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Biomedical subjects

M Mendlowitz

Publications and source records attributed to M Mendlowitz.

16 recordsLinked to original sources
PubMed1991

Characterization of phosphatidylinositol-specific phospholipase C from cultured vascular smooth muscle cells.

Phosphoinositide-specific phospholipase C (PLC) activities have been partially purified from cultured vascular smooth muscle cells and analyzed for substrate specificity, calcium and pH requirements, and molecular weight. The purification procedure involved DEAE-cellulose and heparin-Sepharose chromatographies followed by Mono Q and size exclusion high performance liquid chromatography. This technique resolves multiple peaks of activity using phosphatidylinositol (PI) and PI 4,5-bisphosphate (PIP2) as substrates. The major peak was purified to near homogeneity as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. PLC activity in vascular smooth muscle cells can be divided into two types based on their calcium and pH requirements, substrate preferences, and molecular weights. The low molecular weight PLC hydrolyzes both PI and PIP2, has a molecular mass of 58 kDa, requires the most calcium for full activation, and has a PI-pH profile that shifts slightly with calcium concentration. Screening a cDNA library with oligonucleotides directed against several of the known PLCs identified a highly expressed PLC cDNA that is 99% homologous to PLC-alpha, suggesting that this low molecular weight peak in fact corresponds to PLC-alpha. The high molecular mass peak (157 kDa) shows much greater activity against PI than PIP2, is active at lower calcium concentrations, and has a PI-pH optimum of 5.0 regardless of calcium concentration. Each of the PIP2 PLC activities is strongly dependent on the relative levels of calcium and pH in the assay buffer. These observations suggest that vascular smooth muscle contains both a high and low molecular weight PLC whose activities are affected markedly by the changes in calcium and pH accompanying hormonal stimulation of the cell.

Animals↗
PubMed1991

The aetiology of essential hypertension.

Essential hypertension is primarily hereditary. The property inherited is present in all cells but because of adaptation and differentiation it is particularly prominent in systemic vascular smooth muscle. This inherited property is manifested functionally as increased reactivity to vasoactive substances, such as (-)noradrenaline and angiotensin II. This abnormal function is present before the onset of hypertension. Vascular hypertrophy and hyperplasia are not only caused by hyperactivity of the smooth muscle and by the hypertension itself but are also trophic effect of the agonists, especially noradrenaline. The only two proteins in vascular smooth muscle which can produce both contractile and trophic effects are the guanosine triphosphate binding protein (Gs) and phospholipase C. Phospholipase C has already been demonstrated to be abnormally active in response to agonists in the spontaneously hypertensive rat and in human essential hypertension. The Gs protein is less likely to be critically abnormal since it is active in the vascular smooth muscle relaxation cascade as well as in contraction. None of the other proteins involved in vascular smooth muscle contraction or relaxation affect both contractile reactivity and cellular growth. There are many secondary effects dependent upon the phospholipase C abnormality such as calcium (Ca2+) cellular content, Ca2+ Mg2+ ATPase pump effects and possibly Ca2+ Na+ exchange. There are also many secondary effects impinging on the phospholipase C abnormality including changes in noradrenaline and angiotensin II metabolism. Present antihypertensive therapy is directed largely at secondary factors dependent upon or influencing the primary phospholipase C cascade. The path is now open for a more direct and basic diagnostic and therapeutic attack.

Humans↗
PubMed1989

Adrenergic interactions in uterus and vascular smooth muscle in rats in vivo.

Simultaneous blood pressure and uterine responses to norepinephrine infusions were recorded in urethane-anesthetized, pentolinium-indomethacin treated rats in natural estrus under conditions in which no blockers or blockers of alpha 1-, alpha 2-, and beta-adrenergic receptors or of "reuptake" of norepinephrine were present. The contributions of alpha 1- and alpha 2-adrenergic receptors to the blood pressure response were similar during the initial portion of the response. At later times, however, alpha 1-adrenergic receptors were responsible for the major portion of the response. The tachyphylaxis of the pressor response that occurs during norepinephrine infusion could be prevented by preventing norepinephrine "reuptake" with imipramine. In the uterus, the initial small alpha-adrenergic contractile response (seen only at the lowest infusion rate) was quickly overwhelmed by a beta-adrenergic relaxing component. Administration of the beta-adrenergic receptor blocker, propranolol, during norepinephrine infusion caused similar increases in blood pressure in control, yohimbine-, and prazosin-treated rats. Uterine contractions, in contrast, were only significantly elevated during beta-adrenergic receptor blockade when yohimbine or imipramine had also been administered.

Adrenergic alpha-Agonists↗
PubMed1978

The hypertension complex.

The complex of factors that operate in the genesis as well as the development of various types of hypertensive disease is discussed. Questions are asked and possible answers given to only a few of the unsolved problems of hypertension. The treatment of hypertension especially with drugs, is then discussed in the light of these complex mechanisms.

Acute Disease↗
PubMed1977

Antihypertensive effects of tolamolol.

The antihypertensive and renin-lowering efficacy and side effects of tolamolol, a beta adrenergic blocking drug with cardioselectivity, were examined in 10 patients with mild essential hypertension while on regular diet. Tolamol, at a dose of 300 to 900 mg per day, given over a period of 2 to 4 wk significantly decreased systolic and diastolic blood pressures in both the recumbent and standing positions. Normal blood pressure (140/90 mm Hg or less) was attained in 8 subjects. Mean heart rate and ambulatory midday plasma renin activity (PRA) decreased significantly; however, there was no significant correlation between blood pressure decrease and either the pretreatment PRA or decrease in PRA. Body weight did not change significantly. No adverse side effects were detected and no changes in the liver or renal function or in the blood count were observed. It is concluded that tolamolol is effective in lowering blood pressure and PRA in patients with hypertension.

Adult↗
PubMed1977

Blood pressure responses to catecholamines during beta-adrenergic blockade with propranolol in hypertensive subjects.

In 14 patients with essential hypertension, the response of the heart rate and blood pressure to infusion of norepinephrine and epinephrine separately while off (control period) or on therapy with beta-adrenergic receptor blockade was examined. By titrating dosage against the response of blood pressure and pulse rate, propranolol hydrochloride was administered orally at 160 mg/day in four divided doses. There was a significant decrease in systolic blood pressure and in pulse rate during propranolol therapy, whereas diastolic blood pressure decreased but not significantly so. Normal blood pressure (140/90 mm /g or less) was attained only in five patients. The infusion of epinephrine and then norepinephrine produced a significant increase in both systolic and diastolic blood pressure during propranolol therapy, but the magnitude of the rise was significantly greater than that attained in the control period only during epinephrine infusion. We conclude that the transient hypertensive episodes which have been observed during offive visits in some hypertensive patients treated with propranolol are due mainly to release of epinephrine.

Adult↗
PubMed1976

Alpha- and beta-adrenergic receptor blocking agents combined with a diuretic in the treatment of essential hypertension.

The antihypertensive efficacy and side effects of the combined therapy with propranolol, phenoxybenzamine, and hydrochlorothiazide were examined in 17 patients with moderate and moderately severe hypertension. Following a control period two to three weeks' duration, propranolol was started in nine patients as the sole antihypertensive agent and together with phenoxybenzamine, in eight. By titrating the dosage against pulse rate and blood pressure response, propranolol was given, in divided doses, from 80 to 160 mg and phenoxybenzamine, from 20 to 50 mg per day. When propranolol was given alone in nine patients, for four to 12 weeks, normal blood pressure was not attained in any patients. During three to ten weeks of combined propranolol and phenoxybenzamine therapy in 17 patients, normal blood pressure (150/90 mm Hg or less) or near-normal pressure (150/100 or less) was attained in 12 patients in the recumbent position and in 15 patients in the upright position, while orthostatic hypotension was not observed. Except for a reduction of ejaculation in three out of six male patients, no other side effects were encountered. The addition of hydrochlorothiazide diuretic in all of the above 17 patients, at a dose of 50-100 mg per day with a concomitant decrease in the dose of phenoxybenzamine, produced a further reduction in blood pressure, and normal or near-normal blood pressure was attained in all subjects. Symptomatic orthostatic hypotension, observed in two patients, was treated by a further readjustment of the dose of phenoxybenzamine, while inhibition of ejaculation was persistent in only one patient. It is concluded that the combined administration of propranolol, phenoxybenzamine, and hydrochlorothiazide in individualized doses is very effective in lowering the blood pressure with minimal side effects.

Adrenergic alpha-Antagonists↗
PubMed1976

An approach to the treatment of essential hypertension.

The efficacy and side effects of the combined administration of propranolol and phenoxybenzamine were examined in 19 patients with moderate and moderately severe essential hypertension. By titrating the dosage of both drugs against pulse rate and blood pressure response, propranolol was given between 80 and 160 mg. and phenoxybenzamine between 20 and 50 mg. per day in divided doses. There was a substantial reduction in both systolic and diastolic blood pressure in both recumbent and upright positions without orthostatic hypotension. Normal blood pressure (140/90 mm. Hg or less) or near normal (150/100 mm. Hg or less) was attained in 14 of the patients in the recumbent and 17 in the upright position. Pulse rate also decreased significantly, whereas body weight increased but not significantly so. Except for a reduction of ejaculation in three out of six male subjects, no symptomatic side effects were detected, and no changes in the liver or renal function or in blood count were observed. Despite the short duration of therapy, 3 to 10 weeks, this study clearly demonstrates that propranolol and phenoxybenzamine given together in individualized doses are very effective in lowering arterial blood pressure with minimal side effects.

Adult↗
PubMed1976

The catecholamines in essential hypertension.

The evidence for involvement of the catecholamines and their metabolites in essential hypertension is presented. Labile and established essential hypertension should be considered individually in this respect, although they may exist separately or together. Labile essential hypertension is more related to increased secretion as well as increased response to and decreased retention of epinephrine rather than norepinephrine, whereas established essential hypertension is more related to similar aspects of norepinephrine release and metabolism. Whether pure epinephrine hyperresponsiveness, abnormal metabolism, and secretion evolves into the pure norepinephrine hyperresponsiveness and abnormal metabolism of uncomplicated established essential hypertension can only be proved by long-term longitudinal study. Such investigation would also be required to identify the evolution of mixed types of the disease.

Catecholamines↗
PubMed1975

Neurohumoral mechanisms in hypertension.

Neurohumoral mechanisms operating via the catecholamines are discussed in their relationship to such hypertensive diseases as pheochromocytoma and labile and established essential hypertension. 2. In pheochromocytoma, diagnosis depends almost entirely on identification of increased amounts of catecholamine metabolites in the urine. Because of the danger, manipulative or invasive procedures both for diagnosis and during surgery should be kept at a minimum. 3. In established essential hypertension, reactivity to norepinephrine and plasma norepinephrine are increased, whereas norepinephrine uptake and apparent secretion rate are decreased. 4. In labile essential hypertension, reactivity to epinephrine and probably plasma epinephrine are increased and uptake of epinephrine decreased. 5. Labile hypertension with all its characteristics may or may not coexist with established essential hypertension with all its features. 6. The sympathetic nervous system is also involved in other types of hypertensive disease. Many patients with renovascular hypertension as well as with primary and secondary hyperaldosteronism also have essential hypertension. Angiotensin II affects the sympathetic nervous system and the juxtaglomerular apparatus appears to be beta adrenergic receptor activated, at least in part.

Acetylcholine↗
PubMedDate not supplied

Diminished baroreceptor sensitivity in elderly hypertensives. Possible role of atherosclerosis.

Baroreceptor sensitivity was studied in twelve young normotensive subjects and forty hypertensive patients, separated into two groups according to their age, severity of hypertension and signs of severe atherosclerotic vascular disease. Under stabilized circulatory conditions, the changes of pulse rate in response to changes of blood pressure, attained by infusion of trimethaphan camphorsulfonate alone or with norepinephrine, was examined. There was gradually diminished change of pulse rate in relationship to blood pressure change as age and hypertension advanced. However, although the blood pressure threshold of stimulation was obviously higher in the middle-aged hypertensive subjects than in the normotensive ones, the slightly reduced baroreceptor sensitivity was not significantly different from that in the normotensive group. Only in the elderly hypertensive patients was significantly diminished baroreceptor sensitivity demonstrated, which was also significantly different from that in the middleaged hypertensive patients. It is speculated that the significantly diminished baroreceptor sensitivity found in the elderly hypertensive patients may be due to atherosclerotic changes in the region of the baroreceptor, although proof of that is not available at the present time.

Adult↗
PubMedDate not supplied

Some theories of hypertension: fact and fancy.

1. Various theories on the origin and development of hypertension offered over the years have been assessed critically. 2. It is concluded that no one theory is adequate at the present time to encompass all the known facts. 3. Continuously expanded understanding of hypertensive mechanisms, however, help in the individualization and therefore the improvement of various modalities of therapy, including treatment with presently available agents, as well as with those which may be developed in the future.

Autonomic Nervous System↗