Newsletter 4

Plasma level of endothelin 1, insulin and catecholamines are
not increased in patients with essential HTN and no target
organ damage

Insulin resistance and reactive hyperinsulinaemia commonly occur in-patients with essential hypertension (EHT). However, the link between vascular and metabolic disturbances is still unclear. Endothelin l(ET- 1) is a very potent vasoconstrictor peptide whose role in hypertension is still controversial. Recently, the possibility that hyperinsulinaemia may potentiate ET- 1 gene expression and its receptor mediated action a my be relevant to the role of hyperinsulinaemia in the pathogenesis of cardiovascular diseases. Multiple experimental evidences point to an interaction between ET- 1 and catecholamines (catechols) suggesting that sympathetic activity may be modulated by ET- 1. The aim of the work was to study the plasma levels of these hormones in mild versus severe hypertensive pts and the relation of these hormones to BP levels in these patients.

Forty patients with EHT and no target organ damage were studied. They were not diabetic, not obese and not on antihypertensive treatment for the last 2 weeks. They were assigned to either of 2 groups according to blood pressure (BP) level: Gr A included 20 pts with mild EHT (BP> 14(3)190 and < 160/100). mean age was 52+8 years. Grp B included 20 patients with severe EHT (BP> 1801110). mean age was 52.8 + 9 years. Twenty normotensive volunteers served as controls (C). mean age was 49.6 years. Plasma levels of ET--1 and insulin were measured by specific radioimmunoassay and catechols by high performance liquid chromatography. Molar insulin/glucose ratio (I/G) was calculated in the fasting state and 1h and 2h after an oral glucose load of 75 gm

No significant difference was found between the 3 groups as regards the plasma levels of these hormones. It was only the I/C ratio 2 hours after an oral glucose load which differed significantly between Gr B and Cr A.. No significant correlation was found between plasma levels of studied hormones and systolic, diastolic and mean BP in the same patients.

In conclusion, plasma levels of ET- I, catechols and insulin are not related to B levels in pts with EHT and no target organ damage. Severe hypertension is associated with increasing insulin resistance, which is also unrelated to BP level. The fact that ET-l is mainly an autocrine/paracrine hormone and its circulating level does not reflect the local concentration of the peptide in the vessel wall may explain the lack of correlation between plasma levels of studied hormones as well as the lack of their correlation with the magnitude of BP.

Abstract presented in the 2^ndmeeting of the Egyptian Hypertension Society 1996.

Extent and functional capacity of coronary collateral
circulation in hypertensive patients with
atherosclerotic coronary disease
Aly M. Hegazy, M.D. and Aly Ramzy, M,D.

The aim of this study was the evaluation of coronary collateral circulation in relation to the presence of systemic hypertension and left ventricular hypertrophy. One hundred patients with significant coronary artery disease (>75%) were enrolled in the study. Thirty-five hypertensive patients with left ventricular hypertrophy (LVH) were considered as group I, 35 hypertensive patients without LVH as group II and 30 normotensive patients as group III. Coronary angiography was done for all patients. Class 0: no collaterals, class I: partial filling and class II: complete filling of collaterals were used as angiographically classified coronary collaterals. Echocardiography and graded exercise ECG test were done for all patients. There was a non-significant difference between hypertensive and normotensive patients as regards clinical characteristics. There was a significantly increased number of patients with class II collaterals (p <0.01) among hypertensive patients compared to normotensive patients. There was a non-significant difference between the 3 groups of the study as regards coronary artery disease and stenosis, but there were significantly more proximal lesions in patients with class II collaterals (p<0.0 1) and increases distal lesions in patients without collaterals (p<0.01). There was a significant increase in coronary perfusion pressure (p<0.0 1) in patients with class I and II collaterals. There was a non significant difference between the patients of the 3 study classes as regards the systolic function of the left ventricle and segmental wall motion abnormalities, but there was significantly increased left ventricular mass (LYM) and LVM index (p<0.0l) in the patients of class II than those of class I and class 0. There was a non-significant difference in functional capacity inpatients of class II, I and 0 as there was a non significant difference between the 3 classes of the study as regards the Canadian functional classification, exercise tolerance and ST segment depression.

We concluded that patients with systemic hypertension and coronary artery disease have an increase in coronary collateral circulation corresponding to the left ventricular hypertrophy and that the functional capacity of coronary collateral circulation is not augmented by left ventricular hypertrophy.

Abstract presented in the 2^nd meeting of the Egyptian Hypertension Society, 1996

CARDIAC CYTOPROTECIVE PROFILE OF SOME
ANTI-HYPERTENSIVES IN RATS A CORRELATION
OF THEIR CARDIAC ANTIOXIDANT-BUFFERING
CAPAClTY TO THEIR RELATED RESPIRATORY
ENZYMES.
Nayel O*, and Youssif M** * Pharmacology & Drug
Toxicology Department, Faculty of Medicine, **
Histochemistry & Cell Biology Department, Medical
Research Institute, Alexandria University.

Cardioprotection, vasculoprotection and the possession of inherent antioxidant buffering capacity are recent requisites to be fulfilled in an idea antihypertensive agent. No wonder, the objectives of this study focused on questioning the impact of some available antihypertensives, on cardiac respiratory enzymes, probing in their possible correlative ability to modulate the cardiac antioxidant buffering capacity particularly when binge subjected to peroxidative stress [Hypercholesterolaemia being taken as a model].

The 60 male albino rats experimented comprised; 10 normal controls (N) receiving 2% gum acacia daily, 10 oxidatively stressed gp. (S) receiving atherogenic diet, 40 rats oxidatively stressed while continuously receiving either; Amlodipine 5mg/kg/day (S+A)(n=10), or Isradipine 2mg/kg/day (S+I)(n=10), or Captopril 35mg/kg/day (S+c)(n=l0) or fosinopril 8 mg/kg/day. (S+F)(n=10) for 2 months.

Result revealed that (S) suppressed cardiac cytochrome oxidase, succinic dehydrogenase, ATPase and increased lactate dehydrogenase enzyme activities compared to (N), as assessed hi stochemically. It meanwhile Significantly depleted cardiac enzymatic antioxidant buffering capacity as judged by SOD and catalase activities and significantly increased lipid peroxidation as indexed by MDA seruin levels that were assessed biochemically. On the other hand. The studied antihypertensives variably conferred cardioprotection, where S+I>S+A and S+C>S+F succeeded to revert all cardiac enzymes assessed histocheinically toward (N) as compared to (S)

They also significantly variably elevated cardiac antioxidant buffering capacity and decreased lipid peroxidation when compared to (S).

The underlying mechanism behind the variable cardiocytoprotective potentials of the studied antihypertensives are discussed and the impact of this on their clinical utility is raised. International Conference of: Infectious Diseases & Public Health. A research & Clinical Update Conference Hall, Alexandria, Egypt.

Editorial

SETTING CRITERIA FOR AN IDEAL ANTIHYPERTENSIVE
Omnia A. Nayel Pharmacology & Drug Toxicology
Dept. Faculty of Medicine, Alexandria University.

As we step in the 20^th century, HYPERTENSION still remains one of the leading health problems world wide, inspite of all the available therapeutics set to control it and despite of even sometimes being well controlled !!!!

This appeared clear in data retrieved from the so many therapeutic clinical trials lately conducted; where blood pressure reduction; though paralleled by a reduction in stroke incidence, yet was unfortunately disproportionate to the modest reduction in associated coronary events.

Attempts to unravel the under current loops that dictate this mismatch, has fostered a search of an ideal antihypertensive that can bridge this existing discrepancy, in hope to achieve a parallel reduction in morbidity and mortality specially when speaking of acute coronary insults.

Pharmacodynamically; setting criteria based on cardiovascular molecular level, addresses several issues:

The 1^st issue of concern clears that this antihypertensive in question should be able to reverse back the cardiac and vascular remodeling. These initially develop, as adaptive processes, meant; to protect the vessels and the cardiac pump machinery from elevated pressure constrains. However, with persistence of such constrains they pathologically progress into a deficit that impairs tissue perfusion in end organs, encroach on coronary reserve, alter cardiac diastolic and systolic functions… etc.

Unfortunately, once this situation is achieved, then, unless the proposed antihypertensive is able to regress such cardiac and vascular changes, as much as its ability to reduce the blood pressure, then we will wind up with further impairment in tissue perfusion that can causes subclinical or overt clinical ischaemic events.

In this respect, it is generally agreed that low dose diuretics and ? -blockers are much inferior to convening enzyme inhibitors and Ca antagonists. The latter groups being proven to exert antiproliferative effects that can halt and / or reverse the remodeling process beyond blood pressure controls, thus fulfilling an essential criteria of an ideal antihypertensive.

The 2^nd issue that has been raised, is whether or not the antihypertensive in question is capable of correcting the changes in the microcirculation (i.e. vascular rarefaction) observed in hypertension. The answer to this is as yet not clear because the phenomenon in itself is still left to speculations; being a consequence of (adaptive) or a precipitant to (development deficit) hypertension. Also, whether it is a functional loss amenable to reopening or a true structural loss [apoptotic] that would need genesis of newer avenues. Addressing this logically, implies the urge for an antihypertensive with vasodilating potentials to open functionally rarefied vessels or with an angiogenic potential to trigger new vessel formation.

In this domain, antihypertensives with vasodilating potentials specially vasodilating B-blockers & Ca antagonists are candidates, if rarefaction is functional, while other genuine agents are being scrutinized for their potential to promote angiogenesis.

The 3^rd evolving issue that is now being requested in an ideal antihypertensive, is its possession to an inherent antioxidant nucleus. This is of utmost importance now that we know that the endothelium is the mediator of cardiovascular tone and structure and that pertaining it, functioning normal, is predicted upon a homeostatic balance between NO and reactive oxygen species [ROS], specially superoxide anion that inactivates NO. When local generation of superoxides increase due to endothelial injury as in hypertension per se, or by O-LDL and lysolecithins in atherosclerosis, glycosylation end products in diabetes, thiocyanates in cigarette smoking, etc. then NO level will be suppressed. In consequence, the proatherogenic and vasoconstrictor effects of endothelial dysfunction will contribute to the clinical cardiovascular complications of hypertension specially coronary artery disease. The hazardous spectrum of oxidative stress broadness when it impairs mitochondrial metabolism and encroaches on energy resources of the pumping heart. This creates more lack in an already demanding hypertrophic myocardium, in the face of the existing decrease in oxygen supply through the coronaries; the reserve of which is being suppressed in hypertension.

No wonder, the search for antihypertensives with inherent antioxidant potential is now being sought in newer prototypes or reevaluated in those already available, whereby; lacidipine & carvidiolol do directly, in contrast to some ACE presumably indirectly, fit isuch a criteria.

Pharmacodynamically, other criteria set beyond the direct cardiovascular domain, demands that; an ideal antihypertensive should secure flow reserve and pertain perfusion pressure and metabolism in vital tissues [specially renal & cerebra] coping with the their dynamic demands. It should also be metabolically neutral. In diabetics, it should not enhance hyperglycemia, as thiazides or unmask hypoglycemia as ? -blockers and occasionally ACE inhibitors. On lipid profile, the drug should better possess a lowering (a blockers) or at least a neutral (ACE inhibitors and Ca antagonists) spectrum.

Pharmacokinetically, ideal criteria necessitates: an antihypertensive with high bioavailability that can reach optimum saturation levels in target tissues, better if with balanced dual elimination and a peak-trough ratio more than 60%. In this way, it can act rapidly and selectively, can cover the 24 hour's circadian variations; in activity or at rest and can be given rather safely in borderline hepatic or renal impairments.

With these criteria in hand, an ideal antihypertensive is hoped to bridge the disappointing discrepancy between lowering blood pressure and inducing real reduction in cardiovascular morbidity & mortality for the therapeutic outcome of hypertensive patients.

References

1. Freis ED, Papademetrious V. Current drug treatment patterns with antihypertensive drugs. Drugs 1996: 52(1): 1-16.

2. Zanchetti A. Vascular remodeling and antihypertensive therapy. Medicographia 1996; 18(l): 56-7.

3. Thorn AMcG, England H. Structural aspects of the heart and vessels in hypertension: Impact of disease and treatment. Medicographia 1 996;l 8(1): 63-70.

4. Cooke JP. Therapeutic interventions in endothelial dysfunction: Endothelium as a target organ. Clin Cardiol 1997; 20 (Suppl 11)11-4541-51.

5. Zanind F, Matzinger A, Larche 3. Through I Peak ratio of converting enzyme inhibitors and calcium antagonists, AJLH 1996: 633-43.

Abstracts of World Literature

Systolic Function in Hypertension with Concentric Remodeling

Diego B. Sadler, Gerard P. Aurigemma, David W. Williams, Domenic J. Reda Barry J. Materson, John S. Goftdiener

Hypertensive patients with concentric remodeling (relative wall thickness> 0.45 and normal left ventricular (LV) mass index) may have poor outcomes. It is unclear whether systolic function abnormalities, shown to be present in some patients with concentric LV hypertrophy (increased LV mass index and relative wall thickness> 0.45) are also present in patients with concentric remodeling. To assess LV pump, chamber and myocardial function in hypertensive men with concentric remodeling, clinical and echocardiographic data of 118 hypertensive men with concentric remodeling were compared with data from 104 men with normal relative wall thickness and normal LV mass index. Chamber function was assessed by relating endocardial fractional shortening to end systolic circumferential stress, and pump performance was assessed by stroke volume (Teichholz method). Compared with hypertensive men with normal relative wall thickness. concentric remodeling patients had lower stroke volume (84 + 20 versus 111+20 mL , p<.001). Endocardial shortening was no different between the two groups (38 + 7% versus 40 +7%, p NS), but mid wall shortening was lower in patients with concentric remodeling (20+3% versus 22 + 3%, p<.00l), despite lower end systolic stress (Sit 25 versus 117 + 37glcm2, p<.001). Endocardial and mid wall shortening plots classified 28% and 42%respectively, of the concentric remodeling patients below the 5^th percentile of hypertensive patients with normal geometry. These data indicate that indexes of chamber and myocardial function are lower than those observed in hypertensive patients with normal geometry. Thus indices of chamber, myocardial and pump performance indicate potential abnormalities in systolic function in men with concentric remodeling

(Hypertension 1997; 30:777-781)

Cardiovascular reactivity to stress and LV mass in youth
Michael T. Alien, Karen A Matthews, Frederick S.
Sherman

We studied the relationships of cardiovascular reactivity during mental stress with left ventricular mass index in a group of prepubertal children 8 - 10 years old and in a group of peripubertal or postpubertal adolescents 15-17 years old. One hundred and fifteen participants varying in age group, sex and race (black and white), took part in a laboratory stress protocol consisting of a reaction time task, a mirror tracing task, a cold forehead challenge and a stress interview. Cardiovascular measures included blood pressure and heart rate, as well as cardiac output, stroke volume, total peripheral resistance, and preejection period obtained noninvasively with impedance cardiography. Measures of left ventricular mass were made by echocardiography. Results indicated that across all participants, left ventricular mass index was associated with cardiovascular responses during the mirror tracing and cold forehead tasks, especially with those responses reflecting increased vasoconstriction. Subgroup analyses showed that these associations were significant for males and sometimes adolescents but not for females and children. As mirror tracing and cold forehead tasks most consistently produce alpha adrenergic activation, the results suggest a model in which vasoconstriction due to mental stress is related to increased left ventricular mass index in susceptible individuals, even at young age.

(Hypertension 1997; 30:782-787)

Structure and function of small arteries in salt induced hypertension Effects of chronic endothelin subtype A receptor blockade
Livius V, d'Uscio, Manhias Barton, Sidney Shaw,
Pierre Moreau, Thomas F. Luescher

The involvement of endothelin in salt induced hypertension is unclean In the Dahl rat model, we studied the effects of a selective endothelin-subtype A (ET_A) receptor antagonist LU135252, on blood pressure, vascular structure and function. Dahl salt sensitive and salt resistant rats were treated for 8 weeks with Na Cl alone or in combination with LU135252 taken orally (60 mg/kg per day) The geometry and reactivity of the basilar and mesenteric arteries were studied in vitro under perfused and pressurized conditions using a video dimension analyzer. Chronic salt administration increased systolic blood pressure by 37 + 3 mmHg and media4umen ratio of the basilar and mesenteric arteries of salt sensitive rats (p < .05). These structural changes were caused by eutrophic remodeling in basilar and hypertrophic remodeling in mesenteric arterie. These structural changes were caused by eutrophic remodeling in basilar and hypenrophic remodeling in mesenteric arteries. Endothelium dependent relaxations to acetyicholine and contractions to endothelin1 were impaired in mesenteric arteries of salt sensitive rats on high Na CL diet LU135252 preventedpart of the increase in systolic blood pressure and structural and functional alterations but increased plasma endothelin1 levels (1) <.05 versus salt- treated salt-sensitive rats). These findings suggest that the long term pressor effect of salt administration is mediated in part by the action of endogenous endothelin acting via ET_A receptors. via ET_Areceptors. Thus chronic ETA receptor blockade may be useful therapeutically to lower arterial blood pressure and prevent endothelial dysfunction and hypertrophic remodeling of resistance arteries in salt sensitive forms of hypertension.

(Hypertension 1997; 30:905-911)

Abstracts of Local Literature

ROLE OF ENDOTHELIN-IIN ESSENTIAL HYPERTENSION
ITS RELATION TO INSULIN AND CATECHOLAMINES

Laila H. Kim, Sobhi A. El Kafafi, Mona H. Kandil, Amr
A. El Mohandes, Mahmoud M Hassanein, Hala Abu Heif
Physiology Dept, Faculty of Medicine, Clinical
Pathology Dept, Medical Research Institute, Internal
Medicine Dept, Faculty of Medicine, Alexandria University

Sixty subjects were included in the present study. They were divided into two groups. The first group included 20 healthy normotensive subjects as controls. The second group included 40 patients with essential hypertension (ERT) which was divided into two subgroups according to their blood p: 20 patients with mild EHT and 20 patients with severe EHT. To all subjects the following was done: fasting plasma glucose and insulin levels as well as after one and two hours after an oral glucose load, fasting plasma endothelin-l (ET-l) and fasting plasma catecholamines. ET-l showed no significant difference between mild and severe EHT patients when compared to each other and when compared to controls. However, mild hypertensives showed the highest values amongst the groups suggesting the possibility of increased local production which was not high enough to be significantly reflected on the plasma level in this group. Serum insulin and insulin/glucose (I/G) ratio in both groups did not show significant differences from controls. When compared with mild EHT patients, those with severe EHT showed significantly higher serum insulin concentrations one hour after glucose load and I/G ratio two hours after oral glucose load denoting diminished insulin sensitivity in this group of patients. Plasma catecholamines were estimated to evaluate sympathetic nervous activity. There was a slight increase in hypertensive patients, however no significant difference was detected between the studied groups. The fact that essential hypertension is a heterogenous disease may explain the insignificant differences in plasma levels of the studied hormones between normotensive and hypertensive subjects.

Alexandria Medical Journal Vol 38, No 2,1996

ELECTROCARDIOGRAPHIC DIAGNOSIS OF LEFT VENTRICULAR HYPERTROPHY IN THE PRESENCE OF COMPLETE LEFT BUNDLE BRANCH BLOCK

Moustapha Nawar, Amr Naim, Mohamed Ayman, Hamam Ragheb, Mohammed Sobhy
Cardiology Department, Faculty of Medicine,
Alexandria University

It is usually considered difficult or impossible to make the electrocardiographic diagnosis of left ventricular hypertrophy (LVII) in the face of left bundle branch block (LBBB). The distinction between the two situations, however, may be important, as LVH is an independent risk factor for cardiovascular morbidity and mortality. The aim of this work was to find, if any, an electrocardiographic clue(s) to the diagnosis of LVII in the presence of LBBB. Three groups of patients were included in the study. 12 patients each, the first group included patients with LBBB and no LVII. The second group included patients with LBBB and LVII, and the third group included patients with neither LBBB nor LVH, but LBBB was artificially induced by RV pacing. Comparing groups I and II, a significant increase in voltage in group II did occur in some leads more than group I. In addition there was a significantly higher incidence of left atrial dilatation and left atrial changes in group II. Remembering that both groups showed a common feature, which is LBBB, the difference must be attributed to LVH.

Sensitivities of this feature for electrocardiographic diagnosis of LVH in the presence of LBBB were calculated and the results were values in the range of 26% - 66%. The two criteria SV3 > 15 and SV3 +RAVL> 30 mm are the most sensitive (66%).

Egyptian Heart Journal, Vol XXX N&4, 1994

THE EFFECT OF PINACIDIL (PIN) MONOTHERAPY AND IN COMBINATION WITH CAPTOPRIL (CAP) OR HYDROCHLOROTHIAZIDE (HCTZ) ON SOME CARDIOVASCULAR AND HUMORAL PARAMETERS IN SHRSP.
EI-Dakhakhny M, Bedair KM, Abdel-Reheem, Khedr MM, Bassioni YA, Halim MA.
Pharmacology & Drug Toxicology Department, Faculty of Medicine,
Alexandria University.

The aim of the present study was to compare the effect of 4 week's oral administration of PIN(l mg/Kg) alone and in combination with CAP[l0mg/Kg] or HCTZ[l0 mg/Kg] on systolic blood pressure [SBP], heart rate[HRJ, plasma renin angiotensin system, urinary kallikrin activity (UKA) serum Na and K as well as body weight of treated spontaneous hypertensive rats of stroke - prone strain [SHR-SP] and normotensive Wister Kyoto rats (WKO) as control strain.

In SHR-SP, PIN significantly decreased SBP and increased mean HR value. A better control on SBP was achieved when CAP or HCJZ was combined to it. Moreover, CAP attenuated the effect of PIN on HR.

In WKY, the same treatment regimens significantly lowered SBP with insignificant difference between the efficacy of monotherapy and combined therapy possibly due to an associated counter4egulation developed in response to reduction in BP. Confirming this, it was found that all these treatment regimens significantly increased mean HR values, through it was significantly less with PIN and CAP.

PIN monotherapy significantly increase plasma renin activity [PRA] in WKY rats but not in SHR-SP as compared to controls. Plasma ACE-activity insignificantly varied in these treated groups as compared to control values. Captopril as well as HCJZ monotherapies significantly increased PRA in WICY but not in SHR-SP as compared to controls, while pinacidil + HCTZ were accompanied by a significant increase in PRA and ACE -activity in SHR-SP and WKY.

PIN & CAP significantly decreased plasma aldosterone concentration in SHR-SP and WKY as compared to control and monotherapy groups. UKA was significantly increased in SHR-SP and WICY treated with CAP or HCTZ and in combination with PIN. On the other hand, serum K concentration was significantly increased in SHR-SP and WKY given PIN & CAP possibly due to an additive effect on aldosterone synthesis and or secretion No significant effect between all treatment regimens on mean body weight values of treated groups and corresponding control group.

It is to be concluded that CAP significantly enhanced the efficacy of PIN on SBP in SHR-SP and attenuated the possibly associated reflex tachycardia with PIN monotherapy. The effect of this combination on plasma aldosterone may be beneficial in hypertensive patients with high aldosterone levels, which remains to be verified clinically.

2^nd International Conference of Hypertension Marriot, Cairo December 1966.

On Going / Forth Coming Research

ASSESSMENT OF CORONARY FLOW RESERVE IN ESSENTIAL HYPERTENSION BY TRANSESOPHAGEAL ECHO USING DIPYRIDAMOLE.

M.D. Thesis conducted in the Cardiol Dept Faculty of Medicine, University of Alex. Candidate: Yahia El Rakshy / Supervisors: Hassan Khalil, Ebtihag Hamdy,
Salah El Tahan, Amer Zaki

Reports declare that it is common to meet an impairment in coronary flow reserve in hypertensives, however the incidence and extent seems variable in literature So it is wise to access this in Egyptian patients.

This is by conducting:
Coronary angiography study to exclude coronary artery disease and to record the coronary vasomotor lone using Ach & papaverine.

TEE study to visualize the coronary artery, record its flow velocity and its reserve using dipyridamole. Preliminary data reveal that in essential hypertensive Egyptian patients there is variable degree of encroachment on coronary flow reserve.

Therapeutic awareness necessitates that:
Elder diabetic hypertensives on insulin or sulfonylureas are more prone to hypoglycemia if they receive ك-blockers or ACE inhibitors. This is because;

ك-blockers attenuate some components of the autonomic response to hypoglycemia.

ACE inhibitors increase insulin sensitivity and predispose users to hypoglycemia.

JAMA Mid East 1997; 7(10): 39-42.

There is an association or causation of environmental hazards to hypertension; LEAD EXPOSURE: Whether heavy and excessive in occupational cohorts or as chronic low-level exposures in population-based studies indicate its implication in the pathogenesis of hypertension. For instances, in occupational cohorts; lead mining, lead smelters, lead battery plants or any other lead producing firms as those manufacturing pipes, paints, explosives. etc, are prone to develop renal impairment due to nephrosclerosis. This categories hypertension in such sector to be of renal origin. While on the contrary, in population-based studies; low dose-repeated exposure to lead, as being subjected daily to, inhaled vehicle exhaust [petrolium additives], or ingested canned beverages or food polluted by insecticides or by printed articles that can pollute the hands and / or food, carries the risk of altering vasomotor reactivity. This is because, lead seems to open Ca channe, disrupt Ca cellular homeostasis and subsequently alter vascular ionic permeability. Also lead was found to increase myocardial catecholamine contents and / or to stimulate renin-angiotensin system via neurogenic mediators.

This is all prone to set vasomotor tone on the pressor side, which explains why low-dose lead exposures has become of major cardiovascular risk problem that mandates doctors cognizance and patients awareness.

Epidem Rev 1993; 15(2): 352-73

The Universe of Ramipril

ACE inhibitors were one of the therapeutic breakthroughs in cardiovascular medicine. They allowed treatment of hypertension to move beyond the control of symptoms towards real intervention that tend to modify end-stage-organ disease.

Within the plethora of ACE inhibitors available the selection of which to use depends from the patient's perspectives on the severity of the presenting symptoms and the coexistence of precipitating or complicating disorders, least present. From the drug's perspective, its phamacokinetic and phamacodynamic character and the availability of well documented clinical trials supporting its utility in improving morbidity and mortality outcomes whether in complicated or uncomplicated cases, must all be weighed.

In this context, ramipril the tolerable, long acting ACE inhibitor, available as 1.25, 2.5 or 5 mg tablets once daily, possesses several merits. Its blood pressure lowering effect appears within 1-2 hrs. peaks within 3-6 hrs. and overlasts the 24 hrs. This profile is mainly delineated by the plasma half life [t ½ being; 7 hrs. in rapid initial & l20 hrs in slower late elimination phases] and the extent of binding affinity of the drug in question. Being highly lipophilic, the active moiety ramiprilat, binds tightly in a competitive reversible manner with high affinity and slow dissociation rate, to Ag and bradykinin binding sites of ACE. This high tissue availability together with the long duration of action correlates well with its sustained cardioprotective and vasculoprotective utilities demonstrated in several clinical trials.

Of these, was the acute intervention ramipril efficacy study [AIRE] that determined the effect of this ACE inhibitor in 2006 hemodynamically stable patients after 2-9 days following acute M.I, throughout an average of 15 months duration. A risk reduction of 27% in all cause mortality was the primary and 19% reduction in death, reinfarction, stroke, or development of persistent H.F. was the secondary end points achieved. Moreover these benefits were maintained among 603 patients with H.F. enclosed in AIRE study whom continued in a further extensions limb, the AIREX study; where a 36% reduction in risk of death was observed over 5 years among patients who continued receiving the drug.

This protective utilities of ACE inhibitors, particularly observed, by some of their potent, high tissue available prototypes, as ramipril, by-passes even beyond blood pressure control. Thus, vasculoprotection is achieved through modulation of locally generated autocrine-paracrine mediators governing vascular tone and through regulating vascular cell growth, programmed cell death, matrix modification and cellular migratory activities, governing vascular structure. This is abet to hamper the coronary, cerebral, renal. etc. changes in microcirculation and the hypertrophy and fibrosis in conduit vessels that contribute to LVH changes, in hypertension. Furthermore, cardioprotection is fostered by their ability to regress myocardial mass and to optimize the balance between myocardial O₂ supply an demand in chronic IHD and to reduce the incidence and duration of reperfusion arrhythrnias in acute ischaemic insults. The clinical sequelae of hypertension are thus minimized.

References:

1. Lancet 1993; 342: 821-8.
2. BMJ 1993;306:531-Z
3. Eur Heart J 1994; 15:125-30.
4. Clin Pharmacokinet 1994:26:7-15.
5. Lancet 1997:349:1493-7.
6. Clin Cardiol 1997; 20(11) [Suppl 11]:18-25.

EHS NEWS

The annual EHS meeting was held on Friday, January 16^th, 1998
The chairman thanked Mr. Fikry Abd El Wahab for his distinguished services as head of the Fund Raising Committee and welcomed Mr. Aly Dabbous as its new chairman. He also welcomed a new member of the committee, Mr. Magdi Yacoub.

CALENDAR

International Symposium on Heart Disease From Molecules to Patient Care	Cairo Sheraton, Cairo, 19-21 May, 1998	Contact: Mrs. Amany Kandeel Tel: (202)3624803 Fax: (202)363 9895
17^th Scientific meeting of the International Society of Hypertension	Amsterdam, Netherlands 9-11 June , 1998
Summer Course in Hypertension	Palestine Hotel Alexandria, July 2-3, 1998	Contact: Mrs. Amany Kandil Tel (202)3624803 Fax (202)363 9895