Effects of α₁ and β‐adrenergic antagonists and 5‐hydroxytryptamine receptor antagonist on portal‐systemic collateral vascular resistance in conscious rats with portal hypertension

Abstract

In order to study the acute effects of pharmacological agents on the vascular resistance of portal-systemic collaterals, a model of total portal vein occlusion with 100% portal-systemic shunts was developed in the conscious rat. The haemodynamic effects of several vaso-active substances were evaluated in this model and compared with those obtained after saline administration. Prazosin (0.5 mg), an alpha 1-adrenergic antagonist, significantly reduced mean arterial pressure by 29%, portal pressure from 13.8 +/- 1.0(mean +/- s.e.m.) to 10.1 +/- 0.4 mmHg and portal tributary blood flow (radioactive microspheres) from 13.6 +/- 2.1 to 11.7 +/- 1.2 mL/min. It also decreased portal-systemic vascular resistance from 95 +/- 16 to 73 +/- 9 dyn s/cm5 x 10(3). Propranolol (4 mg), a beta-adrenergic antagonist, significantly reduced mean arterial pressure by 12% and portal pressure from 15.5 +/- 1.2 to 13.3 +/- 0.9 mmHg while reducing portal tributary blood flow from 14.6 +/- 1.5 to 11.0 +/- 1.7 mL/min and increasing portal systemic collateral vascular resistance from 88 +/- 7 to 103 +/- 8 dyn s/cm5 x 10(3). Ketanserin (0.25 mg/kg), a 5-hydroxytryptamine receptor antagonist, reduced portal pressure from 15.8 +/- 1.0 to 13.3 +/- 0.7 mmHg at a dose that did not alter mean arterial pressure or portal tributary blood flow. It achieved this by reducing portal-systemic collateral vascular resistance from 90 +/- 14 to 74 +/- 13 dyn s/cm5 x 10(3). Saline had no significant effect on systemic and splanchnic haemodynamics. This study shows that ketanserin decreases vascular resistance of portal-systemic collaterals while propranolol increases it. Thus, it is suggested that collateral vascular resistance is accessible to pharmacological manipulation.

Portal Hypotensive Effects of DL-028 and Prazosin on Portal Hypertensive Rats

“…The former is the basis for use of vasoconstrictors, the latter, vasodilators [2,3,18]. Prazosin belongs to the category of vasodilators and a decrease of PVR by prazosin has been documented in portal hypertensive patients and rats [9,10]. In the present study, a reduction in MAP as well as TPR by DL-028 and prazosin is in line with the effects of vasodilators [3,18].…”

“…Reduction of PVP, MAP and TPR after acute prazosin administration without cardiac output changes has also been observed in portal hypertensive rats [10] and cirrhotic patients [11]. It is somewhat surprising that in the present study, we did not observe reflex tachycardia after prazosin or DL-028 despite systemic pressure as well as resistance reduction, in contrast to previous animal or human studies [10,11]. We have no satisfactory explanation at hand.…”

Hemodynamic effects of one week of carvedilol administration on cirrhotic rats

“…34,35 Accordingly, the decreased collateral resistance after carvedilol administration was mostly due to its intrinsic α 1 -adrenergic antagonistic activity, which is similar to the effect of prazosin on the portal-systemic collateral venous bed. 36,37 In addition, a hyperresponse to α 1 -adrenergic agonists is observed in the intrahepatic vasculature of the cirrhotic liver, which contributes to the increased intrahepatic resistance in the cirrhotic liver. 38,39 Administration of an α 1 -adrenergic receptor blocker has been shown to reduce intrahepatic resistance in cirrhotic patients.…”

“…Five-milliliter aliquots of the synthesized cDNA were added to 45 µl of the PCR mixture containing 5 µl of 10 × PCR buffer, 1 ml deoxynucleotides, 0.5 µl of sense and antisense primers, and 0.25 µl of DNA polymerase (Gene Amp PCR kit; Perkin Elmer, Foster City, CA, USA). The reaction mixture and amplification was initiated by 10 min of denaturation at 94°C for 1 cycle (initial denaturation), followed by multiple cycles (28)(29)(30)(31)(32)(33)(34)(35)(36)(37) at 94°C for 30 s (denaturation), 60°C for 30 s (annealing), and 72°C for 1 min (extension) using a GeneAmp PCR system 9700 (Perkin Elmer). The amplified PCR products were electrophoresed at 75 V through 2% agarose gels and visualized by ethidium bromide staining.…”

Portal systemic collateral development: Is it a trophic adaptation mechanism to hepatic deprivation?

“…Therefore, normalization of elevated portal pressure can be achieved by correcting the elevated portal resistance in the portal collateral circulation (the 'backward' hypothesis). 4,30 This is the basis of several experimental studies on the effects of different vasoactive substances and drugs on blood flow, the resistance to portal-systemic collaterals, [6][7][8][9][10][11][12][13][34][35][36][37] and their applications in the medical treatment of patients with cirrhosis. 32,38,39 If establishing the significance of alterations associated with portal hypertension could help to elucidate the mechanisms involved in its production and maintenance, we could, then, speculate on the hypothetical purpose of the splanchnic response in portal hypertension.…”