PubMed Health⌕ Search

Biomedical subjects

I Gavras

Publications and source records attributed to I Gavras.

At least 55 records · Page 3Linked to original sources

Models of experimental hypertension in mice.

Experimental models of hypertension in various animals are useful in the research of vasoactive mechanisms. Recombinant DNA technology has produced genetically engineered animals, mostly mice, useful in hypertension research. However, the development of hypertensive models in mice is fraught with technical difficulties. We describe here the successful development in mice of two common types of experimental hypertension: the renovascular two-kidney, one clip and mineralocorticoid deoxycorticosterone-salt models. By adapting technology previously used in rats, we succeeded in developing hypertension (defined as systolic pressures higher than 140 mm Hg) in more than 50% of mice so treated. We also adapted the methodology for indirect tail-cuff blood pressure measurements as well as for direct intra-arterial monitoring of blood pressure in conscious, freely moving mice. Application of these techniques in transgenic or gene knockout mice with altered vasoactive hormones or receptors should allow elucidation of the role of the target gene products in various types of hypertension.

Animals↗

Cardioprotective potential of angiotensin converting enzyme inhibitors.

This is a brief overview of various mechanisms activated by angiotensin converting enzyme (ACE) inhibition that affect the anatomy and function of the heart. The benefits of ACE inhibition include not only a reduction in blood pressure but also improved insulin responsiveness, prevention of potassium loss, diminished myocardial oxygen demand, suppression of catecholamines, and interaction with bradykinin and prostaglandins. These benefits result in improved perfusion of vital organs, diminished cardiac work, and protection of coronary vessels, evident in improved left ventricular systolic and diastolic function, elevation of the anginal threshold in ischemic heart disease, and decreased morbidity and mortality in congestive heart failure. The cardioprotective effects of ACE inhibition have been demonstrated by numerous multicenter long-term trials.

Angiotensin-Converting Enzyme Inhibitors↗

Role of bradykinin in insulin sensitivity and blood pressure regulation during hyperinsulinemia.

The purpose of these experiments was to determine in normotensive rats the role of endogenous bradykinin, prostaglandins, and nitric oxide in glucose metabolism and blood pressure response to hyperinsulinemia. Normotensive Wistar rats were treated with two different bradykinin antagonists, indomethacin or N omega-nitro-L-arginine methyl ester, concurrently with a euglycemic clamp with insulin infusion rates of 3 or 6 mU/kg per minute. Glucose uptake, steady-state plasma insulin levels, and insulin sensitivity index were determined over 2 hours. Bradykinin inhibition dramatically reduced glucose uptake and insulin sensitivity index during both the lower and higher insulin infusion rates to 30% and 32%, respectively, of values observed in control rats. Inhibition of prostaglandins or nitric oxide did not alter glucose metabolism in these rats. Blood pressure remained unchanged in the control group throughout the clamp but increased significantly in rats submitted to inhibition of bradykinin, prostaglandins, or nitric oxide, suggesting that these vasodilator systems tend to counteract the hypertensive effect of hyperinsulinemia. The counterregulatory component attributable to bradykinin was about twice as great as that attributable to nitric oxide. These findings suggest that insulin infusion in normotensive Wistar rats fails to raise blood pressure because its effects are offset by mobilization of vasodilator mechanisms, such as bradykinin, prostaglandins, and nitric oxide. Bradykinin seems to play the most important homeostatic role under these conditions, because its inhibition significantly reduces insulin sensitivity and allows blood pressure to rise.

Animals↗

Suppressing sympathetic activation in congestive heart failure. A new therapeutic strategy.

Neurohormonal activation with increased plasma renin activity and norepinephrine and vasopressin levels is characteristic of congestive heart failure and contributes to further decompensation and poor prognosis. We treated 20 such patients with the centrally acting sympathoinhibitory drug clonidine 0.15 mg BID and obtained hemodynamic measurements by cardiac catheterization and plasma neurohormone levels before and 2 to 3 hours after the first dose; in 7 patients, these measurements were taken again after 1 week of therapy. The initial dose produced significant decreases of 8% in mean arterial pressure, 23% in right atrial pressure, 21% in pulmonary capillary wedge pressure, 19% in mean pulmonary artery pressure, and 12% in heart rate, a 17% increase in stroke volume; and no significant changes in cardiac output and systemic vascular resistance. All changes remained virtually constant after 1 week. Plasma norepinephrine decreased by 28% after the initial dose and 62% after 1 week (P < 0.1), whereas plasma renin activity remained essentially unchanged. Plasma vasopressin tended to increase, its levels being inversely correlated with those of posttreatment norepinephrine (r = -.48 P < .03). Patients with baseline norepinephrine levels > 0.400 ng/mL has significantly poorer baseline hemodynamic parameters and tended to show more improvement with clonidine, although their data remained significantly worse than patients whose baseline norepinephrine was within the normal range. Sympathetic suppression with clonidine in congestive heart failure reduces preload, heart rate, and arterial pressure, all indexes of myocardial energy demand; the lack of significant reduction in systemic vascular resistance and increase in cardiac output might be attributable in part to enhanced release of vasopressin.2+ f2p4

Administration, Oral↗

Cardiovascular effects of a specific nonpeptide antagonist of substance P (NK-1) receptor in DOCA-salt hypertension.

The neurotransmitter substance P acts also as a potent vasodilator. Its participation in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt hypertension was evaluated by an acute infusion of a newly synthesized, potent, specific nonpeptide antagonist of substance P at the NK-1 receptor, the agent CP 96,345. In conscious unrestrained rats, CP 96,345 induced significant and sustained increases in mean arterial pressure of DOCA-salt rats but only small, transient, and nonsignificant rises in blood pressure of sham-treated control rats. The rise in blood pressure was not accompanied by changes in heart rate. Maximal blood pressure increase in DOCA-salt rats was 31.7 +/- 14.8 mm Hg. In a second series of experiments, the hemodynamic effects of this antagonist were evaluated under anesthesia in both DOCA-salt and sham-treated control rats by the thermodilution method. During CP 96,345 infusion, sustained increases in cardiac index and stroke volume and decreases in total peripheral resistance were observed in both DOCA-salt and control rats. In DOCA-salt rats, cardiac index rose by 79.4%, while total peripheral resistance fell by 27.9% of the baseline values. In control rats, the changes were smaller (+27.2% and -22.5%, respectively). Stroke volume changed in parallel to cardiac output in both groups. The data suggest that acute blockade of NK-1 receptors increases blood pressure in DOCA-salt rats mainly by an increase in cardiac output. We conclude that endogenous substance P tends to counteract the DOCA-salt-induced elevation of blood pressure by modulating both cardiac output and peripheral resistance.

Animals↗

Augmentation of coronary blood flow by ACE inhibition: role of angiotensin and bradykinin.

Inhibition of the angiotensin converting enzyme (ACE) is known to enhance coronary blood flow via partial suppression of angiotensin II and potentiation of bradykinin. The purpose of these experiments was to evaluate the contribution of each of these mechanisms to the ACE inhibition induced changes in blood flow in myocardial regions perfused by intact or stenotic coronary arteries. Seven domestic swine were submitted to an 82% stenosis of the left anterior descending artery with the circumflex artery left intact to serve as control area. Regional coronary blood flows were measured by the radioactive microsphere technique in the total area perfused by each coronary artery and in the subepicardial and subendocardial regions of each area separately, at rest and after treatments with captopril, losartan and a bradykinin antagonist given consecutively. We found a significant increase of total flow in both the stenotic and intact areas after captopril. Losartan caused a significant fall in systemic blood pressure with no further changes in overall coronary blood flow and the bradykinin antagonist produced a small but nonsignificant decline in total coronary flow. However, further separate analysis of subregions showed that subendocardial regions had a sharper increase in flow after captopril, and a significantly greater decline after bradykinin inhibition than subepicardial regions, whereas losartan tended to shunt blood from the subendocardial to the subepicardial regions. The results indicate that augmentation of coronary blood flow after ACE inhibition is not further enhanced by angiotensin II blockade and is in part mediated via potentiation of endogenous bradykinin, which exerts a preferential vasodilatory effect on the subendocardial regions of the myocardium.

Angiotensin II↗

Effects of ACE inhibition on the heart.

Inhibition of the angiotensin converting enzyme (ACE) results in suppression of the formation of angiotensin II and delay of the degradation of bradykinin. Hence, the pharmacological effects of ACE inhibitors are attributable to both of these mechanisms. This is a brief review of the haemodynamic, neurohumoral and metabolic alterations following ACE inhibition, with an attempt to separate those attributable to the angiotensin-mediated actions and those attributable to bradykinin-mediated actions as they relate to prevention or attenuation of cardiac damage in hypertension, myocardial ischaemia and congestive heart failure.

Angiotensin II↗

Modern approaches to initiating antihypertensive therapy.

From the five broad classes of antihypertensive drugs that have been in use long enough for adequate clinical experience to be obtained, the most recent report of the Joint National Committee on Hypertension recommends drugs from two older classes--the diuretics and the beta-adrenergic blockers--as first-line treatment. This article argues that newer drugs and in particular the angiotensin-converting enzyme inhibitors may be equally or more appropriate as first choice. Physicians should choose on the basis of a drug's pharmacologic properties and the patient's clinical profile, rather than according to a generic set of rules. Considering that the goals of modern antihypertensive therapy are not only lowering of blood pressure to prevent complications, but also long-term cardioprotection without adverse effects on the quality of life, some newer drugs might even prove more cost-effective in the long run.

Adrenergic beta-Antagonists↗

Pressor mechanisms in adriamycin-induced nephropathy with hypertension in rats.

We explored the role of angiotensin II and vasopressin in the maintenance of blood pressure during the nephrotic syndrome of adriamycin-induced nephropathy in rats. All 91 rats treated with adriamycin developed chronic renal failure with nephrotic syndrome, which was more pronounced in the normotensive rats than the 35% who became hypertensive. Angiotensin II blockade with DuP 753 produced a significantly greater hypotensive response in both the adriamycin-hypertensive (-16 +/- 3 mm Hg) and adriamycin-normotensive (-14 +/- 5 mm Hg) groups than the saline-treated controls (-5 +/- 1 mm Hg, P < .05). Vasopressin blockade with either a V1V2 inhibitor or a selective V1 inhibitor produced a hypotensive response in adriamycin-hypertensive rats only (by -16 +/- 4 and -17 +/- 2 mm Hg, respectively, P < .01), although the nonselective vasopressin inhibitor produced similar fluid loss and body weight reduction in all three groups. The data suggest that in adriamycin-induced nephropathy with nephrotic syndrome, angiotensin II contributes to blood pressure maintenance in both hypertensive and normotensive animals, whereas the pressor action of vasopressin contributes to elevated blood pressure in hypertensive animals only.

Angiotensin II↗

Contribution of vasopressin to orthostatic blood pressure maintenance in essential hypertension.

Arginine vasopressin (AVP) has been found to participate in blood pressure maintenance especially when other pressor systems are endogenously or pharmacologically impaired. The purpose of this study was to assess the pressor contribution of AVP to orthostatic blood pressure maintenance in otherwise healthy patients with essential hypertension. Twenty-seven patients were grouped according to age (young n = 13, elderly n = 14) and race (white n = 13, black n = 14). Integrity of autonomic nervous system (ANS) was assessed by Valsalva's maneuver, cold pressor test and head-up tilt. AVP contribution to blood pressure was estimated by the fall in mean arterial pressure in response to IV injection of 0.5 mg of a V1 AVP inhibitor (AVPi). Elderly subjects were found to have a mild (subclinical) ANS impairment as indicated by absence of bradycardia in phase 4 of Valsalva's maneuver and hypotension without concurrent tachycardia during head up tilt. Depressor responses to AVPi while subjects were in the upright position, were greater in elderly and blacks (-15 +/- 11 mm Hg and -15 +/- 12 mm Hg, respectively, P < .05) than young and whites (-8 +/- 6 and -7 +/- 6 mm Hg, respectively, ns). The greater importance of the AVP component in the elderly may be at least partially explained by a mild ANS impairement, whereas hormonal characteristics of hypertension in blacks may explain greater AVPi induced fall in mean arterial pressure. Our data show that both age and race influence the response to AVPi.

Adult↗

Pressor hormone profile during stress in hypertension: does vasopressin interfere with left ventricular hypertrophy?

Neurohormonal factors may account for the fact that patients with similar severity and duration of hypertension develop different degrees of left ventricular hypertrophy (LVH). The purpose of this work was to compare the pressor hormone profiles of hypertensive subjects off medication during exercise testing. Nineteen patients, stratified according to echocardiographically diagnosed absence (Group I n = 6) or presence (Group II n = 13) of LVH, underwent testing on the treadmill according to the Bruce protocol. Both groups were comparable in age, severity and duration of hypertension and reached similar double product at peak exercise. Measurements of plasma renin activity (PRA), plasma catecholamines and vasopressin (AVP) at baseline, peak exercise and post exercise revealed significant differences between groups: Group I had suppressed PRA levels throughout and had significantly higher baseline AVP levels, which increased further at peak effort. Group II had significantly higher baseline PRA levels, which tended to increase further at peak effort, and had suppressed AVP levels throughout. There was a significant negative correlation between percent increments in AVP and increments in double product. Norepinephrine increased significantly with effort in both groups, but the levels attained were higher in Group I. In view of the known negative inotropic action of AVP and the trophic effect of angiotensin, we speculate that lower baseline AVP and higher PRA, together with inability of AVP to increase with effort, may be causally related to development of LVH.

Adult↗

Inhibition of nitric oxide, bradykinin, and prostaglandins in normal rats.

We assessed the vasodilator effect of endothelium-derived nitric oxide by inhibiting its formation with NG-monomethyl L-arginine (LNMMA) on systemic and regional hemodynamics in conscious, normotensive rats, using the radioactive microsphere technique. In rats injected with 10 mg/kg LNMMA (n = 8), mean blood pressure increased by 16.2 +/- 2.6 mm Hg, and heart rate decreased by 54.3 +/- 16.7 beats per minute. In comparison with rats injected with 5% dextrose (n = 14), cardiac index was lower by 35.6% (p less than 0.01), and total peripheral vascular resistance was higher by 51.6% (p less than 0.01); regional blood flows were lower and vascular resistance higher in most organs. Changes were significant in the heart, kidney, stomach, large intestine, skin, and adrenals (p less than 0.05). Preinjection of 100 mg/kg L-arginine prevented the pressor response but only partially attenuated the other hemodynamic effects of LNMMA. Combination of LNMMA with the bradykinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg)trifluoroacetic acid (50 micrograms/min for 5 minutes) did not produce systemic or regional effects different from those obtained with LNMMA alone. Combination of LNMMA with indomethacin (10 mg/kg) resulted in additional changes in the cerebral circulation, blood flow decreasing by an additional 44.2% (p less than 0.01) and vascular resistance increasing by 75.3% (p less than 0.01) compared with changes produced by LNMMA alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Comparison of systemic and regional hemodynamic effects of a diuretic, an angiotensin II receptor antagonist, and an angiotensin-converting enzyme inhibitor in conscious renovascular hypertensive rats.

The present experiments were designed to compare the antihypertensive action and the systemic and regional hemodynamic effects of a diuretic (furosemide), an angiotensin II (AngII) receptor blocker (Dup 753), and an angiotensin converting enzyme (ACE) inhibitor (enalapril) in conscious, two-kidney, one-clip renovascular hypertensive rats by the radioactive microsphere technique. Measurements were done 3 hours after a single dose treatment. Furosemide (20 mg/kg) produced a marked diuresis and tachycardia with no change in blood pressure; in comparison with control rats, furosemide-treated rats had total peripheral vascular resistance increased by 46.55% (p less than 0.01) and local vascular resistance increased in most organs, to a significant degree in the spleen, muscle, stomach, intestine, and skin (p less than 0.05 to 0.01). Dup 753 (20 mg/kg) and enalapril (10 mg/kg) decreased mean blood pressure by 41.89 +/- 7.17 mm Hg and 47.13 +/- 8.67 mm Hg, respectively (p less than 0.01), with tachycardia only in the Dup 753 group. Total peripheral and local vascular resistances in several tissues were significantly lower in both the Dup 753 and enalapril groups than in the furosemide group. In particular, both antiangiotensin agents, in contrast to furosemide, produced significant decrease in renal vascular resistance by 42.28% and 38.81%, respectively (p less than 0.01), with a tendency to increase the renal blood flow (of the intact kidney). No detectable differences were found in systemic and regional hemodynamic changes between the Dup 753 and enalapril group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗