Suzanne Oparil

Myocardial hypertrophy and ventricular performance in the absence of hypertension in spontaneously hypertensive rats.

Abstract Ventricular performance and myocardial hypertrophy were studied in maturing spontaneously hypertensive (SH) and normotensive Kyoto-Wistar (WKY) rats from 4 through 24 weeks of age. The development of hypertension in the SH rat was prevented by treatment of the newborn rat with nerve growth factor antiserum (NGFAS). NGFAS treatment had no effect on the blood pressure of WKY rats. The hearts of 1-day- and 2-week-old SH and WKY rats were also examined for evidence of hypertrophy. Cardiac indices of SH rats, regardless of NGFAS treatment, were similar to those of WKY rats until 12 weeks of age at which time they became significantly lower. Stroke indices of both SH groups were lower than those of the WKY groups at all ages studied. Heart rates, however, were significantly higher in the SH rats during the early hypertensive phase but later declined to control levels. NGFAS treatment, despite its effects on hypertension, did not prevent the development of myocardial hypertrophy. Left ventricular hypertrophy was found in SH rats from age 1 day to 24 weeks regardless of NGFAS treatment. In SH rats 1 day to 8 weeks of age right ventricualr hypertrophy was also noted. Thus myocardial hypertrophy is present in SH rats before or very early in the course of the development of hypertension and when hypertension is prevented by peripheral immunosympathectomy. These data support our earlier conclusion that the development of myocardial hypertrophy is independent of elevated blood pressure and suggest that myocardial hypertrophy may be a manifestation of an underlying myocardial abnormality which could account for the hemodynamic alterations found in SH rats.

Desoxycorticosterone in normal pregnancy:I. Sequential studies of the secretory patterns of desoxycorticosterone, aldosterone, and cortisol

Plasma concentrations of desoxycorticosterone (DOC) and aldosterone are markedly elevated in pregnancy. Although DOC secretion in nongravid women has been assumed to be dependent mainly on adrenocorticotropic hormone (ACTH), in a previous study of women in the third trimester of pregnancy it was found to be unresponsive to ACTH, dexamethasone, and variations in salt intake. In this study plasma DOC, aldosterone, and cortisol levels, as well as their responses to ACTH stimulation and overnight dexamethasone suppression, were observed sequentially in seven normal women during the course of pregnancy and at three months post partum. Plasma DOC, aldosterone, and cortisol levels rose substantially during gestation, but increments in DOC did not necessarily coincide with those of the other two. Responses of all three corticosteroids to ACTH were enhanced during the first two trimesters compared to the nongravid state; DOC became unresponsive in the third trimester, while aldosterone and cortisol rose to an even greater extent. Elevated maternal DOC was not decreased significantly by dexamethasone at any stage of pregnancy, while plasma cortisol was suppressed. Nonsuppressibility of DOC with dexamethasone and also the lack of correlation of the rise in DOC with the increase in cortisol during the course of pregnancy suggest that increased DOC secretion in pregnancy does not arise from ACTH-dependent pathways of the maternal adrenal. The loss of responsiveness of DOC to ACTH in the third trimester suggests that the maternal adrenals have undergone an alteration in their steroidogenic response to ACTH, but also may indicate that their output of DOC has reached a maximal rate.

Desoxycorticosterone in normal pregnancy

Desoxycorticosterone (DOC) secretion increases during pregnancy. Administration of adrenocorticotropic hormone (ACTH) to women during the third trimester of pregnancy was noted previously to result in marked sodium retention, while aldosterone excretion declined. Since urinary tetrahydrodesoxycorticosterone increased substantially, sodium retention resulting from ACTH was ascribed to enhanced DOC secretion. Surprisingly, the elevated plasma DOC in late pregnancy failed to respond consistently to ACTH. Effects of ACTH upon total plasma concentrations and free indexes of DOC and cortisol were studied in pregnant women in the third trimester. As a result of ACTH, plasma cortisol and the free cortisol index increased strikingly; the plasma free DOC index rose markedly in those subjects in whom the total plasma DOC level was not altered appreciably and was unchanged or even increased slightly in the few subjects in whom the total DOC level decreased. The results support the proposition that the plasma free DOC fraction is increased because of displacement from corticosteroid-binding globulin by the ACTH-induced increment in cortisol. Resultant elevations of free DOC would not be evident from customary measurements of the total DOC concentration but, nonetheless, could contribute to sodium retention and also would be available for hepatic metabolism.

Treatment of hypertension by computer and physician—A prospective controlled study☆

Abstract One hundred and sixteen patients with hypertension were allocated randomly to treatment by a computer program or by physicians. All were under the care of physicians in one of two hypertension clinics, but for computer treated patients (C) the program provided physicians with treatment recommendations which they were free to follow or reject whereas no recommendations were made for physician treated patients (P). The computer program could use thiazide, alphamethyldopa, hydralazine or quanethidine; physicians used whatever drugs they wished. Blood pressure (BP) response was similar for both groups, as were drug side effects and overt non-compliance with treatment. A computer program such as this one could guide allied health workers in settings where expert physicians are scarce, improving large scale treatment of hypertension.

Prevention of Hypertension in the SH Rat: Effects of Differential Central Catecholamine Depletion

Summary Six-hydroxydopamine (6-OHDA) was administered intraventricularly to 6-week-old male spontaneously hypertensive (SH) rats of the Okomoto strain and to normotensive rats of the Kyoto-Wistar strain. In addition, bilateral lateral tegmental lesions were placed in 35-40-day-old SH rats to interrupt ascending noradrenergic pathways. SH rats treated with 6-OHDA did not develop hypertension and had lower heart rates than control rats. Blood pressure and heart rate of Kyoto-Wistar animals were unaffected by the drug treatment. 6-OHDA produced widespread depletion of norepinephrine throughout the CNS of both SH and Kyoto-Wistar rats. Bilateral lateral tegmental lesions interrupted the dorsal noradrenergic bundle and depleted forebrain norepinephrine. These lesions did not prevent the development of hypertension and led to an increased heart rate. It is concluded that 6-OHDA does not produce its effect through a nonspecific lowering of blood pressure, but rather, that it interferes with the expression of the hypertensive syndrome. The lack of effect seen following depletion of forebrain norepinephrine as the result of interruption of the dorsal noradrenergic bundle indicates that the fibers destroyed by this lesion are not essential for the development of genetically determined hypertension. The authors are grateful to Allen Naftilan and Susan Platkin for their excellent technical assistance.

In vivo and in vitro conversion of des-1-Asp angiotensin I to angiotensin III.

Abstract The conversion of exogenous des-Asp angiotensin I to des-Asp angiotensin II (angiotensin III) was studied in vivo in the pulmonary circulation of the intact pentobarbital-anesthetized dog and in vitro in whole blood and heparin-treated plasma by fractionation of 125 I-labeled peptides and by radioimmunoassay. Conversion and hydrolysis of [ 125 I]des-Asp angiotensin I and [ 125 I]angiotensin I were compared in vitro and in vivo . The time course of conversion of des-Asp angiotensin I to angiotensin III in vitro was more rapid than that of angiotensin I to II, but the peak concentration of angiotensin III generated was less than angiotensin II due to the more rapid hydrolysis of the des-Asp peptides. Injection of des-Asp angiotensin I into the right atrium was associated with a pressor response and with the appearance of a small amount of angiotensin III in aortic blood. SQ20881 (a nonapeptide converting enzyme inhibitor) abolished both the pressor response and the generation of angiotensin III. After injection of [ 125 I]des-Asp angiotensin I, only 10 per cent of the labeled material appearing in arterial blood was angiotensin III; 15 per cent was unchanged des-Asp angiotensin I; 15 per cent was an unidentified metabolite; and 60 per cent was tyrosine. This contrasts with the pattern of peptides recovered after injection of [ 125 I]angiotensin I: 70 per cent angiotensin II, 20 per cent intact angiotensin I and only 10 per cent peptide metabolites and tyrosine. Results indicate that conversion of des-Asp angiotensin I to angiotensin III does occur in the pulmonary circulation of the dog but that hydrolysis of the des-Asp peptides by angiotensinases is so rapid that little circulating angiotensin II and only a small pressor response appear. The data suggest that pulmonary conversion of des-Asp angiotensin I is not an important source of circulating angiotensin III in the dog.

Substrate Requirements for Angiotensin I Conversion In Vivo and In Vitro

The substrate requirements for angiotensin I-converting enzyme were studied in vivo in the dog lung and in vitro in plasma, using angiotensin I (AI), 5-D-Ile-AI, 7-D-Pro-AI, and 8-D-Phe-AI which had been synthesized by the solid-phase technique. All peptides were inactive in the rabbit aortic strip preparation. None of the D-amino acid-substituted peptides gave a pressor response in the anesthetized dog; none showed significant immunologic cross-reactivity with anti-AI serum or antiangiotensin II serum. Each peptide was labeled with 125I, and the monoiodinated species was isolated. The iodinated peptides were incubated with diluted dog plasma or injected into the right ventricle of intact anesthetized dogs. In vitro, 125I-AI, 125I-5-D-IIe-AI, and 125I-7-D-Pro-AI were converted to angiotensin II (AII). 8-D-Phe-AI was not converted. In vivo, 15 seconds after injecting 125I-AI, 125I-5-D-IIe-AI, or 125I-7-D-Pro-AI into the right ventricle, 125I-AJI accounted for 70, 60, and 45%, respectively, of the radioactive material in aortic blood. These results and our previous observations on the importance of the C-terminal sequence of AI for conversion indicate that the enzymatic binding sites for AI-converting enzyme in vivo and in vitro extend from position 10 to position 8 but not to position 7. D-amino acid substitution at positions 7 and 5 abolishes biologic and immunologic activity without interfering with conversion.

Effect of peripheral sympathectomy on left ventricular ultrastructure in young spontaneously hypertensive rats.

Abstract Administration of nerve growth factor antiserum (NGFAS) to spontaneously hypertensive (SH) rats during the first week of life prevents or ameliorates the development of hypertension but does not prevent development of left ventricular hypertrophy or dysfunction. Morphometric analysis of electron micrographs prepared from subepicardial myocardial cells of animals sacrificed at age 82 days shows that NGFAS treatment significantly reduces the fall in cellular concentration of mitochondria characteristic of untreated SH controls. In both groups myofibrillar concentrations were identical and correspond to literature values for normotensive rats. The results, which are consistent with independent control mechanisms for growth of mitochondria and myofibrils, suggest that in this model (a) NGFAS affects mitochondrial concentration either via its effect on arterial blood pressure and/or via some other, unidentified mechanism, and (b) the decreased mitochondrial concentration in myocardial cells of untreated SH rats need not be causally related to the observed cardiac dysfunction.

Physician acceptance of computer recommended antihypertensive therapy

Abstract An adaptive treatment algorithm for guiding antihypertensive drug administration has been created, and acceptability of its recommendations to consulting physicians measured. The algorithm generates treatment by using a sequence of rules along with a single numerical score that summarizes the magnitude of blood pressure elevation, end organ damage, and amounts of antihypertensive agents being taken. For drugs with wide dose ranges, the program calculates a dose response curve for each patient and uses this to estimate additional drug needs. Although the program is based upon a number of simplifying assumptions, it generates treatment that accords well with prevailing medical opinion, as physicians, in most instances, have prescribed the treatment regimens the program recommended even though they themselves were held fully responsible for the consequences of treatment.