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H Gavras

Publications and source records attributed to H Gavras.

At least 37 records · Page 2Linked to original sources
PubMed2000

Role of the postsynaptic alpha(2)-adrenergic receptor subtypes in catecholamine-induced vasoconstriction.

Catecholamines induce direct vasoconstriction mediated by postsynaptic alpha-adrenergic receptors (alpha-ARs) of both the alpha(1) and alpha(2) type. To evaluate the contribution of each alpha(2)-AR subtype (alpha(2A), alpha(2B), and alpha(2C)) to this function, we used groups of genetically engineered mice deficient for the gene to each one of these subtypes and compared their blood pressure (BP) responses to their wild-type counterparts. Blood pressure responses to a bolus of norepinephrine (NE) were assessed before and after sequential blockade of alpha(1)-ARs with prazosin and alpha(2)-ARs with yohimbine. The first NE bolus elicited a brief 32 to 44 mm Hg BP rise (p < 0.001 from baseline) in all six groups. Prazosin decreased BP by 23 to 33 mm Hg in all groups, establishing a new lower baseline. Repeat NE at that point elicited lesser but still significant (p < 0.001) brief pressor responses between 32% and 45% of the previous BP rise in five of the six groups. Only the alpha(2A)-AR gene knockouts differed, responding instead with a 20-mm Hg fall in BP, a significant change from baseline (p < 0.001) and different from the pressor response of their wild-type counterparts (p < 0.001). The addition of yohimbine produced no further BP change in the five groups, but it did produce a small 7. 5-mm Hg fall (p < 0.05) in the alpha(2A)-AR knockouts. Norepinephrine bolus during concurrent alpha(1) and alpha(2)-AR blockade produced significant (p < 0.001) hypotensive responses in all subgroups, presumably attributable to unopposed stimulation of beta(2)-vascular wall ARs. We conclude that the alpha(2)-AR-mediated vasoconstriction induced by catecholamines is attributable to the alpha(2A)-AR subtype because mice deficient in any one of the other subtypes retained the capacity for normal vasoconstrictive responses. However, the alpha(1)-ARs account for the major part (as much as 68%) of catecholamine-induced vasoconstriction.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Update on the clinical pharmacology of candesartan cilexetil.

The renin-angiotensin system plays a central role in the regulation of blood pressure through its primary effector hormone angiotensin II. Studies conducted nearly 30 years ago with peptidic angiotensin II receptor blockers (ARB) suggested that disruption of the renin-angiotensin system offered considerable promise for the treatment of hypertension as well as heart failure. This promise was initially realized with the advent of angiotensin converting enzyme inhibitors, and more recently with nonpeptidic ARB that selectively antagonize the AT1-angiotensin receptor subtype. The potent and long-acting agent candesartan cilexetil illustrates how these new ARB fulfill the promises suggested by the early studies. Candesartan cilexetil provides a clinically relevant, dose-dependent reduction in diastolic and systolic blood pressure at doses of 4 to 16 mg once daily in patients with mild to moderate hypertension. Recent studies suggest that further blood pressure lowering is obtained with a 32-mg once daily dose. In comparative clinical trials, 8 mg of candesartan cilexetil and 10 to 20 mg of enalapril provided comparable antihypertensive effects. The safety and tolerability profile of candesartan cilexetil is comparable to placebo. Notably, this agent does not produce the dry, nonproductive cough that often limits use of angiotensin converting enzyme inhibitors, nor does it cause side effects that limit other antihypertensive drug classes. On the basis of the results of initial clinical studies, ARB also possess cardioprotective and renoprotective properties that promise to expand the role that these new agents will play in treating cardiovascular disorders.

Benzimidazoles↗
PubMed2000

The antiarrhythmic potential of angiotensin II antagonism: experience with losartan.

A large body of literature accumulated over the past several years supports the notion that inhibition of the renin-angiotensin system protects the heart and other target organs from hypertensive complications. Various studies have shown that angiotensin-converting enzyme inhibitors reduce morbidity and mortality in the setting of ischemic heart disease and/or congestive heart failure. The improvement in survival has been attributed in part to a significant decrease in the incidence of sudden deaths, possibly due to a decrease in complex arrhythmia episodes. Recently, the angiotensin II type 1 receptor antagonist losartan was shown to reduce mortality by 46% compared with captopril in older patients with chronic congestive heart failure. This paper briefly reviews the arrhythmogenic properties of angiotensin II and the possible pharmacologic mechanisms for the antiarrhythmogenic potential of losartan.

Angiotensin Receptor Antagonists↗
PubMed2000

Role of alpha(2)-adrenergic receptor subtypes in the acute hypertensive response to hypertonic saline infusion in anephric mice.

Experimental evidence suggests that the acute hypertensive response induced in anephric animals by infusion of a hypertonic saline solution is mediated by disinhibition of the presynaptic sympathoinhibitory alpha(2)-adrenergic receptors (alpha(2)-AR) of the central nervous system. The purpose of the present experiments was to dissect the role of the 3 distinct alpha(2)-AR subtypes (alpha(2A)-, alpha(2B), - and alpha(2C)-AR) in this response. Groups of genetically engineered mice deficient in each one of these alpha(2)-AR subtype genes were submitted to bilateral nephrectomy followed by a 0.4-mL infusion of 4% saline over a 2-hour period, with constant direct blood pressure (BP) monitoring. The alpha(2A)-AR-deficient and alpha(2C)-AR-deficient mice responded with significant BP elevations (by 11.8+/-2.5 and 16.7+/-1.7 mm Hg, respectively), and so did their wild-type counterparts (17.8+/-2.5 and 11.8+/-2.0 mm Hg, respectively) and the wild-type alpha(2B) +/+ (13.1+/-2.4 mm Hg). However, the alpha(2B)-AR-deficient mice were unable to raise their BP and had a slightly lowered BP (by -3.0+/-4. 0 mm Hg) at the end of the infusion period. All 6 groups exhibited elevated plasma norepinephrine levels ranging between 0.8 and 1.8 ng/mL at the end of the infusion. In all cases, the alpha(2)-AR-deficient groups tended to have higher norepinephrine levels than their wild-type counterparts. Surprisingly, this difference was significant only in the alpha(2B)-AR-deficient mice, which, despite the elevated norepinephrine, were unable to raise their BP. The data suggest that a full complement of the alpha(2B)-AR is needed to mediate the hypertensive response to acute saline load, even though its absence does not prevent the release of norepinephrine under these conditions.

Acute Disease↗
PubMed2000

Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the framingham heart study.

Hypertension is a leading cause of morbidity and mortality. Efforts to identify hypertension genes have focused on 3 approaches: mendelian disorders, candidate genes, and genome-wide scans. Thus far, these efforts have not identified genes that contribute substantively to overall blood pressure (BP) variation in the community. A 10-centiMorgan (cM) density genome-wide scan was performed in the largest families from 2 generations of Framingham Heart Study participants. Heritability and linkage for long-term mean systolic and diastolic BP phenotypes were analyzed by use of SOLAR software. Heritability estimates were based on BP measurements in 1593 families. Genotyping was performed on 1702 subjects from 332 large families, and BP data were available for 1585 (93%) genotyped subjects who contributed 12 588 longitudinal BP observations. The mean age was 47 years, and mean BP was 127/80 (systolic/diastolic) mm Hg. Long-term systolic and diastolic BP phenotypes had high heritability estimates, 0.57 and 0.56, respectively. For systolic BP, multipoint log-of-the-odds (LOD) scores >2.0 were located on chromosome 17 at 67 cM (LOD 4.7, P=0.0000016) and 94 cM (LOD 2.2). For diastolic BP, LOD scores >2.0 were identified on chromosome 17 (74 cM, LOD 2.1) and chromosome 18 (7 cM, LOD 2.1). Using a genome-wide scan, we found strong evidence for a BP quantitative trait locus on chromosome 17. Follow-up studies are warranted to identify the gene or genes in this quantitative trait locus that influence BP. Such knowledge could extend our understanding of the genetic basis of essential hypertension and have implications for the evaluation and treatment of patients with high BP.

Adolescent↗
PubMed2000

Genetic predisposition to stroke in relatives of hypertensives.

BACKGROUND AND PURPOSE: The genetic basis of stroke is poorly understood. We evaluated patterns of familial aggregation of hypertension and stroke to test the hypothesis that inherited susceptibility to these disorders may be determined by a common set of factors. METHODS: Genealogical and medical history information was obtained for a cohort of 354 hypertensive probands ascertained in a clinic-based setting, their 1427 first-degree relatives, and 239 of their spouses. Risks of stroke and hypertension in biological and nonbiological relatives were compared with the logistic model of the generalized estimating equations adjusted for age and sex. RESULTS: The risk of hypertension was higher for the parents and siblings of the probands than for spouses (odds ratio [OR]=2.4; 95% CI, 1.8 to 3.4; OR=2.2; 95% CI, 1.6 to 3.0, respectively). When the spouses were used as a reference group, the risk of stroke for parents of the hypertensive probands was 7.3 times higher (OR=7.3; 95% CI, 3.6 to 14.8), while a nonsignificant but slightly increased risk for siblings (OR=1.6; 95% CI, 0.8 to 3.3) was observed. Controlling for hypertension, obesity, smoking, coronary heart disease, diabetes, and cholesterol resulted in decreased estimates of the risk of stroke for parents and siblings (OR(parents)=5.4; 95% CI, 2.6 to 11.2; OR(siblings)=1.2; 95% CI, 0.6 to 2.5). The risk of stroke was significantly higher for hypertensive parents and siblings than for nonhypertensive parents (OR=5.2; 95% CI, 2.8 to 9. 7) and siblings (OR=5.8; 95% CI, 2.1 to 15.9). A history of hypertension was not associated with an increased risk for stroke in spouses (OR=0.7; 95% CI, 0.2 to 3.1). The risk of stroke in hypertensive relatives of probands with stroke was higher than that of the normotensive relatives (OR=13.4). A less elevated risk ratio was observed in the relatives of probands who did not have a stroke (OR=4.0). CONCLUSIONS: Our data showing a higher occurrence of hypertension and stroke in parents of hypertensive probands compared with spouses suggest that some of the genetic factors predisposing to these conditions may be the same. The slightly increased risk to siblings compared with spouses was not significant, suggesting that elucidation of these factors through family studies of stroke may be difficult because of secular trends toward improved treatment for hypertension. Although a history of hypertension increases the risk of stroke among parents and siblings, multivariate analyses revealed a familial component to stroke independent of hypertension.

Aged↗
PubMed1999

Mitochondrial DNA mutations in patients with orthostatic hypotension.

We determined the entire sequence of the mitochondrial genome in affected individuals from three families with idiopathic orthostatic hypotension. The disorder in two of these families was recently linked to chromosome arm 18q, while the third family remains unlinked. In all three families, orthostatic hypotension is inherited through the females, suggesting the existence of additional contributing factors, such as genomic imprinting or a mitochondrial modifier. We now report the presence of multiple point mutations in the mitochondrial DNA (mtDNA) in all three families. While most of the changes are common polymorphisms, several novel mutations were found that merit further consideration. In one individual, we detected a T-to-C transition at position 1243 in the 12SrRNA, a change from threonine to alanine at position 67 of the ND1 protein, and from valine to isoleucine at position 197 of the ND2 protein. A second individual harbored a novel substitution of threonine with serine at position 536 of the ND5 protein. Two previously unreported amino acid replacements were detected in a third individual: amino acid 193 of cytochrome b was changed from alanine to threonine, and amino acid 88 of COIII was changed from threonine to alanine. Further studies are required to assess the role of these mutations in blood pressure homeostasis.

DNA, Mitochondrial↗
PubMed1999

Identification of a polymorphic glutamic acid stretch in the alpha2B-adrenergic receptor and lack of linkage with essential hypertension.

Essential hypertension, a clinically significant elevation in blood pressure with no recognizable cause, is believed to be attributable to the collective effect of genetic predisposing factors in combination with specific environmental factors, such as diet and stress. Of the genetic causes, genes coding for proteins involved in blood pressure regulation, such as the alpha- and beta-adrenergic receptors, are obvious candidates. The alpha2-adrenergic receptor plays a key role in the sympathetic nervous system by mediating the effects of epinephrine and norepinephrine. To evaluate the potential role between the alpha2B receptor and essential hypertension, we scanned the alpha2B-receptor gene for genetic variation in 108 affected sibling pairs. The screening revealed two major forms of the receptor. They differ by the presence of either 9 or 12 glutamic acid residues in the acidic domain of the third cytoplasmic loop of the protein. Investigation of the pattern of this variation in hypertensive sibling pairs suggests that the alpha2B receptor locus does not contribute substantially to genetic susceptibility for essential hypertension.

Alleles↗
PubMed1999

Genetic epidemiology of essential hypertension.

This review article is intended to introduce the uninitiated clinician to the basic concepts, aims and early findings of the genetic epidemiology of hypertension. It separates the rare monogenic 'Mendelian' hypertensive disorders from the vast majority of patients with essential hypertension, which is a complex, polygenic, multifactorial disorder resulting from interaction of several genes with each other and with the environment. It highlights some clinical strategies used to enhance searches for 'candidates genes', such as subgrouping of populations into relatively homogenous groups or 'intermediate phenotypes' according to presumably heritable anthropometric, clinical or biochemical characteristics; and some applications of genetic epidemiologic techniques, such as linkage and association studies of certain gene polymorphisms with hypertension using affected sibling pairs and large sibships or wide genomic screens comparing affected and unaffected populations. Although so far there is no genotypic variation proven to be causally related to essential hypertension, its intermediate phenotypes or any of its complications, it is hoped that new, more efficient methods of genetic analysis will yield clinically meaningful information.

Animals↗
PubMed1999

Role of the alpha2B-adrenergic receptor in the development of salt-induced hypertension.

Salt sensitivity is a common trait in patients with essential hypertension and seems to have both an inherited and an acquired component (eg, is influenced by aging and renal insufficiency). Experimental evidence suggests that salt loading induces hypertension via a neurogenic mechanism mediated by the alpha2-adrenergic receptors (alpha2-AR). To explore the alpha2-AR subtype involved in this mechanism, we studied 2 groups of mice genetically engineered to be deficient in one of the 3 alpha2-AR subtype genes (either alpha2B-AR +/- or alpha2C-AR -/- knockout mice) compared with their wild-type counterparts. The mice (n=10 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for up to 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intra-arterial BP recording. The alpha2B-AR-deficient mice had an attenuated BP response in this protocol (baseline 101.8+/-2.7 versus end point 109.9+/-2.8 mm Hg), whereas the BP of their wild-type counterparts went from a baseline 101.9+/-2.3 to an end point 141.4+/-7.1 mm Hg. The other 2 groups had BP increases of 44. 6+/-5.17 and 46.7+/-7.01 mm Hg, with no difference between the mice deficient in the alpha2C-AR gene subtype versus their wild-type counterparts. Body weight, renal remnant weight, and residual renal function were no different among groups. These data suggest that a full complement of alpha2B-AR genes is necessary to raise BP in response to dietary salt loading, whereas complete absence of the alpha2C-AR subtype does not preclude salt-induced BP elevation. It is unclear whether the mechanism(s) involved in this process are of central origin (inability to increase sympathetic outflow), vascular origin (inability to vasoconstrict), or renal origin (inability to retain excess salt and fluid).

Aging↗
PubMed1999

Evidence for linkage between essential hypertension and a putative locus on human chromosome 17.

Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (P=0.0005) and refines the location of the blood pressure QTL.

Aged↗
PubMed1999

Sympathoinhibitory function of the alpha(2A)-adrenergic receptor subtype.

Presynaptic alpha(2)-adrenergic receptors (alpha(2)-AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the alpha(2A)-AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted alpha(2A)-AR gene to their wild-type controls. At baseline, the alpha(2A)-AR gene knockouts (n=11) versus controls (n=10) had higher systolic BP (123+/-2.5 versus 115+/-2.5 mm Hg, P<0. 05), heart rate (730+/-15 versus 600+/-18 b/min, P<0.001), and norepinephrine (1.005+/-0.078 versus 0.587+/-0.095 ng/mL, P<0.01), respectively. When submitted to subtotal nephrectomy and given 1% saline as drinking water, both alpha(2A)-AR gene knockouts (n=14) and controls (n=14) became hypertensive, but the former required 15. 6+/-2.5 days versus 29.3+/-1.4 days for the controls (P<0.001). End-point systolic BP was similar for both at 155+/-2.1 versus 152+/-5.2 mm Hg, but norepinephrine and epinephrine levels were twice as high in the knockouts at 1.386+/-0.283 and 0.577+/-0.143 versus 0.712+/-0.110 and 0.255+/-0.032 ng/mL, respectively, P<0.05 for both. We conclude that the alpha(2A)-AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.

Animals↗
PubMed1999

Effects of eprosartan versus enalapril in hypertensive patients on the renin-angiotensin-aldosterone system and safety parameters: results from a 26-week, double-blind, multicentre study. Eprosartan Multinational Study Group.

A double-blind comparator study was performed in 528 hypertensive patients [baseline sitting diastolic blood pressure (SitDBP) 95-114 mmHg]. The primary objective was to compare the incidence of drug-related cough in patients treated with enalapril and eprosartan. The secondary objective was to compare antihypertensive efficacy between treatments. This paper reports the effects seen on the safety profile, plasma renin activity, aldosterone and angiotensin II (A-II) in each treatment group. Eprosartan was titrated from 200 mg b.i.d. to 300 mg b.i.d. and enalapril from 5 mg o.d. to 20 mg o.d. over 12 weeks. Hydrochlorothiazide (HCTZ) 12.5-25 mg o.d. could be added where required to the treatment for the final six weeks of the titration phase if SitDBP > or = 90 mmHg. Patients received the maximum titrated dosage during the maintenance phase. In the study overall, similar mean changes in blood pressure from baseline were evident with each treatment. Measurement of mean plasma neurohormone levels showed significant increases in renin activity in both groups and statistically significant A-II elevations in the eprosartan group (p < 0.05). Neither eprosartan nor enalapril significantly altered serum lipid profiles or electrolyte levels. Most adverse experiences reported throughout the study were mild or moderate in both treatment groups. Fewer patients receiving eprosartan (4.9%) than enalapril (9.1%) discontinued treatment because of adverse experiences. In conclusion, the results of this study show that eprosartan is well tolerated. Both eprosartan and enalapril significantly increased plasma renin activity while plasma A-II was elevated in the eprosartan group.

Acrylates↗
PubMed1999

Safety and tolerability of eprosartan.

The safety and tolerability of eprosartan were extensively assessed in 17 phase IIb-III studies that included 2709 patients with hypertension. The frequency of adverse events observed with eprosartan was similar to that seen with placebo. Neither the number nor the severity of these effects increased with prolonged therapy, and their frequency was not affected by increased eprosartan dosage or dosing frequency. The drug is equally well tolerated by women and men, by younger (< 65 yrs) and older (> or = 65 yrs) individuals, and by persons of all races. There are no known drug interactions, and eprosartan is well tolerated when given in combination with other frequently prescribed antihypertensive agents, without an increase in adverse events beyond those expected of baseline antihypertensive therapy.

Acrylates↗
PubMed1998

Comparison of spirapril, isradipine, or combination in hypertensive patients with left ventricular hypertrophy: effects on LVH regression and arrhythmogenic propensity.

This study was designed to evaluate in 45 hypertensive patients with left ventricular hypertrophy (LVH) the effects of a 6-month course with one of three different antihypertensive regimens (the calcium channel blocker isradipine, the angiotensin converting enzyme inhibitor spirapril in monotherapy, or a combination of the two drugs, n = 15 per group) on blood pressure, LVH regression, and various functional correlates of LVH. All three treatment modalities decreased significantly LV mass index by an average of 10%, although the combination had the greatest blood pressure-lowering effect and spirapril had the least, as assessed by office resting pressures, ambulatory monitoring, and isometric grip testing. There was no correlation between magnitude of blood pressure lowering and degree of LVH regression. The effects of treatment on pressor hormone profiles differed among groups, as spirapril tended to suppress angiotensin II and norepinephrine, whereas isradipine had opposite effects. Exercise tolerance was prolonged by all three regimens, but significantly more by the combination. All three regimens decreased significantly the double product by 10% to 15%. Indices of electrophysiologic stability calculated from analysis of ambulatory electrocardiogram exhibited significant improvement in several parameters such as QRS duration, presence of late potentials, and measures of heart rate variability, resulting in fewer episodes of simple or complex ventricular arrhythmia. We conclude that all three regimens produce significant LVH regression associated with improved functional capacity and electrical stability. These results reflect the sum of the differential hemodynamic and hormonal effects exerted by each treatment modality.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Renal artery clipping attenuates the progression of adriamycin nephropathy.

This study was designed to analyze the impact of diminished renal perfusion pressure due to renal clipping on the rat model of adriamycin nephropathy. Male Wistar rats, divided into four groups (n = 9 per group) were injected with saline as control (C), adriamycin 3 ml/kg (Ad), saline with the left renal artery clipped (Rv), and adriamycin plus clip (AdRv). After 24 weeks mean arterial pressure (MAP), inulin, and p-aminohippurate (PAH) clearances were performed to evaluate renal function. Morphologic analysis included histologic criteria of percentage of glomerulosclerosis and tubulointerstitial lesion index (TILI). The MAP (mm Hg) was similar between Rv (143+/-13) and AdRv (154+/-20), but higher (P < .05) than C (120 +/-8) and Ad (124+/-11). Inulin clearance (mL/min/ 100 g) in Ad (0.2+/-0.05) was smaller than in C (0.53+/-0.17) and Rv (0.4+/-0.01) (P < .05), and was at an intermediate level in AdRv (0.33+/-0.2). The level of PAH (mL/min/100 g) was normal at 1.76 in C, and diminished more in Ad (0.58) than in Rv (1.06) and AdRv (1.18) (P < .05). Both Ad and the AdRv nonclipped kidneys had the highest degree of glomerulosclerosis (33% and 25%) and TILI (7% and 8%), respectively, compared with C and Rv (both 0%), whereas the clipped kidneys displayed intermediate degrees (9% and 5%) (P < .05 v nonclipped). The data suggest that diminished perfusion pressure of the clipped kidney, by decreasing the intraglomerular pressure, protects the glomerulus from damage and attenuates the evolution of adriamycin nephropathy.

Animals↗