Increased peripheral resistance in heart failure: new evidence suggests an alteration in vascular smooth muscle function

Abstract

Increased peripheral resistance is a hallmark of chronic heart failure and has been primarily attributed to neurohumoral pathways involving both the renin-angiotensin and sympathetic nervous systems. The increased resistance is thought to serve as a compensatory mechanism to help maintain perfusion to the vital organs by sustaining blood pressure in the fate of a failing heart. Local mechanisms, and in particular endothelial dysfunction, have also been shown to be important contributors in regulating arterial resistance and vascular remodeling in this disease. In this issue of the British Journal of Pharmacology, Gschwend et al. (2003) present new data suggesting that in the absence of a functional endothelium, myogenic constriction of small pressurized mesenteric arteries, an intrinsic property of vascular smooth muscle cells, is enhanced in a coronary artery ligation-induced myocardial infarction model of congestive heart failure (CHF) in the rat. The increased myogenic tone appears to be tightly linked to angiotensin II type 1 receptors (AT(1)). The possibility that CHF-induced stimulation of myogenic constriction is due to the local release of preformed angiotensin II or constitutive upregulation of the AT(1) receptor signaling pathways are discussed along with other potential cellular and molecular mechanisms previously suggested to play a role in myogenic reactivity.

Figure 1

Sequence of major neurohumoral systems activated in CHF following myocardial infarction. Reduction in cardiac output and resulting arterial underfilling trigger a cascade of reflexes via various afferent pathways that signal the cardiovascular centers in the brain to increase sympathetic tone. The increase in central sympathetic activity is also enhanced by immune and stress signaling molecules (cytokines, Ang II) released locally in the peripheral vasculature. The RAS is stimulated in response to enhanced sympathetic tone that directly increases peripheral resistance by enhancing vascular smooth muscle contraction (mainly via angiotensin type 1 receptors), and indirectly by increasing blood volume in response to stimulation of aldosterone production and Na⁺ retention by the kidney, and enhanced water retention due indirectly to Na⁺ reuptake by the kidney and directly through stimulation of antidiuretic hormone production (AVP). AVP may also participate in increasing vascular resistance by stimulating vascular smooth muscle contraction. In the short term (ACUTE), the increase in peripheral resistance allows for restoration of arterial blood pressure to near-normal levels. However, as heart function slowly progresses towards decompensation, enhanced peripheral resistance and afterload may further exacerbate cardiac mechanics (CHRONIC) leading to congestion of the left and right ventricles and pulmonary circulation.

Figure 2

Signaling pathways potentially involved in altered AT₁ receptor function and enhanced myogenic reactivity in CHF. Evidence provided by Gschwend et al. (2003) suggests that myogenic constriction is enhanced in heart failure and appears to be linked to altered AT₁ receptor function. These authors suggest that preformed and stored Ang II is released and local elevated Ang II levels increase myogenic tone. An alternative hypothesis is that the AT₁ receptor itself, its coupling to G_q and/or phospholipase C (PLC) is (are) modified in heart failure leading to constitutive activation of this pathway. Future studies should be designed to investigate the possible role of downstream events such as smooth muscle membrane potential, voltage-dependent and stretch-activated cation and anion channels, mechanisms regulating global intracellular Ca²⁺ levels, the ryanodine receptor (RyR) which is responsible for generating Ca²⁺ sparks and inositol-tris-phosphate (IP₃)-Ca²⁺ release channels, protein kinase C (PKC) and other kinases (Rho, Ras, MAPK, Erk, etc.), cytoskeletal and contractile proteins, all of which have been implicated to play role in generating myogenic tone (Davis & Hill, 1999).