hoechst), and one received only dextrose as the first injection to serve as controls. The bradykinin antagonist produced an average increase in mean arterial pressure of approximately 13 mm Hg for all groups. In five animals, however, the first injection of B4146 produced a hypotensive effect, whereas the second one consistently produced a rise in blood pressure. Pretreatment with the angiotensin converting enzyme inhibitor did not affect the magnitude of the subsequent blood pressure increase in response to B4146. Since smaller doses of B4146, sufficient to block exogenous bradykinin, do not cause changes in normal blood pressure, we conclude that endogenous bradykinin does contribute to normal blood pressure maintenance, but its effect can be demonstrated only if very high doses of its antagonist are injected, maybe because a high concentration of the compound is necessary to displace not only circulating but possibly tissue receptor-bound bradykinin as well.

Animals↗
PubMed1986

Vasodepressor role of endogenous bradykinin assessed by a bradykinin antagonist.

This study was designed to examine the contribution of bradykinin to the depressor effect of different antihypertensive drugs in two-kidney renovascular hypertensive rats, using a new specific antagonist of bradykinin. First, the inhibitory capacity of this peptide for exogenously injected bradykinin (75-200 ng) was tested. An inhibition of the vasodepressor action of bradykinin by over 50% was found when the bradykinin inhibitor was infused at a rate of 40 micrograms/min, with little difference at higher rates of infusion. This inhibitor then was infused in three groups of renovascular hypertensive rats after their blood pressure had been decreased by pretreatment with the converting enzyme inhibitor enalapril (MK 421), saralasin, or sodium nitroprusside, respectively. Infusion of the inhibitor produced an immediate 30% increase in blood pressure only in the enalapril-treated group. These results indicate that bradykinin is involved in the decrease of blood pressure produced by converting enzyme inhibition in experimental renovascular hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

The adrenergic system and the release and pressor action of vasopressin.

We studied the effect of various adrenergic components on vasopressin in groups of anephric rats. Pharmacological interventions included alpha 1-, alpha 2-, and beta-adrenergic receptor blockade and infusions of sodium nitroprusside to achieve a baseline blood pressure fall similar to that obtained by alpha 1-blockade, followed by hypertonic saline infusion to stimulate vasopressin release and administration of a specific V1 vascular vasopressin inhibitor to test the degree of blood pressure dependency on vasopressin. The combined hypotensive and osmolar stimuli of nitroprusside followed by hypertonic saline led to the highest level of plasma vasopressin (104 +/- 17 pg/ml, p less than 0.01) but only a 7 +/- 1 mm Hg fall in blood pressure in response to the vasopressin inhibitor. Rats subjected to alpha 1-blockade and saline infusion had the largest blood pressure reduction in response to the vasopressin inhibitor (43 +/- 5 mm Hg, p less than 0.001), despite a modest rise in vasopressin levels (18 +/- 2 pg/ml). Other pharmacological maneuvers produced intermediate responses in terms of vasopressin release and blood pressure response to the vasopressin inhibitor. There was no correlation between vasopressin levels achieved by each maneuver and the magnitude of blood pressure reduction in response to the vasopressin inhibitor. We conclude that 1) plasma levels of vasopressin under these conditions do not permit an accurate estimate of the magnitude of its pressor contribution to the maintenance of a given blood pressure level, which can be demonstrated only by the depressor response to a vasopressin inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1985

alpha-Adrenoceptor agonists applied in the area of the nucleus tractus solitarii in the rat: effect of anesthesia on cardiovascular responses.

We investigated the blood pressure and heart rate responses to unilateral local application of norepinephrine or clonidine in the area of the nucleus tractus solitarii (NTS) of conscious rats and rats anesthetized by 3 general anesthetics commonly used in cardiovascular research. In the conscious state, microinjection of either substance produced an immediate, sharp increase in blood pressure and decrease in heart rate with a gradual return to baseline over a period of more than 30 min. However, light ether anesthesia, nembutal, or urethane drastically reduced, abolished or even reversed the pressor effect of local microinjection of the same substance. Our results suggest that in conscious rats, the initial effect of alpha agonists in the NTS area is to modulate baroreceptor reflexes towards higher blood pressure levels and that general anesthesia may significantly alter or mask the cardiovascular responses to various experimental manipulations.

Adrenergic alpha-Agonists↗
PubMed1985

Hypertensive response to saline microinjection in the area of the nucleus tractus solitarii of the rat.

We investigated the blood pressure response elicited by microinjection of various hypertonic solutions into the area of the nucleus tractus solitarii (NTS) of the brainstem, an area rich in catecholaminergic neurons. Equiosmolar solutions of NaCl, dextrose, LiCl and KCl were employed. NaCl produced a prolonged blood pressure rise; LiCl and normal saline produced a similar rise of short duration; and KCl produced epileptic-type seizures with postictal hypertension. Dextrose had no effect and neither had NaCl microinjection in areas relatively distant from the NTS. The rise in blood pressure was not reversed by a vasopressin antagonist injected systemically, but was totally abolished by systemic alpha-adrenergic blockade with phentolamine. These findings suggest that sodium can cause hypertension by direct stimulation of the central sympathetic nervous system without participation of peripheral mechanisms such as fluid volume expansion or alteration of the vascular wall.

Animals↗
PubMed1985

Nifedipine in the treatment of essential hypertension.

The antihypertensive efficacy of nifedipine as a second-step drug in 24 patients, uncontrolled by a diuretic alone, was studied according to a double-blind placebo-controlled protocol. A significant blood pressure lowering was observed in nine out of 12 patients receiving the active drug and four out of 12 receiving placebo. Average mean blood pressure decreased by 13 +/- 1 mm Hg in the active drug group versus 5 +/- 3 mm Hg in the placebo group (P less than .02). There were no consistent changes or significant differences in heart rate or in the levels of plasma renin activity and plasma catecholamines between the two groups. In conclusion, nifedipine appears to be a safe and effective antihypertensive agent when used in conjunction with a diuretic for the treatment of moderately severe hypertension.

Blood Pressure↗
PubMed1985

Sodium chloride-induced partial inhibition in vivo of alpha 2-adrenoceptor agonist function.

Recent research has demonstrated that sodium diminishes the affinity of alpha 2-adrenoceptors for agonists in vitro. Clonidine, a highly specific agonist for alpha 2-receptors, has a transient hypertensive effect when administered parenterally. We studied in conscious anephric Wistar rats the effect of equimolar saline or mannitol solutions on the hypertensive response to clonidine administered subcutaneously in doses of 10, 100 and 1000 micrograms/kg body weight. Prior saline infusion reduced the hypertensive response to the two higher doses of clonidine by 65 and 70%, and displaced the slope of the dose-response curve downwards, but mannitol had no such effect. Pre-treatment with the alpha 2-antagonist yohimbine abolished the differences in clonidine-induced pressor response between saline-treated, mannitol-treated and control rats. On the contrary, after pre-treatment with the alpha 1-antagonist prazosin, the pressor action of clonidine was significantly reduced in the saline-infused rats compared to the other two groups. Thus the saline-induced blunting of the pressor response elicited by clonidine could be negated by prior alpha 2- but not alpha 1-blockade, indicating that sodium interfered with the stimulation of post-synaptic vascular alpha 2-adrenoceptors. These findings indicate that loading with sodium chloride attenuates the alpha 2-adrenoceptor function in vivo. Based on this, we suggest that the mechanism by which sodium excess causes a rise in blood pressure involves modification of the alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1984

Acute cardiovascular effects of two central phenylethanolamine-N-methyl-transferase inhibitors in unanesthetized desoxycorticosterone-salt hypertensive rats.

SKF 64139, an inhibitor of phenylethanolamine-N-methyltransferase (PNMT), has a marked hypotensive effect in models of sodium-dependent hypertension. The mechanism of this effect is obscure, the compound having in addition alpha-adrenoceptor blocking properties. We compared the acute effects of SKF 64139 with those of LY 134046, another PNMT inhibitor with minimal alpha-blocking capacity, in desoxycorticosterone-salt hypertensive rats. The former agent produced profound hypotension whereas the latter caused only bradycardia. Both induced a similar pronounced suppression of PNMT activity in the C1 and C2 region of the medulla oblongata. These results suggest that the alpha-adrenergic effect rather than PNMT inhibition accounts for the acute lowering of blood pressure in this model.

Animals↗
PubMed1984

Vasopressin response to hyperosmotic stimulus: blood pressure effect in normal subjects and patients with impaired sympathetic system.

We have investigated the interaction of plasma vasopressin and plasma catecholamines in quadriplegic patients (with severed sympathetic tracts) and compared them to others with intact sympathetic system following I.V. administration of a hyperosmolar radiocontrast agent during a routine diagnostic pyelography. Baseline systolic and diastolic pressure as well as plasma norepinephrine were significantly lower in the quadriplegic subjects. At 5 minutes after administration of the hyperosmolar solution, systolic and diastolic pressure as well as plasma vasopressin rose in the quadriplegic subjects but not in normal subjects despite a significant and equal rise in serum osmolality occurring in both groups. These results demonstrate that an interaction between the two systems exists in humans: an intact sympathetic nervous system attenuates the vasopressin response to hyperosmolar stimuli and in its absence vasopressin may function as a pressor agent.

Adult↗
PubMed1984

Regional blood flows and cardiac hemodynamics in renovascular and mineralocorticoid hypertensive rats.

Regional blood flows and cardiac hemodynamics were studied in 3 models of hypertensive rats: one-kidney DOC-saline, one-kidney, one-clip and two-kidney, one-clip hypertension and in normotensive control rats. All hypertensive models were characterized by increased peripheral vascular resistance and normal cardiac output. Coronary and cerebral blood flows varied among the hypertensive models but did not significantly differ from the normotensive rats. However, coronary blood flow of one-kidney, one-clip rats (8.4 +/- 1.3 ml X min-1 X g-1) was significantly higher than that of the two-kidney one-clip rats (6.5 +/- 1.2 ml X min.-1 X g-1, P less than 0.05). Cerebral blood flow of DOC-saline rats was lower than that of two-kidney one-clip or one-kidney one-clip renovascular rats. Renal blood flows of the unclipped kidney of two-kidney renovascular rats (3.77 +/- 0.85 ml X min-1 X g-1) and DOC-saline rats (2.95 +/- 0.83 ml X min-1 X g-1) were significantly lower than those of normotensive rats (5.92 +/- 1.16 ml X min-1 X g-1, P less than 0.05). In conclusion, although vascular resistance becomes elevated in all models of experimental hypertension, regional vascular resistance and blood flow distribution may differ depending on the vasoconstrictor mechanisms that participate in each model.

Animals↗
PubMed1984

Evidence for dopaminergic regulation of vasopressin release in the anephric rat.

Arginine vasopressin (AVP) release elicited by osmotic stimuli induces variable hypertensive responses. In normotensive anephric rats, a significantly greater blood pressure response was elicited by hypertonic saline than by mannitol infusion, and was further enhanced by previous dopaminergic receptor blockade. Plasma levels of AVP were significantly more elevated after saline than after mannitol despite more pronounced elevation of plasma osmolality in the latter animals, and were the highest in dopaminergically blocked animals. These findings indicate that dopamine exerts an inhibitory effect on the release of AVP.

Animals↗
PubMed1983

Systemic and regional hemodynamic effects of propranolol in intact and anephric rats.

We studied the changes in systemic and regional hemodynamics (using the radioactive microsphere technique) and catecholamine levels produced by propranolol in conscious semi-restrained intact or nephrectomized rats. Blood pressure increased by 17 +/- 2 and 32 +/- 2 mmHg in intact and anephric rats respectively, total peripheral vascular resistance by 61.5% and 176.5%, heart rate decreased by 23% and 35% respectively, cardiac index decreased by 35% and 57%, and stroke volume index by 14% and 30%. All changes were significantly more pronounced in anephric rats (p less than 0.05). Baseline norepinephrine, epinephrine, and dopamine were significantly higher in anephric versus intact animals and did not change significantly after B-blockade except for norepinephrine of the anephric rats which decreased. After B-blockade regional blood flows in most organs (including coronary flow) decreased in proportion to the diminished cardiac index except for brain flow which decreased by only 12% in intact and 25% in anephric animals. Local vascular resistances increased concomitantly and these changes were far more pronounced in the absence of kidneys. Thus, anephric state exacerbates all systemic and regional hemodynamic alterations caused by B-blockade in the rat.

Animals↗
PubMed1983

Captopril and enalapril.

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Angiotensin-Converting Enzyme Inhibitors↗