Altered Vascular Responsiveness: Initial Hypotensive Mechanism of Thiazide Diuretics

Abstract

The thiazide diuretics are well known for their effectiveness in the treatment of hypertension. However, the mechanisms whereby arterial pressure is reduced in hypertension remain unresolved. Implicated are those which involve contraction of intravascular volume, sodium depletion, altered vascular responsiveness and/or altered neural activity (1).Because of the conflicting information the present study was designed to define the immediate systemic hemodynamic effects of chlorothiazide and to separate those changes related to altered vascular responsiveness from alterations in intravascular volume and electrolyte concentrations.Methods. Fifteen mongrel dogs of both sexes averaging 18 kg in weight, were anesthetized with sodium pentobarbital (30 mg/kg) . After the trachea was intubated and connected to a mechanical respirator (Harvard apparatus), a left thoracotomy was performed and a noncannulating electromagnetic flow transducer (Micron Instruments) was placed around the ascending aorta. The pericardium and chest were then closed and negative thoracic pressure was reestablished. The flow transducer was connected to an electromagnetic flowmeter (Biotronics) with the first nine dogs, and to a Micron electromagnetic flowmeter (last six dogs), and direct writing polygraph recorder (Sanborn) .All flow transducers had been previously calibrated using excised dog aortas through which blood flow was regulated a t varied levels equivalent to that expected in the in vivo preparation. The calibration of the flow probes of the first nine and last six dogs differed in magnitude, however, the quantita-tive directional changes were identical.A femoral artery and vein were cannulated for recording mean arterial pressure and for intravenous injection of the pharmacological agents, respectively. Another catheter was placed in the right brachial artery for recording continuous phasic arterial pressure and heart rate. After disconnecting the respirator the animals were allowed to stabilize for 20 min. Total peripheral resistance was calculated by dividing the difference between mean arterial and central venous pressures by aortic blood flow; and stroke volume was calculated by dividing aortic flow by heart rate. Hereafter, aortic blood flow will be referred to as cardiac output even though coronary arterial flow was not included in the electromagnetically sensed aortic flow.In nine dogs following the 20 min stabilization period, single bolus injections of 1.0, 3.0 and 5.0 pg I-norepinephrine base of levophed bitartrate, and 0.1, 0.3 and 0.5 pg Val-5-angiotensin (angiotensin 11) were injected intravenously. Each bolus was immediately followed by a 5 ml normal saline flush injection. Approximately 5 min were allowed between each injection to allow the hemodynamic measurements to return to control levels. After obtaining these dose-response relationships, a 10 ml blood sample was withdrawn for determination of serum sodium, potassium, chloride, and total protein concentrations, using flame photometry (electrolytes) and the Biuret metho...

Hemodynamic correlates of prolonged thiazide therapy: Comparison of responders and non responders

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Effects of Prolonged Administration of Certain Antihypertensive Agents

“…It is by no means conclusive that this chronic hypovolemia is solely responsible for long-term hypotensive effect of thiazides in essential hypertension, but this volumereducing effect may play a role in potentiating other antihypertensive agents. (199) noted a reduction in cardiac output unaccompanied by an alteration in fluid volume during acute infusion of chlorothiazide to anesthetized mongrel dogs. Conway and Lauwers (198) demonstrated the value of long-term therapy with chlorothiazide as the sole antihypertensive drug.…”