A. Salvetti

Myocardial Ultrasonic Backscatter in Hypertension Relation to Aldosterone and Endothelin

Abstract—A disproportionate accumulation of fibrillar collagen is a characteristic feature of hypertensive heart disease, but the extent of myocardial fibrosis may differ in different models of hypertension. In experimental studies, aldosterone and endothelins emerge as important determinants of myocardial fibrosis. Changes in myocardial extracellular matrix and collagen deposition can be estimated noninvasively by analysis of the ultrasonic backscatter signal, which arises from tissue heterogeneity within the myocardium and describes myocardial texture. This study was designed to investigate the relations between myocardial integrated backscatter and circulating aldosterone and immunoreactive endothelin in human hypertension. The study population consisted of 56 subjects: 14 healthy normotensive volunteers and 42 hypertensive patients (14 with primary aldosteronism, 7 with renovascular hypertension, and 21 with essential hypertension). The patients with essential and secondary hypertension were matched for age, gender, body mass index, and blood pressure. Myocardial integrated backscatter at diastole was 19.8±2.0 and 20.8±2.9 decibels in normotensive control subjects and patients with essential hypertension and significantly higher in patients with primary aldosteronism (27.4±3.8 decibels, P <0.01) and renovascular hypertension (26.8±4.8 decibels, P <0.01). In the population as a whole, as well as in the hypertensive subpopulation, myocardial integrated backscatter was directly related to plasma aldosterone (r =0.73 and 0.71, P <0.01 for both) and immunoreactive endothelin (r =0.60 and 0.56, P <0.01 for both). The data of this study suggest that in human hypertension, circulating aldosterone and immunoreactive endothelin may induce alterations in left ventricular myocardial texture, possibly related to increased myocardial collagen content.

Early impairment of coronary flow reserve and increase in minimum coronary resistance in borderline hypertensive patients.

Objective To evaluate relations between coronary flow velocity and myocardial oxygen demand at rest, as well as coronary vasodilator capacity and flow reserve, in asymptomatic subjects with borderline hypertension as compared to normotensive controls and patients with sustained high blood pressure (HBP) and without left ventricular hypertrophy (LVH). Subjects and methods Forty-two asymptomatic males were studied: 13 healthy normotensive volunteers; 12 subjects with borderline HBP and 17 asymptomatic subjects with sustained systemic hypertension. Coronary flow velocity in left anterior descending artery and coronary flow reserve were assessed by transesophageal echodoppler at baseline and during intravenous adenosine infusion. Left ventricular mass, peak systolic wall stress (PSWS; Pa), and midwall fractional shortening (MFS; %) were obtained from M-mode images of the left ventricle in transthoracic long-axis view and in transesophageal transgastric view. Results Coronary flow velocity at baseline was not significantly different in the three groups, despite significantly higher rate-pressure product (RPP) in the hypertensive groups as compared with controls. Only in control subjects, was resting coronary flow velocity significantly correlated with RPP (y = 4279 + 200x, r = + 0.58, P < 0.05) and PSWS (y = 17.2 + 5.1x, r = + 0.62, P < 0.05). Coronary reserve was 3.5 ± 0.65 in controls and significantly lower (P < 0.05) in borderline hypertensive (2.87 ± 0.46) and in sustained hypertensive subjects (2.66 ± 0.56). Minimum coronary resistance was significantly increased in both hypertensive groups (1.30 ± 0.29 and 1.39 ± 0.48 mmHg/s per cm) as compared to normotensive controls (0.93 ± 0.20 mmHg/s per cm, P < 0.01). Conclusions In asymptomatic subjects with borderline hypertension and without LVH, a significant reduction in coronary flow reserve is already detectable and appears almost entirely related to an impaired coronary vasodilator capacity rather than to an increased myocardial oxygen demand.

Apoptosis control and proliferation marker in human normal and neoplastic adrenocortical tissues

We evaluated by immunohistochemistry the expression of the Bcl-2 and p53 proteins, as markers of apoptosis control, and of MIB-1, as a marker of cell proliferation, in a series of normal and neoplastic adrenocortical tissues. The specimens were 13 normal adrenals, 13 aldosterone-producing adenomas, 13 non-functioning adenomas and 16 carcinomas. Results were calculated as percentage of immunostained cells by using specific antibodies. No p53 protein was detected in any of the adrenocortical adenomas (functioning and non functioning) or normal adrenals, while p53 was overexpressed in 15 out of 16 carcinomas. In particular, 10 adrenal cancer specimens (62.5%) showed strong staining in a high percentage (range 10–50%) of the malignant cells. The percentage of Bcl-2 positive cells was higher (P<0.05 or less) in non-functioning adenomas (8.1±1.9%) and in carcinomas (14.9±5.6%) than in normals (2.9±0.9%) and aldosterone-producing adenomas (5.3±1.3%) since four specimens of the non-functioning adenomas-group (30.7%) and six of the carcinomas-group (37.5%) showed over 10% positivity (cut-off for normal values, set at 90th percentile of our controls). MIB-1 positivity was 0.50±0.36% in normals, 0.54±0.08% in non-functioning adenomas and 0.54±0.08% in aldosterone-producing adenomas. MIB-1 was expressed in all carcinomas with values (13.7±3.1%) significantly (P<0.0006) higher than in the other groups. In conclusion, the present data indicate that the apoptosis control and proliferation activity evaluated by the p53 and MIB-1 proteins are impaired in adrenal carcinomas but preserved in adenomas, independently of their functional status. Therefore, these immunohistochemical markers, overexpressed in carcinomas only, may be useful in the diagnosis of malignancy in adrenocortical tumours. Whether Bcl-2 positivity found in some carcinomas and non-functioning adenomas may constitute, in the latter, a negative prognostic marker is still unknown.

CALCIUM ENTRY BLOCKADE AND AGONIST-MEDIATED VASOCONSTRICTION IN HYPERTENSIVE PATIENTS

The effects of two chemically unrelated calcium channel blockers—nicardipine and verapamil—on vascular responses to exogenous norepinephrine were evaluated in uncomplicated hypertensive patients. Each drug was infused into the brachial artery at rates that did not affect systemic blood pressure or heart rate, and forearm blood flow was measured using strain gauge venous plethysmography. Nicardipine 1 μg/100 ml forearm tissue/min dilated the forearm artenoles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil 1 μg/100 ml tissue/min was ineffective, even though both drugs relaxed basal tone to the same extent. The difference between nicardipine and verapamil was also evident when reflex forearm vasoconstriction was elicited by the application of a lower body negative pressure and the drugs were infused intra-arterially at 1 and 3 μg/100 ml tissue/min, respectively. To evaluate whether a comparable behavior might also hold for nonsympathomimetic agents, increasing doses of angiotensin II were administered to the forearm vascular bed after pretreatment with either nicardipine or verapamil. Both drugs increased forearm blood flow, but only nicardipine antagonized the effect of angiotensin II in the forearm, showing that the impairment of vasoconstrictor mechanisms was not dependent on a specific receptor. Important differences seem to exist between nicardipine and verapamil with regard to agonist-mediated vasoconstriction in hypertensive patients, which is consistent with the heterogeneity of calcium channel blockers as a pharmacological class. Preferential antagonism of a series of vasoconstrictor stimuli may characterize the vasodilatory and, possibly, the antihypertensive effect of nicardipine.

Naloxone Does Not Modify the Hemodynamic and Neuroendocrine Effects of Clonidine in Normal Humans

Summary: The relationship between central opioidergic and noradrenergic central control mechanisms of blood pressure was investigated in normal men by evaluating the interference exerted by naloxone, a specific opiate antagonist, on the cardiovascular (blood pressure and heart rate) and neuroendocrine [human growth hormone (HGH) stimulation] effects of clonidine, a centrally acting α-adrenergic agonist, according to two different protocols. In series 1, the effects of placebo (normal saline), clonidine (0.15 mg i.v.), and naloxone (0.4 mg i.v.) were compared with that of clonidine plus naloxone (0.15 and 0.4 mg i.v., respectively), in seven normal male subjects. Clonidine decreased blood pressure and heart rate, and increased HGH levels. Naloxone administered alone (0.4 mg i.v.) did not modify blood pressure, heart rate, and HGH levels, while naloxone (0.4 mg) pretreatment left unaltered the hemodynamic and neuroendocrine effects of clonidine. In series 2, in five additional normal males, the effect of increasing doses of naloxone (0.4, 2.0, and 8.0 mg i.v.) on the pharmacodynamic activity of clonidine (0.15 mg i.v.) was further evaluated. Clonidine alone decreased blood pressure and heart rate and increased HGH levels, while naloxone pretreatment, in the whole range of doses studied, did not significantly modify the action of clonidine. These data suggest that a central opioidergic tone does not modulate the effect of central α-noradrenergic stimulation in normal humans.